Leonard F Liebes, Ph.D.

The possible role of the kynurenine pathway in anhedonia in adolescents
Gabbay, Vilma; Ely, Benjamin A; Babb, James; Liebes, Leonard
2012 Feb;119(2):253-260, Journal of neural transmission
To address the heterogeneous nature of adolescent major depression (MDD), we investigated anhedonia, a core symptom of MDD. We recently reported activation of the kynurenine pathway (KP), a central neuroimmunological pathway which metabolizes tryptophan (TRP) into kynurenine (KYN) en route to several neurotoxins, in a group of highly anhedonic MDD adolescents. In this study, we aimed to extend our prior work and examine the relationship between KP activity and anhedonia, measured quantitatively, in a group of MDD adolescents and in a combined group of MDD and healthy control adolescents. Thirty-six adolescents with MDD (22 medication-free) and 20 controls were included in the analysis. Anhedonia scores were generated based on clinician- and subject-rated assessments and a semi-structured clinician interview. Blood KP metabolites, collected in the AM after an overnight fast, were measured using high-performance liquid chromatography. The rate-limiting enzyme of the KP, indoleamine 2,3-dioxygenase (IDO), was estimated by the ratio of KYN/TRP. Pearson correlation tests were used to assess correlations between anhedonia scores and KP measures while controlling for MDD severity. IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD (r = 0.42, P = 0.05) and in a combined group of MDD subjects and healthy controls (including medicated patients: r = 0.30, P = 0.02; excluding medicated patients: r = 0.44, P = 0.004). In conclusions, our findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD. These results emphasize the importance of dimensional approaches in the investigation of psychiatric disorders
— id: 150556, year: 2012, vol: 119, page: 253, stat: Journal Article,

Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
Axelrod FB; Liebes L; Simson GG; Mendoza S; Mull J; Leyne M; Norcliffe-Kaufmann L; Kaufmann H; Slaugenhaupt SA
2011 Nov;70(5):480-483, Pediatric research
Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::
— id: 139909, year: 2011, vol: 70, page: 480, stat: Journal Article,

The numbers of FoxP3+ lymphocytes in sentinel lymph nodes of breast cancer patients correlate with primary tumor size but not nodal status
Gupta, Raavi; Babb, James S; Singh, Baljit; Chiriboga, Luis; Liebes, Leonard; Adams, Sylvia; Demaria, Sandra
2011 Jul;29(6):419-425, Cancer investigation
Regulatory T cells, lymphocytes marked by expression of the transcription factor Forkhead Box Protein P3 (FoxP3), inhibit the activation of tumor-specific T cells in tumor-draining lymph nodes. Immunohistochemical analyses of sentinel lymph nodes (SLNs) from 104 breast cancer patients showed a significant association (p = .0028, Pearson correlation) between the number of FoxP3+ cells and the size of primary breast invasive ductal carcinoma. In contrast, there was no correlation between the number of FoxP3+ cells and the presence of SLN metastases, or other clinicopathological parameters. These results suggest the presence of an immune suppressive environment in SLNs of larger tumors
— id: 138850, year: 2011, vol: 29, page: 419, stat: Journal Article,

Combining aminocyanine dyes with polyamide dendrons: a promising strategy for imaging in the near-infrared region
Ornelas, Catia; Lodescar, Rachelle; Durandin, Alexander; Canary, James W; Pennell, Ryan; Liebes, Leonard F; Weck, Marcus
2011 Mar 21;17(13):3619-3629, Chemistry (Weinheim an der Bergstrasse, Germany)
Cyanine dyes are known for their fluorescence in the near-IR (NIR) region, which is desirable for biological applications. We report the synthesis of a series of aminocyanine dyes containing terminal functional groups such as acid, azide, and cyclooctyne groups for further functionalization through, for example, click chemistry. These aminocyanine dyes can be attached to polyfunctional dendrons by copper-catalyzed azide alkyne cycloaddition (CuAAC), strain-promoted azide alkyne cycloaddition (SPAAC), peptide coupling, or direct S(NR)1 reactions. The resulting dendron-dye conjugates were obtained in high yields and displayed high chemical stability and photostability. The optical properties of the new compounds were studied by UV/Vis and fluorescence spectroscopy. All compounds show large Stokes shifts and strong fluorescence in the NIR region with high quantum yields, which are optimal properties for in vivo optical imaging
— id: 134137, year: 2011, vol: 17, page: 3619, stat: Journal Article,

Construction of a well-defined multifunctional dendrimer for theranostics
Ornelas, Catia; Pennell, Ryan; Liebes, Leonard F; Weck, Marcus
2011 Mar 4;13(5):976-979, Organic letters
A dendrimer-based building block for theranostics was designed. The multifunctional dendrimer is polyamide-based and contains nine azide termini, nine amine termini, and fifty-four terminal acid groups. Orthogonal functionalization of the multifunctional dendrimer with a near-infrared (NIR) cyanine dye afforded the final dendrimer that shows fluorescence in the NIR region and no toxicity toward T98G human cells. The synthetic strategy described here might be promising for fabricating the next generation of materials for theranostics
— id: 134151, year: 2011, vol: 13, page: 976, stat: Journal Article,

Bortezomib: understanding the mechanism of action
Piperdi, Bilal; Ling, Yi-He; Liebes, Leonard; Muggia, Franco; Perez-Soler, Roman
2011 Nov;10(11):2029-2030, Molecular cancer therapeutics
— id: 146229, year: 2011, vol: 10, page: 2029, stat: Journal Article,

Erlotinib added to carboplatin and paclitaxel as first-line treatment of ovarian cancer: A phase II study based on surgical reassessment
Blank, Stephanie V; Christos, Paul; Curtin, John P; Goldman, Noah; Runowicz, Carolyn D; Sparano, Joseph A; Liebes, Leonard; Chen, Helen X; Muggia, Franco M
2010 Dec;119(3):451-456, Gynecologic oncology
BACKGROUND: The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC). METHODS: Patients with stage III-IV OFPC initiated treatment within 12weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175mg/m(2)) and carboplatin (AUC 6) every 3weeks for up to 6 cycles, plus oral erlotinib 150mg daily. The primary objective was to determine whether the pCR rate at reassessment surgery was at least 60% after optimal cytoreduction at initial surgery (< 1cm residual disease), or at least 40% after suboptimal cytoreduction (at least 1cm residual disease) using a two-stage design (alpha=0.10, beta=0.10). RESULTS: The study population included 56 patients with stage III-IV OFPC. EGFR gene amplification was present in 15% of the 20 tumors evaluated. Twenty-eight patients had protocol therapy after optimal cytoreduction (stratum I), 23 had protocol therapy either after suboptimal cytoreduction (stratum II), and 5 received neoadjuvant therapy prior to cytoreduction (stratum III). Pathologic CR was confirmed in 8 patients (29%; 95% confidence intervals 13%, 49%) in stratum I and 3 patients (11%, 95% C.I. 2%, 28%) in stratum II, which did not meet the prespecified efficacy endpoint in either stratum. CONCLUSIONS: Among unselected patients, erlotinib plus carboplatin-paclitaxel did not improve pCR rates compared with historical experience with carboplatin-paclitaxel alone in patients with stage III-IV OFPC
— id: 114176, year: 2010, vol: 119, page: 451, stat: Journal Article,

The possible role of the kynurenine pathway in adolescent depression with melancholic features
Gabbay, Vilma; Klein, Rachel G; Katz, Yisrael; Mendoza, Sandra; Guttman, Leah E; Alonso, Carmen M; Babb, James S; Hirsch, Glenn S; Liebes, Leonard
2010 Aug;51(8):935-943, Journal of child psychology & psychiatry & allied disciplines
BACKGROUND: Although adolescent major depressive disorder (MDD) is acknowledged to be a heterogeneous disorder, no studies have reported on biological correlates of its clinical subgroups. This study addresses this issue by examining whether adolescent MDD with and without melancholic features (M-MDD and NonM-MDD) have distinct biological features in the kynurenine pathway (KP). The KP is initiated by pro-inflammatory cytokines via induction of the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) into kynurenine (KYN). KYN is further metabolized into neurotoxins linked to neuronal dysfunction in MDD. Hypotheses were that, compared to healthy controls and to NonM-MDD adolescents, adolescents with M-MDD would exhibit: (i) increased activation of the KP [i.e., increased KYN and KYN/TRP (reflecting IDO activity)]; (ii) greater neurotoxic loads [i.e., increased 3-hydroxyanthranilic acid (3-HAA, neurotoxin) and 3-HAA/KYN (reflecting production of neurotoxins)]; and (iii) decreased TRP. We also examined relationships between severity of MDD and KP metabolites. METHODS: Subjects were 20 adolescents with M-MDD, 30 adolescents with NonM-MDD, and 22 healthy adolescents. MDD episode duration had to be >or= 6 weeks and Children's Depression Rating Scale-Revised (CDRS-R) scores were >or= 36. Blood samples were collected at AM after an overnight fast and analyzed using high-performance liquid chromatography. Group contrasts relied on analysis of covariance based on ranks, adjusted for age, gender, and CDRS-R scores. Analyses were repeated excluding medicated patients. Fisher's protected least significant difference was used for multiple comparisons. RESULTS: As hypothesized, KYN/TRP ratios were elevated and TRP concentrations were reduced in adolescents with M-MDD compared to NonM-MDD adolescents (p = .001 and .006, respectively) and to healthy controls (p = .008 and .022, respectively). These findings remained significant when medicated patients were excluded from the analyses. Significant correlations were obtained exclusively in the M-MDD group between KYN and 3-HAA/KYN and CDRS-R. CONCLUSIONS: Findings support the notion that adolescent M-MDD may represent a biologically distinct clinical syndrome
— id: 111344, year: 2010, vol: 51, page: 935, stat: Journal Article,

The kynurenine pathway in adolescent depression: preliminary findings from a proton MR spectroscopy study
Gabbay, Vilma; Liebes, Leonard; Katz, Yisrael; Liu, Songtao; Mendoza, Sandra; Babb, James S; Klein, Rachel G; Gonen, Oded
2010 Feb 1;34(1):37-44, Progress in neuro-psychopharmacology & biological psychiatry
BACKGROUND: Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins. The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho; and, ii) the anticipated correlations would be more pronounced in the melancholic subtype group. METHODS: Fourteen adolescents with MDD (seven with melancholic features) and six healthy controls were enrolled. Minimums of 6 weeks MDD duration and a severity score of 40 on the Children's Depression Rating Scale-Revised were required. All were scanned at 3T with MRI, multi-voxel 3-dimensional, high, 0.75 cm(3), spatial resolution proton magnetic resonance spectroscopic imaging. Striatal tCho concentrations were assessed using phantom replacement. Spearman correlation coefficients were Bonferroni-corrected. RESULTS: Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate (r=0.93, p=0.03) and the left putamen (r=0.96, p=.006), respectively. CONCLUSIONS: These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD. Larger studies should follow
— id: 106492, year: 2010, vol: 34, page: 37, stat: Journal Article,

Increased shedding of HU177 correlates with worse prognosis in primary melanoma
Hamilton, Heather K; Rose, Amy E; Christos, Paul J; Shapiro, Richard L; Berman, Russell S; Mazumdar, Madhu; Ma, Michelle W; Krich, Daniel; Liebes, Leonard; Brooks, Peter C; Osman, Iman
2010 Feb 23;8(1):19-19, Journal of translational medicine
ABSTRACT: BACKGROUND: Increased levels of cryptic collagen epitope HU177 in the sera of melanoma patients have been shown to be associated with thicker primary melanomas and with the nodular histologic subtype. In this study, we investigate the association between HU177 shedding in the sera and clinical outcome in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Serum samples from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (mean age=58, mean thickness=2.09 mm, stage I=136, stage II=41, stage III=32, median follow-up=54.9 months) were analyzed for HU177 concentration using a validated ELISA assay. HU177 serum levels at the time of diagnosis were used to divide the study cohort into two groups: low and high HU177. DFS and OS were estimated by Kaplan-Meier survival analysis, and the log-rank test was used to compare DFS and OS between the two HU177 groups. Multivariate Cox proportional hazards regression models were employed to examine the independent effect of HU177 category on DFS and OS. RESULTS: HU177 sera concentrations ranged from 0-139.8 ng/ml (mean and median of 6.2 ng/ml and 3.7 ng/ml, respectively). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. Higher HU177 serum level was associated with an increased rate of melanoma recurrence (p=0.04) and with increasing mortality (p=0.01). The association with overall survival remained statistically significant after controlling for thickness and histologic subtype in a multivariate model (p=0.035). CONCLUSIONS: Increased shedding of HU177 in the serum of primary melanoma patients is associated with poor prognosis. Further studies are warranted to determine the clinical utility of HU177 in risk stratification compared to the current standard of care
— id: 107363, year: 2010, vol: 8, page: 19, stat: Journal Article,

A Phase II Trial of Sorafenib in Metastatic Melanoma with Tissue Correlates
Ott, Patrick A; Hamilton, Anne; Min, Christina; Safarzadeh-Amiri, Sara; Goldberg, Lauren; Yoon, Joanne; Yee, Herman; Buckley, Michael; Christos, Paul J; Wright, John J; Polsky, David; Osman, Iman; Liebes, Leonard; Pavlick, Anna C
2010 ;5(12):e15588-e15588, PLoS ONE
BACKGROUND: Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-six patients treatment-naive advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously. Tumor BRAF(V600E) mutational status was determined by routine DNA sequencing and mutation-specific PCR (MSPCR). Immunohistochemistry (IHC) staining for cyclin D1 and Ki67 was performed on available pre- and post treatment tumor samples. The main toxicities included diarrhea, alopecia, rash, mucositis, nausea, hand-foot syndrome, and intestinal perforation. One patient had a RECIST partial response (PR) lasting 175 days. Three patients experienced stable disease (SD) with a mean duration of 37 weeks. Routine BRAF(V600E) sequencing yielded 27 wild-type (wt) and 6 mutant tumors, whereas MSPCR identified 12 wt and 18 mutant tumors. No correlation was seen between BRAF(V600E) mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples. CONCLUSIONS/SIGNIFICANCE: Sorafenib monotherapy has limited activity in advanced melanoma patients. BRAF(V600E) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib. TRIAL REGISTRATION: Clinical Trials.gov NCT00119249
— id: 117357, year: 2010, vol: 5, page: e15588, stat: Journal Article,

Effect of mebendazole on melanoma xenograft growth through targeting of bcl-2
Doudican N.A.; Pennell R.; Tu T.; Liebes L.; Pavlick A.; Berman R.; Shapiro R.; Goldberg J.D.; Osman I.; Orlow S.
2009 ;27(15 Suppl 1):9075-9075, Journal of clinical oncology
Background: Defects in apoptosis are thought to contribute to melanoma chemoresistance, making the anti-apoptotic protein Bcl-2 an attractive therapeutic target. We identified mebendazole (MBZ), a microtubule binding agent, as an inducer of melanoma cytotoxicity via a Bcl-2 dependent mechanism in vitro (Mol Cancer Res, Aug 2008). In the present study, we assessed the effect of MBZ on human melanoma tumor growth and progression in a mouse xenograft model and compared the ability of MBZ to inhibit growth of cultured melanoma cells to that of oblimersen (OBL), an antisense drug targeting Bcl-2. Methods: Growth of human M-14 melanoma xenografts in mice administered MBZ orally at doses from 0.1 to 2 mg were compared to tumor growth in mice receiving 100mg/kg intraperitoneal temozolomide (TMZ) or vehicle alone. Tumor diameter, volume, histopathology, and immunohistochemical staining of caspase 3 and Ki67 were assessed. Bcl-2 phosphorylation was determined by immunoblotting. MBZ and OBL-induced melanoma growth inhibition was analyzed by MTT assay. Results: Anti-melanoma effects of MBZ were dose- dependent up to 1 mg which displayed a 72% reduction in tumor volume compared to vehicle treated mice. This reduction in volume was accompanied by a 46% decrease in proliferating cells and an 81% increase in apoptotic cells. Moreover, 1 mg MBZ inhibited tumor growth as effectively as high dose TMZ, the current melanoma standard of care. Orally administered MBZ treatment resulted in Bcl-2 phosphorylation in vivo, further confirming its mechanism of action. MBZ inhibited growth of melanoma cells in culture more effectively than OBL with GI50 values of 0.32 uM and 7.45 uM, respectively. Conclusions: MBZ safely and effectively inhibits melanoma growth and progression in a xenograft model. A phase II clinical trial investigating MBZ's utility as adjuvant therapy in patients with stage IV, resected melanoma is planned
— id: 111807, year: 2009, vol: 27, page: 9075, stat: Journal Article,

The utility of TRC093; A humanized monoclonal antibody directed against cleaved collagen in the detection of patients at risk of ovarian and breast cancer
Liebes L.; Lu J.; Pennell R.; Blank S.; Pua T.; Muggia F.; Fishman D.; Theuer C.; Roth J.; Brooks P.
2009 ;8(12 SUPPL 1):?-?, Molecular cancer therapeutics
Background: TRC093 is a humanized monoclonal antibody that specificallybinds cleaved collagen and has been shown to inhibit angiogenesisand tumor growth in preclinical studies. TRC093 is currentlybeing evaluated in a phase I clinical study for the treatment of metastatic human tumors (Gordon et al. EJC Supp 6, abs #414, pp130, 2008). Interestingly, one of the patients in this studywith granulosa cell carcinoma of the ovary with progressivedisease had a mixed response in the liver after 2 months of treatment. Given these encouraging results, we began to examinethe biological relevance of the cryptic epitope recognized byTRC093 in ovarian carcinoma and whether a soluble form of thiscryptic collagen epitope may represent a clinically useful markerfor patients at risk for ovarian and breast cancer. To thisend, we have adapted an ELISA assay for the detection of theshed collagen cryptic epitope that is defined by this antibodyto examine a patient population at risk for ovarian and breastcancer. Methods: To begin to assess the relevance of the cryptic collagenepitope recognized by TRC093 in ovarian tumor growth, humanSKOV3 ovarian carcinoma cells were injected subcutaneously intonude mice. Six days later when detectable tumors were observed,mice were treated (i.p.) 3x per week with TRC093 over a doserange up to 250 mug/injection for a period of 28 days.To assess the relevance of a shed soluble form of the crypticcollagen epitope in a patient population at risk for ovarianand breast cancer, serum samples from a group of high-risk womenvolunteers prospectively enrolled at the NYU School of Medicinewere analyzed for TRC093 epitope concentration by ELISA as previouslydescribed (Ng et al., Clin Can Res, 14:6253). Results: TRC093 significantly (p< 0.05) inhibited SKOV3 tumorgrowth at 100 mug and 250 mug/injection as comparedto control. These findings suggest that theTRC093 cryptic collagenepitope may represent a relevant therapeutic target for ovariancarcinoma. In a group of 23 high-risk women identified withrespect to their clinical status, a mean mu SEM of 42.9mu 9.8 mug/ml was determined for the patients withovarian/ breast cancer history compared with a mean of 15.3mu 2.9 mug/ml for normal women in this study population(p = 0.0254). Conclusions: The TRC093 shed serum epitope can distinguish betweena high-risk population of women with breast or ovarian cancerand normal clinical status. We are expanding the sample sizewith more ovarian surgical patients. The xenograft studies providefurther support for the potential use of the SKOV3 human ovariancarcinoma model to examine the effect of TRC093 in combinationwith cisplatin and or bevacizumab. The TRC093 epitope may representa key therapeutic target in ovarian cancer
— id: 112583, year: 2009, vol: 8, page: ?, stat: Journal Article,

Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors
Pavlick, Anna C; Wu, Jennifer; Roberts, John; Rosenthal, Mark A; Hamilton, Anne; Wadler, Scott; Farrell, Kathleen; Carr, Michelle; Fry, David; Murgo, Anthony J; Oratz, Ruth; Hochster, Howard; Liebes, Leonard; Muggia, Franco
2009 Sep;64(4):803-810, Cancer chemotherapy & pharmacology
PURPOSE: Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. METHODS: Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. RESULTS: Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 mug/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. CONCLUSIONS: Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved
— id: 97002, year: 2009, vol: 64, page: 803, stat: Journal Article,

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations
Cai, C Q; Peng, Y; Buckley, M T; Wei, J; Chen, F; Liebes, L; Gerald, W L; Pincus, M R; Osman, I; Lee, P
2008 May 15;27(22):3201-3210, Oncogene
While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.Oncogene advance online publication, 14 January 2008; doi:10.1038/sj.onc.1210983
— id: 76447, year: 2008, vol: 27, page: 3201, stat: Journal Article,

Tolerance and activity of oxaliplatin with protracted topotecan infusion in patients with previously treated ovarian cancer. A phase I study
Hochster, Howard; Chen, Thomas T; Lu, Janice M; Hills, Day; Sorich, Joan; Escalon, Juliet; Ivy, Percy; Liebes, Leonard; Muggia, Franco
2008 Mar;108(3):500-504, Gynecologic oncology
BACKGROUND: Topotecan 14-day infusion combined with cisplatin was highly active in ovarian cancer, but too myelosuppressive. We therefore sought to evaluate the feasibility of substituting oxaliplatin for cisplatin to improve safety. METHODS: Ovarian and primary peritoneal cancer patients, pretreated with at least one prior platinum-containing regimen, performance status (PS) 0-1, without prior pelvic radiation were eligible. Topotecan was continuously infused days 1-15; oxaliplatin was given days 1 and 15; cycles were repeated every 28 days. Five dose levels were explored: topotecan (mg/m2/day)/oxaliplatin (mg/m2) doses: (1) 0.2/65; (2) 0.2/75; (3) 0.2/85; (4) 0.3/85; (5) 0.4/85. RESULTS: Twenty-three patients (20 ovarian, 1 tubal, and 2 peritoneal) were entered: median age 56 years (range, 37-77); PS: 0=12 and 1=11; histology: papillary serous 7, serous 4, adenocarcinoma 8, poorly differentiated 2. Median of 4 cycles were delivered. Grade 3 neutropenia occurred in 3 of 7 patients at level 5 (with fever at levels 4 and 5), without grade 4 neutropenia or thrombocytopenia. Other toxicities were mild and reversible (mainly gastrointestinal), except one grade 3 neuropathy and one oxaliplatin-related grade 3 hypersensitivity reaction. Six objective responses (five of them complete) were documented among 22 patients spanning several dose levels. CONCLUSION: Topotecan continuous infusion, combined with oxaliplatin, was associated with no grade 4 hematologic toxicity and evidence of activity. The recommended phase II dose is topotecan 0.4 mg/m2/day continuous infusion d1-15 with oxaliplatin 85 mg/m2 on days 1 and 15. A phase II evaluation as second-line treatment for both platinum-sensitive and -resistant ovarian cancer recurrences is ongoing
— id: 76389, year: 2008, vol: 108, page: 500, stat: Journal Article,

Shedding of distinct cryptic collagen epitope (HU177) in sera of melanoma patients
Ng, Bruce; Zakrzewski, Jan; Warycha, Melanie; Christos, Paul J; Bajorin, Dean F; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Polsky, David; Mazumdar, Madhu; Montgomery, Anthony; Liebes, Leonard; Brooks, Peter C; Osman, Iman
2008 Oct 1;14(19):6253-6258, Clinical cancer research
PURPOSE: Extracellular matrix remodeling during tumor growth plays an important role in angiogenesis. Our preclinical data suggest that a newly identified cryptic epitope (HU177) within collagen type IV regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo. In this study, we investigated the clinical relevance of HUI77 shedding in melanoma patient sera. EXPERIMENTAL DESIGN: Serum samples from 291 melanoma patients prospectively enrolled at the New York University Medical Center and 106 control subjects were analyzed for HU177 epitope concentration by a newly developed sandwich ELISA assay. HU177 serum levels were then correlated with clinical and pathologic parameters. RESULTS: Mean HU177 epitope concentration was 5.8 ng/mL (range, 0-139.8 ng/mL). A significant correlation was observed between HU177 concentration and nodular melanoma histologic subtype [nodular, 10.3 +/- 1.6 ng/mL (mean +/- SE); superficial spreading melanoma, 4.5 +/- 1.1 ng/mL; all others, 6.1 +/- 2.1 ng/mL; P = 0.01 by ANOVA test]. Increased HU177 shedding also correlated with tumor thickness (< or =1.00 mm, 3.8 +/- 1.1 ng/mL; 1.01-3.99 mm, 8.7 +/- 1.3 ng/mL; > or =4.00 mm, 10.3 +/- 2.4 ng/mL; P = 0.003 by ANOVA). After multivariate analysis controlling for thickness, the correlation between higher HU177 concentration and nodular subtype remained significant (P = 0.03). The mean HU177 epitope concentration in control subjects was 2.4 ng/mL. CONCLUSIONS: We report that primary melanoma can induce detectable changes in systemic levels of cryptic epitope shedding. Our data also support that nodular melanoma might be biologically distinct compared with superficial spreading type melanoma. As targeted interventions against cryptic collagen epitopes are currently undergoing phase I clinical trial testing, these findings indicate that patients with nodular melanoma may be more susceptible to such targeted therapies
— id: 92160, year: 2008, vol: 14, page: 6253, stat: Journal Article,

Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex
Wang, Longgui G; Johnson, Edward M; Kinoshita, Yayoi; Babb, James S; Buckley, Michael T; Liebes, Leonard F; Melamed, Jonathan; Liu, Xiao-Mei; Kurek, Ralf; Ossowski, Liliana; Ferrari, Anna C
2008 Apr 15;68(8):2678-2688, Cancer research
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur alpha and hnRNP-K. Pur alpha expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur alpha expression reduced AR at the transcription and protein levels. Pur alpha knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur alpha protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur alpha is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur alpha and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC
— id: 95063, year: 2008, vol: 68, page: 2678, stat: Journal Article,

Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients
Yu, Jessie Z; Warycha, Melanie A; Christos, Paul J; Darvishian, Farbod; Yee, Herman; Kaminio, Hideko; Berman, Russell S; Shapiro, Richard L; Buckley, Michael T; Liebes, Leonard F; Pavlick, Anna C; Polsky, David; Brooks, Peter C; Osman, Iman
2008 ;6:70-70, Journal of translational medicine
BACKGROUND: Different Insulin-like Growth Factor Binding Proteins (IGFBPs) have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression. METHODS: The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56) prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG) between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients. RESULTS: Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01) A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 microg/ml vs. 3.4 microg/ml, respectively, p = 0.09). However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients. CONCLUSION: Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients
— id: 92159, year: 2008, vol: 6, page: 70, stat: Journal Article,

Inhibition of angiogenesis and tumor metastasis by targeting a matrix immobilized cryptic extracellular matrix epitope in laminin
Akalu, Abebe; Roth, Jennifer M; Caunt, Maresa; Policarpio, Desiree; Liebes, Leonard; Brooks, Peter C
2007 May 1;67(9):4353-4363, Cancer research
Angiogenesis and tumor metastasis depend on extracellular matrix (ECM) remodeling and subsequent cellular interactions with these modified proteins. An in-depth understanding of how both endothelial and tumor cells use matrix-immobilized cryptic ECM epitopes to regulate invasive cell behavior may lead to the development of novel strategies for the treatment of human tumors. However, little is known concerning the existence and the functional significance of cryptic laminin epitopes in regulating angiogenesis and tumor cell metastasis. Here, we report the isolation and characterization of a synthetic peptide that binds to a cryptic epitope in laminin. The STQ peptide selectively bound denatured and proteolyzed laminin but showed little interaction with native laminin. The cryptic laminin epitope recognized by this peptide was selectively exposed within malignant melanoma in vivo, whereas little if any was detected in normal mouse skin. Moreover, the STQ peptide selectively inhibited endothelial and tumor cell adhesion, migration, and proliferation in vitro and inhibited angiogenesis, tumor growth, and experimental metastasis in vivo. This inhibitory activity was associated with a selective up-regulation of the cyclin-dependent kinase inhibitor P27(KIP1) and induction of cellular senescence. These novel findings suggest the existence of functionally relevant cryptic laminin epitopes in vivo and that selective targeting of these laminin epitopes may represent an effective new strategy for the treatment of malignant tumors by affecting both the endothelial and tumor cell compartments.
— id: 72967, year: 2007, vol: 67, page: 4353, stat: Journal Article,

Para-aminobenzoic acid (PABA) enhances the anti-tumor activity of radiotherapy (RT) in the human glioblastoma multiforme T98G cell line both in-vitro and in-vivo
Buckley, Michael T.; Gittleman, Alicia E.; Devitt, Mary L.; Ng, Bruce; Dewyngaert, J. Keith; Brooks, Peter; Formenti, Silvia C.; Liebes, Leonard
2007 ;48(6):738-738, Proceedings (American Association for Cancer Research)
— id: 109225, year: 2007, vol: 48, page: 738, stat: Journal Article,

The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo
Buckley, Michael T; Yoon, Joanne; Yee, Herman; Chiriboga, Luis; Liebes, Leonard; Ara, Gulshan; Qian, Xiaozhong; Bajorin, Dean F; Sun, Tung-Tien; Wu, Xue-Ru; Osman, Iman
2007 Oct 12;5(1):49-49, Journal of translational medicine
ABSTRACT: BACKGROUND: Treatment options for patients with recurrent superficial bladder cancer are limited, necessitating aggressive exploration of new treatment strategies that effectively prevent recurrence and progression to invasive disease. We assessed the effects of belinostat (previously PXD101), a novel histone deacetylase inhibitor, on a panel of human bladder cancer cell lines representing superficial and invasive disease, and on a transgenic mouse model of superficial bladder cancer. METHODS: Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed. Ha-ras transgenic mice with established superficial bladder cancer were randomized to receive either belinostat or vehicle alone, and assessed for bladder weight, hematuria, gene expression profiling, and immunohistochemistry (IHC). RESULTS: Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 micromolar). The 5637 cell line, which was derived from a superficial papillary tumor, was the most sensitive to treatment. Belinostat (100 mg/kg, intraperitoneal, 5 days each week for 3 weeks) treated mice had less bladder weight (p<0.05), and no hematuria compared with 6/10 control mice that developed at least one episode. IHC of bladder tumors showed less cell proliferation and a higher expression of p21WAF1 in the belinostat-treated mice. Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes. CONCLUSION: Our data demonstrate that belinostat inhibits bladder cancer and supports the clinical evaluation of belinostat for the treatment of patients with superficial bladder cancer
— id: 74320, year: 2007, vol: 5, page: 49, stat: Journal Article,

Disruption of endothelial cell interactions with the novel HU177 cryptic collagen epitope inhibits angiogenesis
Cretu, Alexandra; Roth, Jennifer M; Caunt, Maresa; Akalu, Abebe; Policarpio, Desiree; Formenti, Silvia; Gagne, Paul; Liebes, Leonard; Brooks, Peter C
2007 May 15;13(10):3068-3078, Clinical cancer research
PURPOSE: The importance of cellular communication with the extracellular matrix in regulating cellular invasion is well established. Selective disruption of communication links between cells and the local microenvironment by specifically targeting non-cellular matrix-immobilized cryptic extracellular matrix epitopes may represent an effective new clinical approach to limit tumor-associated angiogenesis. Therefore, we sought to determine whether the HU177 cryptic collagen epitope plays a functional role in regulating angiogenesis in vivo. EXPERIMENTAL DESIGN: We examined the expression and characterized the HU177 cryptic collagen epitope in vitro and in vivo using immunohistochemistry and ELISA. We examined potential mechanisms by which this cryptic collagen epitope may regulate angiogenesis using in vitro cell adhesion, migration, proliferation, and biochemical assays. Finally, we examined the whether blocking cellular interactions with the HU177 cryptic epitope plays a role in angiogenesis and tumor growth in vivo using the chick embryo model. RESULTS: The HU177 cryptic epitope was selectively exposed within tumor blood vessel extracellular matrix, whereas little was associated with quiescent vessels. An antibody directed to this cryptic site selectively inhibited endothelial cell adhesion, migration, and proliferation on denatured collagen type IV and induced increased levels of cyclin-dependent kinase inhibitor p27(KIP1). Systemic administration of mAb HU177 inhibited cytokine- and tumor-induced angiogenesis in vivo. CONCLUSIONS: We provide evidence for a new functional cryptic regulatory element within collagen IV that regulates tumor angiogenesis. These findings suggest a novel and highly selective approach for regulating angiogenesis by targeting a non-cellular cryptic collagen epitope
— id: 73410, year: 2007, vol: 13, page: 3068, stat: Journal Article,

Irinotecan: a potential new chemotherapeutic agent for atypical or malignant meningiomas
Gupta, Vinay; Su, Yuzhuang S; Samuelson, Christian G; Liebes, Leonard F; Chamberlain, Marc C; Hofman, Florence M; Schonthal, Axel H; Chen, Thomas C
2007 Mar;106(3):455-462, Journal of neurosurgery
OBJECT: There is currently no effective chemotherapy for meningiomas. Although most meningiomas are treated surgically, atypical or malignant meningiomas and surgically inaccessible meningiomas may not be removed completely. The authors have investigated the effects of the topoisomerase I inhibitor irinotecan (CPT-11) on primary meningioma cultures and a malignant meningioma cell line in vitro and in vivo. METHODS: The effects of irinotecan on cellular proliferation in primary meningioma cultures and the IOMM-Lee malignant meningioma cell line were measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide assay and flow cytometry. Apoptosis following drug treatment was evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and the DNA laddering assays. The effects of irinotecan in vivo on a meningioma model were determined with a subcutaneous murine tumor model using the IOMM-Lee cell line. Irinotecan induced a dose-dependent antiproliferative effect with subsequent apoptosis in the primary meningioma cultures (at doses up to 100 microM) as well as in the IOMM-Lee human malignant meningioma cell line (at doses up to 20 microM) irinotecan. In the animal model, irinotecan treatment led to a statistically significant decrease in tumor growth that was accompanied by a decrease in Bcl-2 and survivin levels and an increase in apoptotic cell death. CONCLUSIONS: Irinotecan demonstrated growth-inhibitory effects in meningiomas both in vitro and in vivo. Irinotecan was much more effective against the malignant meningioma cell line than against primary meningioma cultures. Therefore, this drug may have an important therapeutic role in the treatment of atypical or malignant meningiomas and should be evaluated further for this purpose
— id: 95850, year: 2007, vol: 106, page: 455, stat: Journal Article,

Whole body MRI at 7 tesla using a 1H/19F elliptic body coil with whole-body, fat-signal insensitive, three dimensional magnetic field shim algorithm
Liebes, L; Lee, R; Liu, S; Buckley, MT; Hochster, H; Gonen, O
2007 DEC ;6(12):3479S-3479S, Molecular cancer therapeutics
— id: 75902, year: 2007, vol: 6, page: 3479S, stat: Journal Article,

Clinical relevance of neutral endopeptidase (NEP/CD10) in melanoma
Velazquez, Elsa F; Yancovitz, Molly; Pavlick, Anna; Berman, Russell; Shapiro, Richard; Bogunovic, Dusan; O'Neill, David; Yu, Yi-Lo; Spira, Joanna; Christos, Paul J; Zhou, Xi Kathy; Mazumdar, Madhu; Nanus, David M; Liebes, Leonard; Bhardwaj, Nina; Polsky, David; Osman, Iman
2007 ;5:2-2, Journal of translational medicine
BACKGROUND: Overexpression of Neutral Endopeptidase (NEP) has been reported in metastatic carcinomas, implicating NEP in tumor progression and suggesting a role for NEP inhibitors in its treatment. We investigated the role of NEP expression in the clinical progression of cutaneous melanoma. METHODS: We screened 7 melanoma cell lines for NEP protein expression. NEP-specific siRNA was transfected into the lines to examine the role of gene transcription in NEP expression. Immunohistochemistry was done for 93 specimens and correlated with clinicopathologic parameters. Thirty-seven metastatic melanoma specimens were examined for NEP transcript expression using Affymetrix GeneChips. In a subset of 25 specimens for which both transcript and protein expression was available, expression ratios were used to identify genes that co-express with NEP in GeneChip analysis. RESULTS: NEP was overexpressed in 4/7 human melanoma cell lines, and siRNA knock-down of NEP transcripts led to downregulation of its protein expression. NEP protein overexpression was significantly more common in metastatic versus primary tumors (P = 0.002). Twelve of 37 (32%) metastatic tumors had increased NEP transcript expression, and an association was observed between NEP transcript upregulation and protein overexpression (P < 0.0001). Thirty-eight genes were found to significantly co-express with NEP (p < 0.005). Thirty-three genes positively correlated with NEP, including genes involved in the MAP kinase pathway, antigen processing and presentation, apoptosis, and WNT signaling pathway, and 5 genes negatively correlated with NEP, including genes of focal adhesion and the notch signaling pathways. CONCLUSION: NEP overexpression, which seems to be largely driven by increased transcription, is rare in primary melanoma and occurs late in melanoma progression. Functional studies are needed to better understand the mechanisms of NEP regulation in melanoma
— id: 74679, year: 2007, vol: 5, page: 2, stat: Journal Article,

Proceedings of a GOG workshop on intraperitoneal therapy for ovarian cancer
Alberts, DS; Markman, M; Muggia, F; Ozols, RF; Eldermire, E; Bookman, MA; Chen, T; Curtin, J; Hess, LM; Liebes, L; Young, RC; Trimble, E
2006 DEC ;103(3):783-792, Gynecologic oncology
Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal ding delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCl Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop. (c) 2006 Elsevier Inc. All rights reserved
— id: 69631, year: 2006, vol: 103, page: 783, stat: Journal Article,

Para-aminobenzoic acid (PABA) enhances responses to low and high dose rate radiotherapy (RT) in glioblastoma cell lines
Buckley, Michael T.; Kang, Josephine; Brooks, Peter; Devitt, M. L.; Dewyngaert, J. Keith; Ng, Bruce; Formenti, Silvia C.; Liebes, Leonard; Vlachaki, Maria T.
2006 ;47(6):139-139, Proceedings (American Association for Cancer Research)
— id: 109226, year: 2006, vol: 47, page: 139, stat: Journal Article,

Enhancement of glioblastoma cell killing by combination treatment with temozolomide and tamoxifen or hypericin
Gupta, Vinay; Su, Yuzhuang S; Wang, Weijun; Kardosh, Adel; Liebes, Leonard F; Hofman, Florence M; Schonthal, Axel H; Chen, Thomas C
2006 ;20(4):E20-E20, Neurosurgical focus
OBJECT: The chemotherapeutic agent temozolomide has demonstrated antitumor activity in patients with recurrent malignant glioma. Because responses are not enduring and recurrence is nearly universal, further improvements are urgently needed. METHODS: In an effort to increase the clinical activity of temozolomide, the authors investigated whether its antitumor activity could be enhanced by adding tamoxifen or hypericin, two drugs that are known to inhibit the activity of protein kinase C. Human glioblastoma multiforme cell lines A172 and LA567 were treated with combinations of temozolomide and tamoxifen or hypericin in vitro, and cell survival was analyzed using various methods. Tamoxifen and hypericin were able to greatly increase the growth-inhibitory and apoptosis-stimulatory potency of temozolomide via the downregulation of critical cell cycle-regulatory and prosurvival components. Furthermore, with the use of an in vivo xenograft mouse model, the authors demonstrated that hypericin was able to enhance the antiglioma effects of temozolomide in the in vivo setting as well. CONCLUSIONS: Taken together, analysis of the results indicated that combination therapy involving temozolomide and tamoxifen or hypericin potently inhibited tumor growth by inducing apoptosis and provided an effective means of treating malignant glioma
— id: 95851, year: 2006, vol: 20, page: E20, stat: Journal Article,

Gemcitabine (G) plamsa and intracellular pharmacokinetics in E6201: Greater metabolite levels using fixed dosing rate (FDR) delivery
Liebes, L; Levy, DE; Poplin, E; Mendoza, S; Fry, D; Buckley, M; Zoloratov, A; Benson, A; Hochster, H
2006 JUN 20 ;24(18):85S-85S, Journal of clinical oncology
— id: 69295, year: 2006, vol: 24, page: 85S, stat: Journal Article,

Topotecan continuous infusion: CA-125 responses including patients pretreated with other schedules of topotecan
Muggia, Franco; Kosloff, Rebecca; Liebes, Leonard; Hochster, Howard
2006 May;11(5):529-531, Oncologist
— id: 69425, year: 2006, vol: 11, page: 529, stat: Journal Article,

Increase in circulating bone marrow progenitor cells after myocardial infarction
Spevack, Daniel M; Cavaleri, Salvatore; Zolotarev, Alexander; Liebes, Leonard; Inghirami, Giorgio; Tunick, Paul A; Kronzon, Itzhak
2006 May;17(4):345-349, Coronary artery disease
BACKGROUND: Most circulating blood cells expressing the marker CD34 are bone marrow progenitor cells. These cells differentiate into cardiomyocytes, endothelial and smooth muscle cells after myocardial infarction in vivo. Mobilization of bone marrow progenitor cells into the peripheral blood after myocardial infarction may supply these cells to the heart. Rise in CD34+ cell concentrations following myocardial infarction would support the existence of myocardial-initiated mobilization. METHODS: Serial measurements of circulating CD34+ cells were made in 42 consecutive patients presenting with first ST-elevation myocardial infarction. Measurement of serum concentrations of monocyte chemoattractant protein-1, stromal derived factor-1, hepatocyte growth factor, interleukin-17 and thrombopoietin was also performed. Samples were drawn on day 1 after myocardial infarction, and on days 4, 8 and 12. Levels of CD34+ cells and cytokines were also measured in 15 controls. RESULTS: By day 8, the mean concentration of CD34+ cells rose by 74% above mean control level of 2527 cells/ml, and 41% above day 1 mean (P=0.02). This rise was sustained on day 12 (P=0.05). On day 1, there was a 9.3-fold rise in hepatocyte growth factor above the control level of 589 pg/ml (P=0.002). Hepatocyte growth factor levels declined from the day 1 mean of 6061 to 1485 pg/ml on day 12 (P=0.002). No significant change in stromal derived factor-1, interleukin-17, monocyte chemoattractant protein-1 and thrombopoietin was observed. Elevations in CD34+ cells and hepatocyte growth factor were not related to infarction size as estimated on echocardiography. CONCLUSIONS: Elevation in the concentration of circulating CD34+ cells after myocardial infarction suggests that myocardial initiated bone marrow progenitor cell mobilization exists in humans. The cytokines studied in our protocol are not likely to play a direct role in bone marrow progenitor cell mobilization
— id: 69237, year: 2006, vol: 17, page: 345, stat: Journal Article,

The vitamin-like dietary supplement para-aminobenzoic acid enhances the antitumor activity of ionizing radiation
Xavier, Sandhya; Macdonald, Shannon; Roth, Jennifer; Caunt, Maresa; Akalu, Abebe; Morais, Danielle; Buckley, Michael T; Liebes, Leonard; Formenti, Silvia C; Brooks, Peter C
2006 Jun 1;65(2):517-527, International journal of radiation oncology biology physics
PURPOSE: To determine whether para-aminobenzoic acid (PABA) alters the sensitivity of tumor cells to ionizing radiation in vitro and in vivo. METHODS AND MATERIALS: Cellular proliferation was assessed by WST-1 assays. The effects of PABA and radiation on tumor growth were examined with chick embryo and murine models. Real-time reverse transcriptase-polymerase chain reaction and Western blotting were used to quantify p21CIP1 and CDC25A levels. RESULTS: Para-aminobenzoic acid enhanced (by 50%) the growth inhibitory activity of radiation on B16F10 cells, whereas it had no effect on melanocytes. Para-aminobenzoic acid enhanced (50-80%) the antitumor activity of radiation on B16F10 and 4T1 tumors in vivo. The combination of PABA and radiation therapy increased tumor apoptosis. Treatment of tumor cells with PABA increased expression of CDC25A and decreased levels of p21CIP1. CONCLUSIONS: Our findings suggest that PABA might represent a compound capable of enhancing the antitumor activity of ionizing radiation by a mechanism involving altered expression of proteins known to regulate cell cycle arrest
— id: 64379, year: 2006, vol: 65, page: 517, stat: Journal Article,

A phase I study of oxaliplatin (OX) in combination with bortezomib (B) in patients with advanced malignancy
Chang, R; Beric, A; Liebes, LF; Wright, J; Ivy, P; Norwood, B; Escalon, J; Muggia, FM; Hochster, HS
2005 JUN 1 ;23(16):880S-880S, Journal of clinical oncology
— id: 57806, year: 2005, vol: 23, page: 880S, stat: Journal Article,

Select forms of tumor cell apoptosis induce dendritic cell maturation
Demaria, Sandra; Santori, Fabio R; Ng, Bruce; Liebes, Leonard; Formenti, Silvia C; Vukmanovic, Stanislav
2005 Mar;77(3):361-368, Journal of leukocyte biology
Dendritic cells (DC) play a crucial role in initiating immune responses to tumors. DC can efficiently present antigens from apoptotic tumor cells, but apoptotic cells are thought to lack the inflammatory signals required to induce DC maturation. Here, we show that apoptosis of 67NR mouse carcinoma cells via the Fas (CD95) pathway or induced by the anticancer drug bortezomib (PS-341) but not by ultraviolet irradiation is associated with the production of maturation signals for DC. These data have important implications for the effects of chemotherapy on antitumor immunity in solid and hematologic malignancies
— id: 48257, year: 2005, vol: 77, page: 361, stat: Journal Article,

Intravital observation of Plasmodium berghei sporozoite infection of the liver
Frevert, Ute; Engelmann, Sabine; Zougbede, Sergine; Stange, Jorg; Ng, Bruce; Matuschewski, Kai; Liebes, Leonard; Yee, Herman
2005 Jun;3(6):e192-e192, PLoS biology
Plasmodium sporozoite invasion of liver cells has been an extremely elusive event to study. In the prevailing model, sporozoites enter the liver by passing through Kupffer cells, but this model was based solely on incidental observations in fixed specimens and on biochemical and physiological data. To obtain direct information on the dynamics of sporozoite infection of the liver, we infected live mice with red or green fluorescent Plasmodium berghei sporozoites and monitored their behavior using intravital microscopy. Digital recordings show that sporozoites entering a liver lobule abruptly adhere to the sinusoidal cell layer, suggesting a high-affinity interaction. They glide along the sinusoid, with or against the bloodstream, to a Kupffer cell, and, by slowly pushing through a constriction, traverse across the space of Disse. Once inside the liver parenchyma, sporozoites move rapidly for many minutes, traversing several hepatocytes, until ultimately settling within a final one. Migration damage to hepatocytes was confirmed in liver sections, revealing clusters of necrotic hepatocytes adjacent to structurally intact, sporozoite-infected hepatocytes, and by elevated serum alanine aminotransferase activity. In summary, malaria sporozoites bind tightly to the sinusoidal cell layer, cross Kupffer cells, and leave behind a trail of dead hepatocytes when migrating to their final destination in the liver
— id: 62739, year: 2005, vol: 3, page: e192, stat: Journal Article,

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle
Hamilton, A L; Eder, J P; Pavlick, A C; Clark, J W; Liebes, L; Garcia-Carbonero, R; Chachoua, A; Ryan, D P; Soma, V; Farrell, K; Kinchla, N; Boyden, J; Yee, H; Zeleniuch-Jacquotte, A; Wright, J; Elliott, P; Adams, J; Muggia, F M
2005 Sep 1;23(25):6107-6116, Journal of clinical oncology
PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea
— id: 57888, year: 2005, vol: 23, page: 6107, stat: Journal Article,

Preliminary studies regarding the application of localized fluorine magnetic resonance spectroscopy (19F-MRS) at ultra high magnetic field (7 Tesla), for non invasive, in vivo monitoring of gemcitabine and its active anabolic by-product tri-phosphate (dFdCTP) in human pancreatic cancer cells
Liebes, LF; Gonen, O; Mendoza, S; Zolaratov, A; Hochster, H
2005 DEC 15 ;11(24):9098S-9099S, Clinical cancer research
— id: 62404, year: 2005, vol: 11, page: 9098S, stat: Journal Article,

Phase I study of combined pegylated liposomal doxorubicin with protracted daily topotecan for ovarian cancer
Mirchandani, Deepu; Hochster, Howard; Hamilton, Anne; Liebes, Leonard; Yee, Herman; Curtin, John P; Lee, Sang; Sorich, Joan; Dellenbaugh, Cornelia; Muggia, Franco M
2005 Aug 15;11(16):5912-5919, Clinical cancer research
PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity of Doxil with low-dose continuous infusion topotecan and subsequently with low-dose oral topotecan. Other specific aims were preliminary assessment of activity in advanced ovarian and tubal malignancies, pharmacokinetics of oral topotecan, and correlation of response with topoisomerase I and II expression in tumors. METHODS: Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status <2, and adequate organ functions. Doxil (30-40 mg/m2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m2/d) for 14 to 21 days, in 28-day cycles. Fifty-seven patients, 23 with epithelial ovarian or tubal cancers were enrolled. Plasma levels of lactone form of topotecan were determined on patients receiving oral topotecan. RESULTS: Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m2/day 1) and continuous infusion topotecan at 0.4 mg/m2/days 1 to 14 could be safely given and is the recommended phase II dose. Oral topotecan was limited by low and erratic plasma topotecan levels and frequent gastrointestinal toxicity. Particularly long partial responses and stable disease were observed in patients with epithelial ovarian or tubal cancers. Clinical benefit (objective responses and stable diseases) correlated with elevated expression of both topoisomerases by immunohistochemistry in four of six epithelial ovarian or tubal cancer tumor samples. CONCLUSION: Doxil with 14-day topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. Frequent gastrointestinal toxicity and/or erratic absorption complicate treatment with a longer topotecan infusion or with oral topotecan, respectively, and these combinations are not recommended
— id: 61253, year: 2005, vol: 11, page: 5912, stat: Journal Article,

Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo
Roth, Jennifer M; Akalu, Abebe; Zelmanovich, Anat; Policarpio, Desiree; Ng, Bruce; MacDonald, Shannon; Formenti, Silvia; Liebes, Leonard; Brooks, Peter C
2005 Mar;166(3):901-911, American journal of pathology
Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the alpha2(IV)NC1 domain of type-IV collagen could bind integrins alpha1beta1 and alphavbeta3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant alpha2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, alpha2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant alpha2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, alpha2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments
— id: 51099, year: 2005, vol: 166, page: 901, stat: Journal Article,

Thalidomide in advanced hepatocellular carcinoma with optional low-dose interferon-alpha2a upon progression
Schwartz, Jonathan D; Sung, Max; Schwartz, Myron; Lehrer, Deborah; Mandeli, John; Liebes, Leonard; Goldenberg, Alec; Volm, Matthew
2005 Oct;10(9):718-727, Oncologist
PURPOSE: To evaluate thalidomide in advanced hepatocellular carcinoma (HCC) and to evaluate combined thalidomide and low-dose interferon-alpha2a (IFN-alpha2a) after tumor progression on thalidomide. Systemic therapy is minimally effective in HCC and tumor angiogenesis is a potential therapeutic target. PATIENTS AND METHODS: Patients with unresectable HCC were eligible if they had preserved hepatic and renal function. The initial thalidomide dosage was 200 mg daily and was adjusted for toxicity. Upon progression, patients could continue thalidomide with additional low-dosage (one million units twice daily) IFN-alpha2a. RESULTS: Thirty-eight enrolled patients were predominantly hepatitis C virus infected (53%), Child-Pugh class A (79%), and Eastern Cooperative Oncology Group performance status 0-1 (92%); 60% had extrahepatic metastasis. Confirmed disease control was seen in seven patients (18%) and included one complete and one partial response (5% response rate). The median progression-free survival was 2.1 months, and median overall survival was 5.5 months. Tumor invasion of the portal vein or vena cava, large (>10 cm) tumor, and younger age were associated with shorter overall survival. Toxicity included fatigue in 74% of patients. Six patients stopped therapy because of side effects, including two patients (5%) with grade 4 arteriothrombotic events. Five patients continued thalidomide upon progression with the addition of IFN-alpha2a; there was no disease control and 80% had grade 3 toxicity. CONCLUSIONS: Thalidomide is not well tolerated and confers limited disease control in advanced HCC. Combination thalidomide and low-dose IFN-alpha2a is neither safe nor efficacious in this population
— id: 76325, year: 2005, vol: 10, page: 718, stat: Journal Article,

Potentiation of radiation-induced growth inhibition of non-small cell lung cancer by borteomib and para-aminobenzoid acid
Vlachaki, Maria T.; Cho, Jennie J.; Buckley, Mike T.; Brooks, Peter; Devitt, Mary L.; Formenti, Silvia C.; Hoschster, Howard; Liebes, Leonard F.
2005 ;46(6):341-341, Proceedings (American Association for Cancer Research)
— id: 109228, year: 2005, vol: 46, page: 341, stat: Journal Article,

Potentiation of radiation induced growth inhibition of glioma cells with combinations of nM levels of bortezomib and hypericin
Buckley, Michael; Ng, Bruce; Zolotarov, Alex; Devitt, Mary Lou; Formenti, Silvia; Liebes, Leonard
2004 ;45(6):1126-1126, Proceedings (American Association for Cancer Research)
— id: 109229, year: 2004, vol: 45, page: 1126, stat: Journal Article,

Structural and dynamic studies of diastereomers of Mo-tripeptides (M = Tc, Re) and extension to peptide radiopharmaceuticals
Cantorias, MV; Howell, RC; Kramer, IE; Liebes, L; Buckley, M; Ng, B; Francesconi, LC
2004 AUG 22 ;228(2):U7-U7, Abstracts of papers (American Chemical Society)
— id: 48252, year: 2004, vol: 228, page: U7, stat: Journal Article,

Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated
Demaria, Sandra; Ng, Bruce; Devitt, Mary Louise; Babb, James S; Kawashima, Noriko; Liebes, Leonard; Formenti, Silvia C
2004 Mar 1;58(3):862-870, International journal of radiation oncology biology physics
PURPOSE: Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal effect. Although it has been reported in multiple malignancies, the abscopal effect remains a rare and poorly understood event. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells' activation of tumor-specific T cells. We therefore tested the hypothesis that the abscopal effect elicited by radiation is immune mediated. This was directly tested by enhancing the number of available dendritic cells using the growth factor Flt3-Ligand (Flt3-L). METHODS AND MATERIALS: Mice bearing a syngeneic mammary carcinoma, 67NR, in both flanks were treated with Flt3-L daily for 10 days after local radiation therapy (RT) to only 1 of the 2 tumors at a single dose of 2 or 6 Gy. The second nonirradiated tumor was used as indicator of the abscopal effect. Data were analyzed using repeated measures regression. RESULTS: RT alone led to growth delay exclusively of the irradiated 67NR tumor, as expected. Surprisingly, growth of the nonirradiated tumor was also impaired by the combination of RT and Flt3-L. As control, Flt3-L had no effect without RT. Importantly, the abscopal effect was shown to be tumor specific, because growth of a nonirradiated A20 lymphoma in the same mice containing a treated 67NR tumor was not affected. Moreover, no growth delay of nonirradiated 67NR tumors was observed when T cell deficient (nude) mice were treated with RT plus Flt3-L. CONCLUSIONS: These results demonstrate that the abscopal effect is in part immune mediated and that T cells are required to mediate distant tumor inhibition induced by radiation
— id: 42588, year: 2004, vol: 58, page: 862, stat: Journal Article,

Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors
Mani, Sridhar; McDaid, Hayley; Hamilton, Anne; Hochster, Howard; Cohen, Marvin B; Khabelle, Dineo; Griffin, Tom; Lebwohl, David E; Liebes, Leonard; Muggia, Franco; Horwitz, Susan Band
2004 Feb 15;10(4):1289-1298, Clinical cancer research
PURPOSE: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550. RESULTS: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m(2). At 50 mg/m(2), 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m(2) (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m(2), the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m(2). Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naive breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course 1 for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m(2) (recommended Phase II dose) dose level were 21 liters/h/m(2), 826 liters/m(2), and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar. CONCLUSIONS: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m(2), although more long-term observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study
— id: 44739, year: 2004, vol: 10, page: 1289, stat: Journal Article,

A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor
Pavlick, Anna C; Chodkiewicz, Catherine; Liebes, Leonard; Hamilton, Anne; Wasserheit, Carolyn; Hochster, Howard; Speyer, James; Phillips, Zoe; Downey, Andrea; Sorich, Joan; Muggia, Franco
2004 Feb;15(2):119-125, Anti-cancer drugs
The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers
— id: 44738, year: 2004, vol: 15, page: 119, stat: Journal Article,

TNF can select for upregulated NF-kB in breast cancer progression, providing resistance to apoptosis and radiation
Schneider, RJ; Formenti, S; Liebes, L; Braunstein, S
2004 APR ;60(1):S325-S325, International journal of radiation oncology biology physics
— id: 48943, year: 2004, vol: 60, page: S325, stat: Journal Article,

Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions
Chanan-Khan, A; Szebeni, J; Savay, S; Liebes, L; Rafique, N M; Alving, C R; Muggia, F M
2003 Sep;14(9):1430-1437, Annals of oncology
BACKGROUND: Pegylated liposomal doxorubicin (Doxil) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date. PATIENTS AND METHODS: Patients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate. RESULTS: Moderate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate. CONCLUSIONS: C activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors
— id: 44752, year: 2003, vol: 14, page: 1430, stat: Journal Article,

Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma
Chen, Thomas C; Su, Susan; Fry, David; Liebes, Leonard
2003 May 1;97(9 Suppl):2363-2373, Cancer
The topoisomerase-I inhibitor irinotecan (CPT-11) is currently used in Phase I/II trials for the treatment of patients with recurrent malignant gliomas. Protein kinase C (PKC) inhibitors such as high-dose tamoxifen and hypericin also have been used in the treatment of malignant gliomas. The current study examined the role of PKC inhibitors as chemosensitizers for CPT-11 and their proposed mechanism of action. Two glioma cell lines (A-172 and U-87) and one primary glioma cell culture (LA-567) were used. Proliferation ((3)H-thymidine) and cytotoxicity (methylthiotetrazole) studies were performed using CPT-11 (0-100 microM) alone, 7-ethyl-10-hydroxy camptothecin (SN-38) (0-1000 nM) alone or in the presence of a PKC inhibitor, tamoxifen (10 microM), hypericin (10 microM), calphositin C (400 nM), or staurosporine (10 nM). The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay was used to determine apoptosis as the mechanism of cytotoxicity; alterations in bcl-2 and bax expression were determined using Western blot analysis. Conversion of CPT-11 to SN-38 by glioma cells was determined using high-performance liquid chromatography (HPLC) analysis. Increasing CPT-11 and SN-38 concentrations induced cytotoxic morphologic changes, decreased proliferation, and increased cytotoxicity on all glioma cell lines tested. These changes were increased in the presence of a PKC inhibitor. The mechanism of the cytotoxicity was determined to be apoptosis by the TUNEL assay. The combination of a PKC inhibitor with CPT-11 or SN-38 led to decreased expression of the antiapoptotic protein bcl-2, and increased expression of the proapoptotic protein bax. HPLC analysis demonstrated conversion of CPT-11 to SN-38 by glioma cells. A combination of CPT-11 or SN-38 with a PKC inhibitor was found to lead to a decrease in proliferation and an increase in apoptosis in malignant glioma cells. The induction of apoptosis was secondary to a decrease in bcl-2 and an increase in bax expression. Glioma cells are capable of converting CPT-11 to SN-38 by intrinsic tumor carboxylesterases
— id: 44753, year: 2003, vol: 97, page: 2363, stat: Journal Article,

Optimized schedules of topotecan combined with Y-90 huBrE3 radioinummotherapy show enhanced tumor response in an in vivo ovarian carcinoma model
Kramer, E; Ng, B; Liebes, L; Furmanski, JG; Goldberg, J; Mukhi, V; Ceriani, R; Curtin, J
2003 DEC 1 ;9(16):6190S-6190S, Clinical cancer research
— id: 42541, year: 2003, vol: 9, page: 6190S, stat: Journal Article,

Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines
Ling, Yi-He; Liebes, Leonard; Jiang, Jian-Dong; Holland, James F; Elliott, Peter J; Adams, Julian; Muggia, Franco M; Perez-Soler, Roman
2003 Mar;9(3):1145-1154, Clinical cancer research
PURPOSE: PS-341 is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo antitumor activity that induces mechanisms of apoptosis by unknown mechanisms. EXPERIMENTAL DESIGN: Human non-small cell lung cancer cell lines were used to investigate effects PS-341 on cell proliferation, cell cycle progression, and the induction of apoptosis. RESULTS: PS-341 was 38-360-fold more cytotoxic against H460 cells when compared with the proteasome inhibitors MG-132 and PSI. Differential PS-341 cytotoxic effects were found with respect to P53 function: H322 cells (p53 mutant) were 6-fold less sensitive as compared with H460 cells (p53 wild type); and H358 cells (p53 null) were 1.6-fold more sensitive as compared with H460 cells (p53 wild type). A concentration- and time-dependent cell cycle blockade at G(2)-M phase was seen for H460 cells without any direct effects on microtubule polymerization or depolymerization. PS-341 exposure in H460 cells led to stabilization of p53, induction of p21(cip/waf-1) and MDM2 expression, an increase in cyclin B and cyclin A, and the activation of cyclin B and cyclin A kinases. MDM2 induction was found only in H460 cells, whereas in H322 and H358 cells, G(2)-M-phase arrest, p21(cip/waf-1) induction, and an increase in cyclin B1 were found. The commitment of G(2)-M-phase cells to apoptosis was verified by the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in drug-free medium. CONCLUSIONS: Our data suggest that the PS-341-induced G(2)-M-phase arrest may be associated with the inhibition of degradation of cell cycle regulators and that the up-regulation of p21(cip/waf-1) expression may be via p53-dependent and/or -independent pathways. The resulting disturbance of cell cycle progression leads either to growth inhibition or to the initiation of apoptotic pathways
— id: 44754, year: 2003, vol: 9, page: 1145, stat: Journal Article,

Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells
Ling, Yi-He; Liebes, Leonard; Zou, Yiyu; Perez-Soler, Roman
2003 Sep 5;278(36):33714-33723, Journal of biological chemistry
Bortezomib, a proteasome inhibitor, shows substantial anti-tumor activity in a variety of tumor cell lines, is in phase I, II, and III clinical trials and has recently been approved for the treatment of patients with multiple myeloma. The sequence of events leading to apoptosis following proteasome inhibition by bortezomib is unclear. Bortezomib effects on components of the mitochondrial apoptotic pathway were examined: generation of reactive oxygen species (ROS), alteration in the mitochondrial membrane potential (Delta psi m), and release of cytochrome c from mitochondria. With human H460 lung cancer cells, bortezomib exposure at 0.1 microM showed induction of apoptotic cell death starting at 24 h, with increasing effects after 48-72 h of treatment. After 3-6 h, an elevation in ROS generation, an increase in Delta psi m, and the release of cytochrome c into the cytosol, were observed in a time-dependent manner. Co-incubation with rotenone and antimycin A, inhibitors of mitochondrial electron transport chain complexes I and III, or with cyclosporine A, an inhibitor of mitochondrial permeability transition pore, resulted in inhibition of bortezomib-induced ROS generation, increase in Delta psi m, and cytochrome c release. Tiron, an antioxidant agent, blocked the bortezomib-induced ROS production, Delta psi m increase, and cytochrome c release. Tiron treatment also protected against the bortezomib-induced PARP protein cleavage and cell death. Benzyloxycarbonyl-VAD-fluoromethyl ketone, an inhibitor of pan-caspase, did not alter the bortezomib-induced ROS generation and increase in Delta psi m, although it prevented bortezomib-induced poly(ADP-ribose) polymerase cleavage and apoptotic death. In PC-3 prostate carcinoma cells (with overexpression of Bcl-2), a reduction of bortezomib-induced ROS generation, Delta psi m increase was correlated with cellular resistance to bortezomib and the attenuation of drug-induced apoptosis. The transient transfection of wild type p53 in p53 null H358 cells caused stimulation of the bortezomib-induced apoptosis but failed to enhance ROS generation and Delta psi m increase. Thus ROS generation plays a critical role in the initiation of the bortezomib-induced apoptotic cascade by mediation of the disruption of Delta psi m and the release of cytochrome c from mitochondria
— id: 39183, year: 2003, vol: 278, page: 33714, stat: Journal Article,

Coating of culture plates with collagen increases the in vitro effects of both PS-341 and ionizing radiation (RT)
Ng, Bruce; Snell, Jamaal; Brooks, Peter; Liebes, Leonard; Formenti, Silvia
2003 ;44(6):247-247, Proceedings (American Association for Cancer Research)
— id: 109234, year: 2003, vol: 44, page: 247, stat: Journal Article,

Evidence of bone marrow stem cell mobilization following myocardial infarction
Spevack, DM; Cavaleri, S; Zolotarev, A; Inghirami, G; Liebes, L; Tunick, PA; Knonzon, I
2003 OCT 28 ;108(17):502-502, Circulation
— id: 42529, year: 2003, vol: 108, page: 502, stat: Journal Article,

Liposome-induced hypersensitivity reactions: The role of complement activation
Szebeni, J; Baranyi, L; Savay, S; Milosevits, J; Bunger, R; Laverman, P; Metselaar, JM; Storm, G; Chanan-Khan, A; Liebes, L; Muggia, FM; Cohen, R; Barenholz, Y; Alving, CR
2003 AUG 7 ;13(1):47-48, Journal of liposome research
— id: 37173, year: 2003, vol: 13, page: 47, stat: Journal Article,

Complement activation underlying pseudoallergic drug reactions
Szebeni, J; Baranyi, L; Savay, S; Milosevits, J; Chanan-Khan, AA; Liebes, L; Muggia, FM; Barenholz, Y; Bunger, R; Alving, CR
2003 SEP ;40(2-4):180-180, Molecular immunology
— id: 55475, year: 2003, vol: 40, page: 180, stat: Journal Article,

Chemotherapy can induce apoptosis of cancer cells coupled to the production of maturation signals for dendritic cells
Demaria, Sandra; Ng, Bruce; Santori, Fabio R.; Liebes, Leonard; Vukmanovic, Stanislav; Formenti, Silvia C.
2002 ;43(6):678-678, Proceedings (American Association for Cancer Research)
— id: 109236, year: 2002, vol: 43, page: 678, stat: Journal Article,

Pre-clinical studies of concomitant PS-341 and ionizing radiation therapy: local and systemic anti-tumor effects
Formenti, S; Demaria, S; Liebes, L; Ng, B; Devitt, M; Babbs, J; Muggia, F
2002 NOV ;38(4):34-A256, European journal of cancer
— id: 98237, year: 2002, vol: 38, page: 34, stat: Journal Article,

PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis
Ling, Yi-He; Liebes, Leonard; Ng, Bruce; Buckley, Michael; Elliott, Peter J; Adams, Julian; Jiang, Jian-Dong; Muggia, Franco M; Perez-Soler, Roman
2002 Aug;1(10):841-849, Molecular cancer therapeutics
Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce BcI-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr 23,000 fragment was observed with other anticancer agents. The formation of the Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at approximately 12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), beta-catenin, and DNA fragmentation (at approximately 36 h posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G2-M phase arrest and the induction of apoptosis
— id: 44756, year: 2002, vol: 1, page: 841, stat: Journal Article,

Randomized, placebo-controlled trial of dietary supplementation of alpha-tocopherol on mutagen sensitivity levels in melanoma patients: a pilot trial
Mahabir, S; Coit, D; Liebes, L; Brady, MS; Lewis, JJ; Roush, G; Nestle, M; Fry, D; Berwick, M
2002 Feb;12(1):83-90, Melanoma research
We evaluated the effects of vitamin E (DL-alpha-tocopherol) on mutagen sensitivity levels in a randomized placebo-controlled pilot trial. In brief, a dietary supplement of 1000 mg/day vitamin E or a placebo was randomly administered for 3 months to melanoma outpatients clinically free of the disease. Plasma vitamin E and mutagen sensitivity levels were measured at baseline and at the end of the trial after 3 months. At baseline, we found no significant differences in plasma vitamin E and mutagen sensitivity levels between the two groups. We also measured dietary intake at baseline and found dietary vitamin E to be a poor predictor of plasma levels of vitamin E. After 3 months of supplementation, we found that plasma levels of alpha-tocopherol increased significantly (P = 0.0005) in the vitamin E compared to the placebo group. We also found a non- significant, but consistent decrease in plasma gamma-tocopherol concentrations in the vitamin E supplemented compared to the placebo group. We did not find any significant difference between the vitamin E and placebo groups in mutagen sensitivity levels either at baseline or after 3 months of supplementation. We conclude that short term vitamin E supplementation, although it causes increased blood levels of alpha-tocopherol, does not provide protection against bleomycin-induced chromosome damage. (C) 2002 Lippincott Williams Wilkins
— id: 27541, year: 2002, vol: 12, page: 83, stat: Journal Article,

Phase I and pharmacologic study of i.p. 9-aminocamptothecin given as six fractions over 14 days
Muggia, Franco M; Liebes, Leonard; Hazarika, Maitreyee; Wadler, Scott; Hamilton, Anne; Hornreich, Gila; Sorich, Joan; Chiang, Chung; Newman, Elliot; Potmesil, Milan; Hochster, Howard
2002 Sep;13(8):819-825, Anti-cancer drugs
We sought to define the tolerance of 9-amino-20(S)-camptothecin (9-AC) when given by the i.p. route to patients with cancer in the peritoneal cavity consisting of nodules that did not exceed 1 cm in maximum diameter. 9-AC was given in six fractions over 12 days, at doses ranging from 1.25 to 13.5 mg/m(2) in cycles repeated every 28 days. Dose escalations after the first two dose levels took place in cohorts of three patients, with expansion of the dose level once a dose-limiting toxicity (DLT) was encountered. All patients had blood and i.p. pharmacokinetic (PK) analysis during cycle 1 of each dose level. Topoisomerase (Topo) I signal was serially measured in peripheral blood mononuclear cells (PBMCs) in blood and cells collected in i.p. cytologic washings. Twelve patients received 31 cycles of 9-AC. Tolerance to repeated i.p. drug administration was generally excellent. The DLT was neutropenia encountered at the highest dose level in two patients, whereas the dose of 9 mg/m(2) was well tolerated. The DLTs were associated with peak plasma levels ranging from 47 to 81 ng/ml and also depletion of Topo I in PBMCs. The i.p.:plasma AUC ratio (+/-SD) was 11.5 (+/-3.8). Two patients had objective evidence of clinical benefit and only one of seven patients deemed evaluable for response had progressive disease. We conclude that i.p. 9-AC demonstrates excellent local tolerance at a dose and schedule associated with evidence of systemic effects. A dose of 9 mg/m(2)/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity
— id: 39386, year: 2002, vol: 13, page: 819, stat: Journal Article,

Effect of ionizing radiation with paclitaxel, docetaxel and PS-341 in melanoma cells
Ng, Bruce; Fong, Dean; Devitt, Mary Louise; Formenti, Silvia; Liebes, Leonard
2002 ;43(6):480-480, Proceedings (American Association for Cancer Research)
— id: 109237, year: 2002, vol: 43, page: 480, stat: Journal Article,

Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies
Szebeni, J; Baranyi, L; Savay, S; Milosevits, J; Bunger, R; Laverman, P; Metselaar, J M; Storm, G; Chanan-Khan, A; Liebes, L; Muggia, F M; Cohen, R; Barenholz, Y; Alving, C R
2002 Feb-May;12(1-2):165-172, Journal of liposome research
Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles
— id: 44755, year: 2002, vol: 12, page: 165, stat: Journal Article,

Enhanced sensitivity of mammary carcinoma cell lines to the effects of the proteasome inhibitor PS-341 when Fas signal transduction is perturbed
Demaria, S; Ng, B; Liebes, L; Elliott, P; Formenti, S
2001 NOV 2 ;69(3):309-309, Breast cancer research & treatment
— id: 54807, year: 2001, vol: 69, page: 309, stat: Journal Article,

Inhibition of H-ras membrane binding and topoisomerase-1 in a phase I trial of topotecan combined with the farnesyl transferase inhibitor, R115777 (Zarnestra)
Hochster, H; Liebes, L; Buckley, M; Sorich, J; Fry, D; Hamilton, A; Wright, J; Muggia, F
2001 NOV ;7(11):3710S-3710S, Clinical cancer research
— id: 54797, year: 2001, vol: 7, page: 3710S, stat: Journal Article,

Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John's Wort plant, in patients with chronic hepatitis C virus infection
Jacobson, JM; Feinman, L; Liebes, L; Ostrow, N; Koslowski, V; Tobia, A; Cabana, BE; Lee, DH; Spritzler, J; Prince, AM
2001 FEB ;45(2):517-524, Antimicrobial agents & chemotherapy
Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log(10). Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 mug/ml x hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection
— id: 55226, year: 2001, vol: 45, page: 517, stat: Journal Article,

High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: application to studies with 2-phenethyl isothiocyanate
Liebes L; Conaway CC; Hochster H; Mendoza S; Hecht SS; Crowell J; Chung FL
2001 Apr 15;291(2):279-289, Analytical biochemistry
Dietary and pharmacologic isothiocyanates (ITCs) may play a role in reducing the risk of certain cancers. The quantification of ITCs in humans is important both for epidemiological and pharmacokinetic studies. We describe a modification of an HPLC-based assay of urinary ITCs for use with human plasma. The assay utilizes the cyclocondensation reaction of 1,2-benzenedithiol with ITCs present in human plasma, followed by a two-step hexane extraction and analysis by HPLC using UV detection at 365 nm. The method shows linearity and reproducibility with human plasma over a range of 49-3003 nM phenethyl isothiocyanate (PEITC) (r(2) = 0.996 +/- 0.003). A similar degree of linearity was seen with two other biologically occurring conjugates of PEITC: PEITC-N-acetylcysteine (PEITC-NAC) and PEITC-glutathione (PEITC-GSH). The recovery of PEITC assessed on multiple days was 96.6 +/- 1.5% and was 100% for PEITC-GSH and PEITC-NAC. The reproducibility of the assay on multiday samplings showed a mean %CV of 6.5 +/- 0.3% for PEITC, 6.4 +/- 4.3 for PEITC-NAC and 12.3 +/- 3.9 for PEITC-GSH. In clinical studies, mean plasma ITC level of 413 +/- 193 nM PEITC equivalents was determined for a non-dietary-controlled group of 23 subjects. Multiday analysis data from pharmacokinetic plasma sets of 3 subjects taking a single dose of PEITC at 40 mg showed a good CV (range: 16-21%). The applicability of the methodology to pharmacokinetic studies of PEITC in humans is demonstrated.
— id: 20614, year: 2001, vol: 291, page: 279, stat: Journal Article,

A unique combination effect on cytotoxic activity is observed with H460 cells following sequential administration of the proteasome inhibitor, PS-341 and the chemopreventative agent, 2-phenethyl isothiocyanate (PEITC)
Mendoza, S; Ng, B; Hamilton, A; Elliott, PJ; Muggia, F; Liebes, L
2001 NOV ;7(11):3750S-3750S, Clinical cancer research
— id: 54798, year: 2001, vol: 7, page: 3750S, stat: Journal Article,

Radiosensitization of tumor-targeted radioimmunotherapy with prolonged topotecan infusion in human breast cancer xenografts
Ng B; Kramer E; Liebes L; Wasserheit C; Hochster H; Blank E; Ceriani R; Furmanski P
2001 Apr 1;61(7):2996-3001, Cancer research
Clinical radioimmunotherapy (RIT) of solid tumors holds great promise, but as yet has been unable to deliver tumoricidal radiation doses without unacceptable toxicity. Our experimental approach aims to potentiate the therapeutic action of radioimmunoconjugates at the tumor site and thus improve the efficacy of RIT by combination with other treatment modalities. The topoisomerase I inhibitors are a unique class of chemotherapeutic agents that interfere with DNA breakage-reunion by inhibiting the action of topoisomerase I. Preclinical studies suggest that prolonged infusion of topoisomerase I inhibitors enhances cell toxicity due to ionizing radiation. We evaluated the efficacy of combined treatment with continuous administration of topotecan and 90Y-MX-DPTA BrE3 monoclonal antibody (which recognizes an epitope of breast epithelial mucin expressed in most breast cancers) on human mammary carcinoma xenografts in nude mice. Topotecan or 90Y-BrE3 treatment alone delayed overall tumor growth rate transiently but did not affect survival. The combination of RIT with topotecan substantially reduced growth of relatively large established tumors and caused complete tumor regressions and prolonged tumor-free survival in a substantial proportion of treated animals. In vitro studies demonstrated an increase in apoptotic rate and a decrease in cell proliferation of tumor cell lines treated with this combination. We combined the radiosensitization property of topotecan and the specificity of systemic RIT to establish a novel therapy for solid tumors in an experimental tumor xenograft model
— id: 25619, year: 2001, vol: 61, page: 2996, stat: Journal Article,

Increased breast cancer tumor localization and enhanced cytotoxicity of radioimmunotherapy and chemotherapy combinations
Ng, B; Kramer, E; Ceriani, R; Volm, M; Hamilton, A; Muggia, F; Formenti, S; Furmanski, P; Liebes, L
2001 ;69(3):303-303 #527, Breast cancer research & treatment
— id: 109250, year: 2001, vol: 69, page: 303, stat: Journal Article,

Proteasome inhibitor, PS-341, enhances in vitro radiosensitivity of human breast cancer cells treated with radiotherapy or radioimmunotherapy
Ng, B; Kramer, E; Devitt, ML; Elliott, PJ; Ceriani, R; Hamilton, A; Furmanski, P; Formenti, S; Liebes, L
2001 NOV ;7(11):3806S-3806S, Clinical cancer research
— id: 54802, year: 2001, vol: 7, page: 3806S, stat: Journal Article,

Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli
Conaway, CC; Getahun, SM; Liebes, LL; Pusateri, DJ; Topham, DKW; Botero-Omary, M; Chung, FL
2000 JUL ;38(2):168-178, Nutrition & cancer
The cancer-chemopreventive effects of broccoli maybe attributed, in part to isothiocyanates (ITCs), hydrolysis products of glucosinolates. Glucosinolates are hydrolyzed to their respective ITCs by the enzyme myrosinase, which is inactivated by heat. In this study, the metabolic fate of glucosinolates after ingestion of steamed and fresh broccoli was compared in 12 male subjects in a crossover design. During each 48-hour baseline period, no foods containing glucosinolates or ITCs were allowed. The subjects then consumed 200 g of fresh or steamed broccoli; all other dietary sources of ITCs were excluded. Blood and urine samples were collected during the 24-hour period after broccoli consumption. Total ITC equivalents in broccoli and total ITC equivalents in plasma and urine were assayed by high-performance liquid chromatography as the cyclocondensation product of 1,2-benzenedithiol. The content of ITCs in fresh and steamed broccoli after myrosinase treatment was found to be virtually identical (1.1 vs. 1.0 mu mol/g wet wt). The average 24-hour urinary excretion of ITC equivalents amounted to 32.3 +/- 12.7% and 10.2 +/- 5.9% of the amounts ingested for fresh and steamed broccoli, respectively. Approximately 40% of total ITC equivalents in urine, 25.8 +/- 13.9 and 6.9 +/- 2.5 mu mol for fresh and steamed broccoli, respectively, occurred as the N-acetyl-L-cysteine conjugate of sulforaphane (SFN-NAC). Total ITC metabolites in plasma peaked between 0 and 8 hours, whereas urinary excretion of total ITC equivalents and SFN-NAC occurred primarily between 2 and 12 hours. Results of this study indicate that the bioavailability of ITCs from fresh broccoli is approximately three times greater than that from cooked broccoli, in which myrosinase is inactivated. Considering the cancer-chemopreventive potential of ITCs, cooking broccoli may markedly reduce its beneficial effects on health
— id: 54947, year: 2000, vol: 38, page: 168, stat: Journal Article,

Proteasome inhibition by PS-341: A phase I study
Hamilton, A; Eder, JP; Pavlick, A; Clark, JW; Chachoua, A; Ryan, DP; Farrell, K; Wasserstrom, H; Liebes, L; Wright, J; Elliott, P; Adams, J; Muggia, F
2000 NOV ;6(6):4549S-4549S, Clinical cancer research
— id: 54445, year: 2000, vol: 6, page: 4549S, stat: Journal Article,

Intraperitoneal topoisomerase-I inhibitors. Preliminary findings with 9-aminocamptothecin
Muggia F; Liebes L; Potmesil M; Hamilton A; Hochster H; Hornreich G; Sorich J; Downey A; Wasserstrom H
2000 ;922(1):178-187, Annals of the New York Academy of Sciences
The i.p. administration of topoisomerase I (Topo I) inhibitors has a pharmacologic advantage over intravenous application, including preservation of the biologically active lactone form. In our ongoing study, patients have received 9-amino-20(S)-camptothecin (9-AC) i.p. on days 1, 3, 5, 8, 10, and 12, repeated every 4 weeks. The daily dose has been escalated to level IV of 1.5 mg/m2 (9.0 mg/m2 per course), median of 3 cycles, range 1-4, with a reversible Grade 3 neutropenia in one patient. Responses included one CR (resolution of a pleural effusion), two patients without progressive disease (PD), two not evaluable, and two patients too early for evaluation. The area under the curve (AUC)i.p./AUCpl ratio (pharmacologic advantage) ranged from 7.6 to 16.5 on average, and, using nonlinear modeling, the pharmacologic decay data were fit to one- or two-compartmental models. Overall, a 9-AC i.p. application is well tolerated and anticipated to be an active regimen against i.p. malignancies, particularly those known to be sensitive to systemic Topo-I inhibitors
— id: 39489, year: 2000, vol: 922, page: 178, stat: Journal Article,

Effect of the proteasome inhibitor PS-341 on cell cycle progression and bcl-2: A potentially unique mechanism of action
Perez-Soler, R; Ling, YH; Ng, B; Adams, J; Elliott, P; Liebes, L
2000 NOV ;6(6):4549S-4549S, Clinical cancer research
— id: 54444, year: 2000, vol: 6, page: 4549S, stat: Journal Article,

Strategies for evaluation of enveloped virus inactivation in red cell concentrates using hypericin
Prince AM; Pascual D; Meruelo D; Liebes L; Mazur Y; Dubovi E; Mandel M; Lavie G
2000 Feb;71(2):188-195, Photochemistry & photobiology
Photodynamically induced virus inactivation appears promising in preventing transmission of enveloped virus infections in transfusible blood products. The potential for utilizing hypericin as a photosensitizer to inactivate key enveloped viruses in packed red cell concentrates (PRC) was evaluated. In addition to inactivating effectively > or = 10(6) TCID50 of human immunodeficiency virus (HIV), inactivation of bovine viral diarrhea virus (BVDV) in PRC was used as a model for hepatitis C virus to overcome the deficiency in reliable experimental systems for hepatitis C virus (HCV) inactivation. BVDV was two orders of magnitude more sensitive to inactivation by hypericin than HIV. As part of the virucidal efficacy analyses, the effects of photosensitization on hemopoietic cell lines carrying quiescent integrated HIV provirus were studied as models for evaluating virus inactivation in latently infected cells. Phorbol ester-induced virus production by these cells was effectively prevented by photosensitization with hypericin. A refinement of the illumination conditions, incorporating a monochromatic sodium light source with an emission spectrum coinciding with the absorption peak of hypericin, was highly virucidal, however, caused unacceptable levels of hemolysis. Red blood cells could be protected from phototoxic cellular damage by complexing hypericin with human serum albumin (albumin-hypericin), but the decrease in hemolysis was at the expense of virucidal efficacy. Thus, excitation of hypericin with a fluorescent source appears to be useful potentially for virus inactivation in PRC
— id: 57560, year: 2000, vol: 71, page: 188, stat: Journal Article,

Disposition and pharmacokinetics of phenethyl isothiocyanate and 6-phenylhexyl isothiocyanate in F344 rats
Conaway CC; Jiao D; Kohri T; Liebes L; Chung FL
1999 Jan;27(1):13-20, Drug metabolism & disposition
Naturally occurring phenethyl isothiocyanate (PEITC) and its synthetic homolog 6-phenylhexyl isothiocyanate (PHITC) are both effective inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor development in A/J mice and F344 rats. To help explain why PHITC is considerably more efficacious than PEITC in chemopreventive potency, comparative disposition and pharmacokinetics data for male F344 rats were obtained after a single gavage dose of 50 micromol/kg (3.71 microCi/micromol) [14C]PEITC or 50 micromol/kg (6.59 microCi/micromol) [14C]PHITC in corn oil. After [14C]PEITC dosing, whole blood 14C peaked at 2.9 h, with an elimination half-life (T1/2e) of 21.7 h; blood 14C from [14C]PHITC-treated rats peaked at 8.9 h, with an T1/2e of 20.5 h. In lungs, the target organ, the T1/2e for [14C]PHITC and its labeled metabolites were more than twice that for [14C]PEITC and its labeled metabolites. The effective dose (area under the concentration-time curve) for 14C from PHITC was greater than 2.5 times the area under the concentration-time curve of 14C from PEITC in liver, lungs, and several other tissues. During 48 h, approximately 16.5% of the administered dose of [14C]PHITC was expired as [14C]CO2, more than 100 times the [14C]CO2 expired by rats treated with [14C]PEITC. In rats given [14C]PEITC, 88.7 +/- 2.2% and 9.9 +/- 1.9% of the dose appeared in the urine and feces, respectively, during 48 h; however, rats given [14C]PHITC excreted 7.2 +/- 0.8% of the dose of 14C in urine and 47.4 +/- 14.0% in the feces. Higher effective doses of PHITC in the lungs and other organs may be the basis, in part, for its greater potency as a chemopreventive agent
— id: 7316, year: 1999, vol: 27, page: 13, stat: Journal Article,

Phase I studies of hypericin, the active compound in St. John's Wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258
Gulick RM; McAuliffe V; Holden-Wiltse J; Crumpacker C; Liebes L; Stein DS; Meehan P; Hussey S; Forcht J; Valentine FT
1999 Mar 16;130(6):510-514, Annals of internal medicine
BACKGROUND: Hypericin, the active compound in St. John's Wort, has antiretroviral activity in vitro. Many HIV-infected persons use St. John's wort. OBJECTIVE: To evaluate the safety and antiretroviral activity of hypericin in HIV-infected patients. DESIGN: Phase I study. SETTING: Four clinical research units. PATIENTS: 30 HIV-infected patients with CD4 counts less than 350 cells/mm3. INTERVENTION: Intravenous hypericin, 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin, 0.5 mg/kg daily. MEASUREMENTS: Safety was assessed at weekly visits. Antiretroviral activity was assessed by changes in HIV p24 antigen level, HIV titer, HIV RNA copies, and CD4 cell counts. RESULTS: Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48% [95% CI, 27% to 69%]) evaluable patients, and dose escalation could not be completed. Virologic markers and CD4 cell count did not significantly change. CONCLUSIONS: Hypericin caused significant phototoxicity and had no antiretroviral activity in the limited number of patients studied
— id: 6055, year: 1999, vol: 130, page: 510, stat: Journal Article,

Activity and pharmacodynamics of 21-Day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy. New York Gynecologic Oncology Group
Hochster H; Wadler S; Runowicz C; Liebes L; Cohen H; Wallach R; Sorich J; Taubes B; Speyer J
1999 Aug;17(8):2553-2561, Journal of clinical oncology
PURPOSE: Twenty-one-day topotecan infusion was administered as second-line therapy in patients with previously treated ovarian cancer (based on our prior favorable phase I experience) to determine its activity, time to progression, and pharmacodynamics. PATIENTS AND METHODS: Ovarian cancer patients with measurable lesions and one prior platinum-containing regimen were eligible. Topotecan 0.4 mg/m(2)/d 21-day continuous ambulatory intravenous infusion, with appropriate dose modifications for toxicity, was administered every 28 days. Weekly blood levels of topotecan and topoisomerase-1 (topo-1) levels in peripheral-blood mononuclear cells (PBMCs) were determined for pharmacodynamic correlation. RESULTS: Twenty-four patients were entered onto the study (six cisplatin-refractory, five relapsing within < 6 months and 13 relapsing > 6 months after platinum-based therapy). A total of 128 cycles of topotecan (median, four cycles per patient; range, one to 12 cycles) were administered. The major toxicity was neutropenia (29% grade 3 in all cycles and 4% grade 4). One episode of grade 4 thrombocytopenia (4%) occurred. Fifty-two percent of the patients had anemia that required transfusions. Eight of 23 patients with measurable disease (35%; 95% confidence interval [CI], 15% to 54%) had partial responses (PRs) lasting longer than 1 month. Two of these patients had minor residual computed tomographic changes but had clinical complete remissions that lasted up to 53 weeks while they were not undergoing further therapy. One patient with nonmeasurable disease had a PR (by CA-125 criteria) that lasted 6 months, for an overall response rate of 38% in nine of 24 patients (95% CI, 18% to 57%). The median time to progression was 26 weeks. Pharmacodynamic analysis demonstrated a statistically significant decrease in free PBMC topo-1 level at weeks 2 and 3 of drug administration. There was a strong statistical correlation between the decrease in free topo-1 levels and increasing area under the curve (AUC) for topotecan. This was confirmed in a pharmacodynamic model. CONCLUSION: Twenty-one-day infusion is a well-tolerated method of administering topotecan. Pharmacodynamic studies demonstrate correlations between (1) the week of infusion and the PBMC topo-1 level, (2) the AUC of topotecan and the decrease in topo-1 levels, and (3) the change in topo-1 level and the neutrophil nadir. The objective response rate of 35% to 38% (95% CI, 15% to 57%) in this small multicenter study is at the upper level for topotecan therapy in previously treated ovarian cancer. Prolonged topotecan administration therefore warrants further investigation in larger, randomized studies comparing this 21-day schedule with the once-daily-for-5-days schedule
— id: 11932, year: 1999, vol: 17, page: 2553, stat: Journal Article,

Clinical pharmacodynamics of topoisomerase-1 inhibitor therapy: lessons and issues for future studies
Hochster, H; Liebes, L; Wadler, S; Runowicz, C; Potmesil, M; Speyer, J; Muggia, F
1999 NOV ;5(4):3775S-3776S, Clinical cancer research
— id: 53799, year: 1999, vol: 5, page: 3775S, stat: Journal Article,

Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer
Sparano JA; Speyer J; Gradishar WJ; Liebes L; Sridhara R; Mendoza S; Fry D; Egorin MJ
1999 Mar;17(3):880-886, Journal of clinical oncology
PURPOSE: To determine the maximum-tolerable dose (MTD) of paclitaxel given as a 3-hour intravenous (IV) infusion that could be used in conjunction with doxorubicin and dexrazoxane, and to determine the effect of dexrazoxane on the pharmacokinetics of paclitaxel and doxorubicin. PATIENTS AND METHODS: Twenty-five patients with advanced breast cancer received dexrazoxane (600 mg/m2 by IV infusion over 15 minutes), followed 15 minutes later by doxorubicin (60 mg/m2 IV), followed 15 minutes later by paclitaxel (150 or 175 mg/m2 by IV infusion over 3 hours) in cohorts of three to six patients using a standard phase I design without (group A) and with (group B) granulocyte colony-stimulating factor (G-CSF). Treatment continued until there was a substantial decrease in the left ventricular ejection fraction (LVEF), congestive heart failure, progressive disease, or physician discretion to discontinue. RESULTS: The MTD of paclitaxel was 150 mg/m2, and adjunctive therapy with G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no significant effect on the pharmacokinetics of paclitaxel or doxorubicin. After a median cumulative doxorubicin dose of 360 mg/m2 (range, 60 to 870 mg/m2), no patient developed congestive heart failure or had a decrease in LVEF below normal. An objective response occurred in all five patients with locally advanced breast cancer and in eight of 20 patients (40%; 95% confidence interval, 19% to 61%) with metastatic breast cancer. CONCLUSION: When combined with doxorubicin (60 mg/m2) and dexrazoxane (600 mg/m2), paclitaxel given as a 3-hour infusion had an MTD of 150 mg/m2, and G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no effect on the pharmacokinetics of paclitaxel or doxorubicin. No patient in this trial had a decrease in the LVEF below normal, compared with about 20% to 50% of patients treated with doxorubicin and paclitaxel without dexrazoxane in other trials
— id: 7452, year: 1999, vol: 17, page: 880, stat: Journal Article,

Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer
Kramer EL; Liebes L; Wasserheit C; Noz ME; Blank EW; Zabalegui A; Melamed J; Furmanski P; Peterson JA; Ceriani RL
1998 Jul;4(7):1679-1688, Clinical cancer research
To evaluate radiometal-labeled humanized BrE-3 (huBrE-3) monoclonal antibody as a radioimmunolocalization and therapeutic agent in breast cancer patients, tumor localization, pharmacokinetics, radiation dosimetry, and immunogenicity of (111)In-labeled combined 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyldiethylenetriamine pentaacetic acid (MX-DTPA) huBrE-3 were studied. Seven women with BrE-3 antigen-positive, metastatic breast carcinoma underwent (111)In huBrE-3 infusion (5 mCi; 50 mg), followed by serial gamma camera imaging and plasma sampling. Region of interest analysis of images was used to make radiation absorbed dose estimates for (111)In huBrE-3. Data were extrapolated to 90Y huBrE-3. Human anti-human antibody (HAHA) response was measured in serum samples obtained up to 3 months after infusion. Patients tolerated infusions well. Seventy-six percent of 105 known sites of disease were identified on planar and single-photon emission computed tomography scans. For six of seven patients, a biexponential model fit the plasma time-activity curve best with an average T1/2alpha=10.6+/-8.5 (SD) h and average T1/2beta=114.2+/-39.2 h. Radiation absorbed dose estimates for (111)In huBrE-3 for whole body averaged 0.53+/-.08 rads/mCi. Dose estimates for 90Y huBrE-3 for marrow averaged 8.4+/-11.9 rads/mCi, and for tumors, 70+/-31.5 rads/mCi. Liver radioactivity uptake averaged 19.7+/-8.8% injected dose at 24 h after infusion, translating into an average radiation absorbed dose 21.1+/-12 rads/90Y mCi administered. Only one of seven patients demonstrated a low level of HAHA response. Although the plasma half-lives are longer and marrow dose higher for radiolabeled huBrE-3 compared with the murine construct, the excellent tumor localization, good tumor dosimetry, and low immunogenicity support the use of 90Y-huBrE-3 antibody for radioimmunotherapy of breast cancer
— id: 7634, year: 1998, vol: 4, page: 1679, stat: Journal Article,

Pharmacodynamics of topoisomerase I inhibition: Western blot determination of topoisomerase I and cleavable complex in patients with upper gastrointestinal malignancies treated with topotecan
Liebes L; Potmesil M; Kim T; Pease D; Buckley M; Fry D; Cho J; Adler H; Dar K; Zeleniuch-Jacquotte A; Hochster H
1998 Mar;4(3):545-557, Clinical cancer research
Analogues of camptothecins are specific inhibitors of eukaryotic DNA topoisomerase I (topo I) that lead to DNA damage and, eventually, cellular cytotoxicity. Camptothecin analogues bind to this target enzyme in the course of its normal function and stabilize the DNA-enzyme adduct to form a 'cleavable complex.' Preclinical experiments using Western blot analyses have shown cleavable complex formation to be the key intermediate step in topo I inhibition. In this series of experiments, it was our goal to convert this laboratory technique into a useful clinical assay, allowing measurement of the target enzyme and detection of the key intermediate in clinical specimens taken from patients being treated with the topo I inhibitor topotecan. Because available antibodies were not sufficiently sensitive at the start of this project, we identified a highly specific human SCL-70 antibody from a patient with scleroderma, which allowed quantitative determination of topo I copy number in HeLa and HT-29 cell lines. Additional refinements of the Western blot technique were accomplished to improve signal:noise ratio. In surgical tumor specimens, we found the median topo I level to be 30.1 x 10(5) copies/cell for gastric adenocarcinomas, compared to 18.4 x 10(5) copies/cell for normal gastric mucosae in the same samples. For lung adenocarcinoma, the median protein level was 21.5 x 10(5) copies/cell, compared with the normal tissue counterpart protein level of 12.7 x 10(5) copies/cell. The median tumor:normal ratios from paired samples of these tumor types were 1.51 and 1.84, respectively. As part of a Phase II study evaluating the efficacy of topotecan (1.5-2.0 mg/m2 daily for 5 days) in upper gastrointestinal malignancies, we obtained tumor and normal mucosa biopsies in 11 patients with gastric or esophageal cancer, 30 min after administration on day 4 or 5. Three patients with gastric adenocarcinoma had stable disease as their best response, with the remainder of patients progressing. Improvement in Western blotting methodology allowed the quantitation of topo I levels in these gastric and esophageal cancer biopsies, which could be augmented by brief heating to release complexed topo I. We were also able to directly visualize high molecular weight topo I-containing bands, which were shown to be cleavable complexes by heat reversal, with restoration of the topo I Mr 100,000 band. Using this heat reversal technique, we determined the presence of cleavable complex in a total of 7 of 11 patient biopsy samples (5 tumors and 2 normal mucosae). In patients treated with topotecan on this dose and schedule, we determined that a median of 73% of the total tumor topo I was involved in cleavable complex (range, 18.3-91%). The intensity of the Mr 100,000 topo I band in biopsy specimens of patients receiving topotecan represented 'free' or noncomplexed topo I. The median copy number for the residual, noncomplexed topo I (n = 11) was 7.36 x 10(5) copies/cell, significantly less than the median of 30.1 x 10(5) copies/cell for random tumor specimens from patients with gastric adenocarcinomas (P < 0.001). Pharmacodynamic analysis demonstrated a negative correlation between the noncomplexed topo I copy number and topotecan area under the curve (Spearman rank test: r(s) = -0.81, P = 0.003). Nonlinear regression analyses of these data were best fit with an inhibitory maximum effect model, yielding parameter estimates for Emax and EC50 of 29.3 x 10(5) copies/cell (coefficient of variation = 22%) and 43.1 ng x h/ml (coefficient of variation = 27%), respectively. Through a series of careful modifications and refinements, we have improved the Western blot assay for topo I for use in clinical monitoring. We have demonstrated the ability to directly visualize cleavable complex in patients being treated with topo I inhibitor therapy and have directly quantitated free topo I, as well as the key topo I intermediate (cleavable complex), in biopsy specimens obtained from pat
— id: 57194, year: 1998, vol: 4, page: 545, stat: Journal Article,

Biologic activity of interleukin 1 (IL-1) alpha in patients with refractory malignancies
Rosenthal MA; Dennis D; Liebes L; Furmanski P; Caron D; Garrison L; Wiprovnick J; Peace D; Oratz R; Speyer J; Chachoua A
1998 Sep;21(5):371-378, Journal of immunotherapy
Interleukin 1 alpha (IL-1 alpha) is a cytokine with pleiotropic effects, including cytotoxic-cytostatic activity against some tumor cell lines. We have conducted a phase I study of recombinant human IL-1 alpha (rhIL-1 alpha) in 17 patients with refractory malignancies to examine its toxicity and biologic activity. rhIL-1 alpha was given as a 2-h IV infusion daily for 5 days at five dose levels (0.08, 0.2, 0.8, 2.0, and 5.0 micrograms/m2). Seventeen patients with malignancies were treated, with no objective tumor responses noted. Common toxicities included: fever (100%), rigors and/or chills (96%), myalgia (54%), and headache (48%). Three patients developed grade III hypotension. The maximum tolerated dose was 2.0 micrograms/m2. rhIL-1 alpha induced a significant increase in absolute neutrophil count over baseline (p < 0.05), a delayed but significant increase in platelet count over baseline (p < 0.05), and there was a marked increase in the number of progenitors [colony-forming units (CFU)-G, CFU-M, CFU-GM, CFU-GEMM and burst-forming units (BFU-E)] observed in the peripheral blood. Nine of 12 evaluable patients showed an increase in bone marrow cellularity or myeloid:erthyroid ratio. Immunophenotyping did not demonstrate an increase in peripheral blood or bone marrow CD34+ cells. Interferon-gamma-mediated monocyte cytotoxicity (MCCTX) was significantly enhanced from baseline (p < 0.001), although an increase in direct MCCTX did not reach statistical significance. In summary, rhIL-1 alpha administration is well tolerated at a dose of 2.0 micrograms/m2 with fever, rigors, myalgia, and headache being the most frequent toxicities. Although there were no objective tumor responses, we have demonstrated significant biologic activity with increased neutrophil and platelet counts, increased peripheral blood progenitor cells, and enhanced interferon-gamma-mediated MCCTX
— id: 7436, year: 1998, vol: 21, page: 371, stat: Journal Article,

Phase II study of 21-day topotecan continuous infusion for metastatic colorectal cancer (ECOG study 4293)
Hochster H; Hibrahim J; Liebes L; O'Dwyer P; Benson A 3rd
1997 ;16:A1032-A1032, Proceedings (American Society of Clinical Oncology)
Topotecan (TPT), a topoisomerase-1 inhibitor, may have greater therapeutic index when given by prolonged infusion. Pre-clinical studies have shown activity of camptothecin analogs in colon xenografts. The phase I trial of escalating low-dose infusion found the MTD = 0.53 mg/m2/d x 21d for previously treated pts (JCO; 12:553 1994). Eligibility included no prior chemotherapy, measurable disease, PS 0-1, normal heme parameters and Creat less than 1.6. 26 pts enrolled included 15 male and 11 female; 20 caucasian, 3 black, 3 Hispanic; median age = 61 yrs (range 39-77). 19 pts presented with Duke's stage D and 7 stage C (3 with prior adjuvant rx more than 6 months prior). PS was 0 (19 pts) and 1 (6). All pts began rx at 0.5 mg/m2/day and were escalated until grade 2 or higher toxicity. 73 cycles were given: 40 cycles at 0.5 mg/m2/d; 14 pts were escalated to 0.6 (17 cycles), 2 pts to 0.7 (5 cycles), and 6 were reduced to 0.4 (11 cycles). Median nadir cts (range) for the first cycle were: WBC 4.8 (0.8-7.8), ANC 3185 (71-5187), and plt 203 (10-307). Worst toxicity in all courses (grade 3/4) included: Leukopenia 3/2; Neutropenia 3/6; Thrombopenia 5/1 and anemia 11/0. Non-heme tox included grade 3 tox: Infection = 1; nausea = 1; phlebitis =1; diarrhea = 1 and GU 1 grade 4; no catheter related complications occurred. Responses included 2 PR, 4 SD, 16 PD and 4 NE (completed 1 or more cycle). Overall response rate is 2 PR/22 evaluable = 9% (95% CI =1-29%) or 2/26 entered (RR = 8%, CI = 0.9-25%). One response with lung nodules was unconfirmed with follow-up. Mean (+/- Std Dev) total topotecan level was 3.4+/- 1.0 ng/ml at 0.5 mg/m2 (n = 11), 6.1 +/- 1.7 at 0.6 (n = 6). Weekly PBMC topo-1 levels were obtained for pharmacodynamics (n = 14 cycles) showing med. 4.4 x 10(5) copies/cell baseline and med 30%, 83% and 60% reduction weeks 1, 2 and 3. This response rate is similar to reports by Verwiej et al showing a low level of TPT activity in previously untreated colon ca and suggests a potential for combination therapy at a dose of 0.5 mg/m2/day, given lack of GI and hematologic side effects. (C) American Society of Clinical Oncology 1997
— id: 6027, year: 1997, vol: 16, page: A1032, stat: Journal Article,

Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study
Hochster H; Liebes L; Speyer J; Sorich J; Taubes B; Oratz R; Wernz J; Chachoua A; Blum RH; Zeleniuch-Jacquotte A
1997 Aug;3(8):1245-1252, Clinical cancer research
Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming 'cleavable complex,' a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 'free' topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of </=20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy
— id: 56951, year: 1997, vol: 3, page: 1245, stat: Journal Article,

Localization of In-111 MX-DTPA humanized BRE-3 mab in patients with advanced breast cancer
Kramer, EL; Liebes, L; Wasserheit, C; Blank, E; Noz, M; Dosik, D; Mizrachi, H; Kim, T; Fry, D; Zabalegui, A; Sanger, J; Ceriani, R; Peterson, J; Furmanski, P
1996 MAY ;37(5):739-739, Journal of nuclear medicine
— id: 52891, year: 1996, vol: 37, page: 739, stat: Journal Article,

9-Aminocamptothecin and beyond. Preclinical and clinical studies
Potmesil M; Arbuck SG; Takimoto CH; Liebes L; Hochster H
1996 Dec 13;803:231-246, Annals of the New York Academy of Sciences
— id: 12448, year: 1996, vol: 803, page: 231, stat: Journal Article,

Drug delivery during pregnancy: evaluation in vitro of new drugs
Dancis J; Liebes L
1995 ;7(6):1485-1489, Reproduction, fertility & development
Indications for the treatment of the pregnant woman fall into three general categories: mother and infant require treatment, only the mother should be treated, or only the infant. Directing therapy towards the affected subject is an important aspect of good care, although it is not the only one. It is argued that a rational selection of the appropriate drug can be made without endangering mother or infant, with the aid of select laboratory investigations, including placental perfusion, and a knowledge of placental physiology. Examples are presented to support this contention. The intra-amniotic administration of drugs is briefly discussed. A plea is made to develop drugs that are designed specifically for use during pregnancy
— id: 12825, year: 1995, vol: 7, page: 1485, stat: Journal Article,

Hypericin as an inactivator of infectious viruses in blood components
Lavie G; Mazur Y; Lavie D; Prince AM; Pascual D; Liebes L; Levin B; Meruelo D
1995 May;35(5):392-400, Transfusion
BACKGROUND: Hypericin is a potent virucidal agent with activity against a broad range of enveloped viruses and retroviruses. The effective virucidal activity emanates from a combination of photodynamic and lipophilic properties. Hypericin binds cell membranes (and, by inference, virus membranes) and crosslinks virus capsid proteins. This action results in a loss of infectivity and an inability to retrieve the reverse transcriptase enzymatic activity from the virion. STUDY DESIGN AND METHODS: Since hypericin is devoid of adverse action in most blood components and blood analyses, it is investigated as an additive with potential to inactivate infective viruses in blood components intended for transfusion. RESULTS: Complete inactivation of 10(6) tissue culture-infective doses of human immunodeficiency virus was obtained in whole blood and in diluted packed red cells after illumination with fluorescent light for 1 hour. Loss of viral infectivity to cultured CEM cells has been monitored by use of a detection assay for human immunodeficiency virus p55 in enzyme-linked immunosorbent assay and cytopathic assays. In physiologic media, hypericin interacts with albumin and lipoproteins, retaining the virucidal activity in bound form. The molecule is negatively charged and forms organic and inorganic monobasic salts (ion pairs) in physiologic pH. Various ion pairs differ in virucidal efficacy. CONCLUSION: The apparent transfusibility of hypericin, taken together with the efficacy of the virucidal activity, the broad range of enveloped viruses affected, and the absence of adverse effects on stored red cells, may render hypericin useful for inactivation of infectious viruses in red cells
— id: 56669, year: 1995, vol: 35, page: 392, stat: Journal Article,

Monocyte activation following systemic administration of granulocyte-macrophage colony-stimulating factor
Chachoua A; Oratz R; Hoogmoed R; Caron D; Peace D; Liebes L; Blum RH; Vilcek J
1994 Apr;15(3):217-224, Journal of immunotherapy with emphasis on tumor immunology
Twenty-four patients with solid malignancies were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) on a Phase 1b trial. The objective of the study was to evaluate the effects of GM-CSF on peripheral blood monocyte activation. GM-CSF was administered by subcutaneous injection daily for 14 days. Immune parameters measured were monocyte cytotoxicity against the human colon carcinoma (HT29) cell line, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and in vitro TNF-alpha and IL-1 beta induction. All patients were evaluable for toxicity. Fifteen patients were evaluable for immunologic response. Treatment with GM-CSF led to a statistically significant enhancement in direct monocyte cytotoxicity against HT29 cells. There was no increase in serum TNF-alpha or IL-1 beta and no consistent in vitro induction of TNF-alpha or IL-1 beta from monocytes posttreatment. Treatment was well tolerated overall. We conclude that treatment with GM-CSF can lead to enhanced monocyte cytotoxicity. Further studies are in progress to evaluate the effect of GM-CSF on other parameters of monocyte functions
— id: 12982, year: 1994, vol: 15, page: 217, stat: Journal Article,

Phase Ib trial of granulocyte-macrophage colony-stimulating factor combined with murine monoclonal antibody R24 in patients with metastatic melanoma
Chachoua A; Oratz R; Liebes L; Alter RS; Felice A; Peace D; Vilcek J; Blum RH
1994 Aug;16(2):132-141, Journal of immunotherapy with emphasis on tumor immunology
R24, a murine monoclonal antibody, has been shown to mediate complement- and antibody-dependent cellular cytotoxicity (ADCC) of melanoma tumor targets. We conducted a Phase Ib clinical trial using granulocyte-macrophage colony-stimulating factor (GM-CSF) and R24 in 20 patients with metastatic melanoma. The purpose of this study was to test the hypothesis that treatment with GM-CSF could up-regulate monocyte and granulocyte ADCC and that the combination of GM-CSF plus R24, which mediates ADCC, would lead to enhanced anti-tumor activity in patients with melanoma. GM-CSF was administered by subcutaneous injection daily for 21 days at a dose of 150 micrograms/m2/day. R24 was administered by continuous intravenous infusion on days 8-15 at three dose levels: 0, 10, and 50 mg/m2/day. All 20 patients received one cycle of treatment only. Immune parameters measured were monocyte and granulocyte direct cytotoxicity and ADCC. All patients were evaluable for toxicity. Fifteen patients were evaluable for immune response. Treatment with GM-CSF alone was well tolerated. Toxicity from the combination of GM-CSF plus R24 included diffuse urticaria, nausea and vomiting, hypertension, and hypotension. Hypotension was the dose-limiting toxicity. Two patients on the 50-mg/m2/day dose level of R24 achieved a partial response lasting 2+ and 5+ months. Treatment with GM-CSF led to a statistically significant enhancement of monocyte and granulocyte direct cytotoxicity and ADCC. The maximally tolerated dose of R24 given at this schedule combined with GM-CSF is < 50 mg/m2/day. We conclude that GM-CSF given by subcutaneous injection at 150 micrograms/m2 x 21 days can enhance effector cell ADCC and direct cytotoxicity and that the combination of GM-CSF and R24 can be therapeutic
— id: 6590, year: 1994, vol: 16, page: 132, stat: Journal Article,

Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen
Hochster H; Liebes L; Speyer J; Sorich J; Taubes B; Oratz R; Wernz J; Chachoua A; Raphael B; Vinci RZ
1994 Mar;12(3):553-559, Journal of clinical oncology
PURPOSE: The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS: Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS: The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION: Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer
— id: 6404, year: 1994, vol: 12, page: 553, stat: Journal Article,

Radioimmunolocalization of breast cancer using BrE-3 monoclonal antibody
Kramer EL; DeNardo SJ; Liebes L; Noz ME; Kroger L; Glenn SD; Furmanski P; Ceriani R
1994 ;353:181-192, Advances in experimental medicine & biology
— id: 6665, year: 1994, vol: 353, page: 181, stat: Journal Article,

Radioimmunodetection of non-small cell lung cancer using technetium-99m-anticarcinoembryonic antigen IMMU-4 Fab' fragment. Preliminary results
Kramer EL; Noz ME; Liebes L; Murthy S; Tiu S; Goldenberg DM
1994 Feb 1;73(3 Suppl):890-895, Cancer
BACKGROUND. Although computed tomography and magnetic resonance imaging have improved the staging and evaluation of non-small cell lung cancer (NSCLC), mediastinal staging lacks adequate specificity and sensitivity. Radioimmunodetection may augment computed tomography and magnetic resonance imaging. The authors evaluated the ability of the technetium 99m-anticarcinoembryonic antigen IMMU-4 Fab' fragment to localize NSCLC in vivo, measured its pharmacokinetics, and estimated its radiation dose. METHODS. Seventeen patients with carcinoembryonic antigen-positive NSCLC received 16-30 mCi of technetium 99m IMMU-4 Fab'. Planar imaging was performed at 1-7 hours and 20-24 hours. Single-photon emission computed tomography (SPECT) was performed within 8 hours after injection. In 10 patients, blood sampling, urine collection, and quantitative imaging were performed to determine blood and urine pharmacokinetics and radiation dose estimates. Human anti-mouse antibody response was measured for as long as 3 months after administration. RESULTS. Planar and/or SPECT imaging detected 72% of 32 known lesions. SPECT was more sensitive than planar imaging. T1/2 alpha averaged 0.18 +/- 0.33 hours; T1/2 beta averaged 8.02 +/- 5.53 hours. The mean concentration versus time value was 1.11 +/- 0.56 mg.h. The average whole body dose estimated for administration of 30 mCi was 0.45 +/- 0.08 rads. No human anti-mouse antibody responses were detected. CONCLUSION. The tumor detection rate was high, but the persistent blood pool at < 8 hours complicated image interpretation. An intermediate imaging time point (12-16 hours) might be preferable. SPECT is an important adjunct to imaging with this radioimmunoconjugate. The acceptable dosimetry estimated for 30 mCi Technetium 99m IMMU-4 Fab' and the lack of human anti-mouse antibody responses suggest this is a promising localizing tool for NSCLC
— id: 6427, year: 1994, vol: 73, page: 890, stat: Journal Article,

Analysis of the antimetastatic effects of synthetic muramyl tripeptide (CGP 19835A) encapsulated in liposomes in combination with other immunomodulatory agents and chemotherapeutic drugs
Bezault J; Walsh C; Tarcsay L; Frost H; Liebes L; Furmanski P
1993 Nov-Dec;7(6A):487-491, In vivo
The synthetic molecule muramyl tripeptide (CGP 19835A) encapsulated in liposomes is effective in increasing the survival of mice with spontaneous experimental lung metastases induced by the RENCA renal adenocarcinoma and B16 melanoma tumor models. The present study was aimed at extending the effects of CGP 19835A to another highly metastatic carcinoma model and at evaluating the efficacy of combination therapy with standard cytotoxic agents and other immunomodulators. C57BL/6 mice received whole tumor implants of PancO2, a spontaneously metastasizing pancreatic adenocarcinoma, subcutaneously in the hind leg. Therapeutic effects were measured by increased survival which is a direct function of the growth of spontaneous lung metastases in this system. No therapeutic efficacy was observed with CGP 19835A alone or in combination with any of a series of cytotoxic or biological agents, including cis-platinurn (cis-Pt), mitomycin C (MMC), adriamycin (ADR), cyclophosphamide (CP), interferon gamma (IFN gamma), and interleukin 2 (IL-2). In accord with previous studies, when the B16-F10 melanoma was used as an experimental metastatic tumor model, CGP 19835A, alone and in combination with CP, significantly reduced the number of pulmonary metastases. Cis-Pt, however, partially negated the effects of CGP 19835A when a combination of the two agents was used. The results indicate that CGP 19835A is an effective therapeutic agent in some models of spontaneous or experimental lung metastases, but not others, and that the effects of CGP 19835A are not enhanced by the accompanying cytotoxic drugs tested here
— id: 10178, year: 1993, vol: 7, page: 487, stat: Journal Article,

Nucleoside transport by perfused human placenta
Dancis J; Lee J; Mendoza S; Liebes L
1993 Sep-Oct;14(5):547-554, Placenta
Nucleoside transport and metabolism by human placenta was studied using the dual perfusion technique. With [3H] thymidine added to the maternal perfusate and neither perfusate recirculated (steady-state studies) around 40 per cent of the thymidine in the maternal outflow and 50 per cent of the transferred thymidine was degraded. In similar studies with adenosine, over 95 per cent of the nucleoside was degraded. Even with the bolus technique which sharply limits the duration of contact with the placenta, degradation of adenosine was over 95 per cent. Uptake as calculated by the dual-tracer method ([3H] adenosine/[14C] L-glucose) was equally rapid from the maternal and fetal perfusates, was saturable and inhibited by nitrosobenzylthioinosine, consistent with the facilitated diffusion system for nucleosides. Thymidine was taken up at one-third the rate of adenosine. Thymidine in large excess (500 microM) reduced adenosine uptake suggesting a common transporter. Zidovudine, a thymidine analogue used for the treatment of AIDS in which the ribose is modified at the 2' 3' position, did not compete with adenosine for uptake consistent with previous reports that zidovudine is transferred across the placenta by simple diffusion
— id: 6352, year: 1993, vol: 14, page: 547, stat: Journal Article,

Transfer and metabolism of dideoxyinosine by the perfused human placenta
Dancis J; Lee JD; Mendoza S; Liebes L
1993 Jan;6(1):2-6, Journal of acquired immune deficiency syndrome
Dideoxyinosine (DDI) has been recently approved for the treatment of AIDS. In anticipation of its use in HIV-infected women during pregnancy, the transfer and metabolism of DDI by the perfused human placenta have been investigated. Transfer characteristics are those of simple diffusion: clearance is the same as that for L-glucose (transfer index of 0.98 +/- 0.09), it is equivalent in both directions across the placenta, and the transfer rate is proportional to the transplacental gradient over a very broad range (1 to 500 microM). Because of extensive placental metabolism, only about one-half of the cleared DDI (51 +/- 21%) is transferred intact to the fetal circulation. No dideoxyadenine triphosphate, the antiviral product of DDI, could be detected in the placenta following perfusion. Comparison of the pharmacological information on DDI and zidovudine (ZDV) indicates that treatment of HIV-infected women during pregnancy with DDI will expose the fetus to much less drug than if ZDV were used. DDI may therefore be less effective than ZDV in the treatment of the infected fetus. However, the uninfected fetus of an HIV-infected woman will gain by reduced exposure to a drug that is known to be toxic
— id: 13310, year: 1993, vol: 6, page: 2, stat: Journal Article,

Radioimmunolocalization of metastatic breast carcinoma using indium-111-methyl benzyl DTPA BrE-3 monoclonal antibody: phase I study
Kramer EL; DeNardo SJ; Liebes L; Kroger LA; Noz ME; Mizrachi H; Salako QA; Furmanski P; Glenn SD; DeNardo GL
1993 Jul;34(7):1067-1074, Journal of nuclear medicine
Pharmacokinetics of radiolabeled BrE3 monoclonal antibody (Mab), reactive against a breast mucin epitope, were assessed in 15 patients with advanced breast cancer. Patients received 5 mCi (185 MBq) of 111In-methyl benzyl isothiocyanate DTPA (MX-DTPA) conjugated BrE-3 Mab intravenously with total antibody doses of 10, 50 or 100 mg. Serial quantitative imaging, blood and urine clearance were obtained to measure pharmacokinetics, assess tumor localization and estimate radiation dose. Organ function was followed to determine toxicity. Mild allergic reactions occurred in four patients. Eighty-six percent of 70 known lesions and 5 unsuspected lesions were detected by antibody imaging. Biexponential modeling of radiolabeled antibody in serum showed a T1/2 alpha = 9.5 +/- 2.7 hr and T1/2 beta = 56 +/- 25.4 hr. Total urinary excretion averaged 35.5% +/- 19.3% injected dose (ID) by Day 8. Quantitative imaging showed that 0.02-2.56% ID localized in tumors. Extrapolating dosimetry from 111In-MX-DTPA-BrE-3 to 90Y-MX-DTPA-BrE-3, we estimate therapeutic radiation doses could be delivered to some tumors with tolerable toxicity
— id: 6426, year: 1993, vol: 34, page: 1067, stat: Journal Article,

Further observations on zidovudine transfer and metabolism by human placenta
Liebes L; Mendoza S; Lee JD; Dancis J
1993 Apr;7(4):590-592, AIDS
— id: 43282, year: 1993, vol: 7, page: 590, stat: Journal Article,

A phase I dose escalation study of synthetic hypericin in HIV infected patients (ACTG 150)
Mcauliffe V; Gulick R; Hochster H; Liebes L; Vaccariello J; Hussey S; Bassiakos Y; Balfour H; Stein D; Crumpacker C; et al
1993 Dec 12-16;1:159-159, National Conference on Human Retroviruses & Related Infections
Introduction: Hypericin (HY), an anthracenedione present in Hypericum perforatum (St. John's wort), is active in vitro against HIV. We describe a phase I study of IV dosed synthetic HY. Methods: HIV-infected patients (Pts) with less than or equal to 300 CD4 cells were eligible for enrollment. Pts received IV HY at 0.25 or 0.5 mg/kg BIW or 0.25 mg/kg TIW; with assessments of toxicity, pharmacokinetic (PK) and antiviral activity. 4 Pts received a single oral dose. Results: 25 Pts received HY from 1 to 24 weeks. Phototoxicity (discomfort and erythema of light-exposed areas) developed in all pts, varied in severity, and was dose limiting at 0.5 mg/ kg BIW. PK showed area under the curve of 26.0 +/- 5.0 (Mean +/- SD) and 53.7 +/- 27.2 +/- micrograms/hr/ml at IV doses of 0.25 and 0.5 mg/kg, respectively; peak levels were 4.2 +/- 1.1 and 7.7 +/- 2.0 micrograms/ml and fell below 1 microgram/ml at 5 and 11 hours. Elimination half lives were 23.7 +/- 7.3 and 35.3 +/- 9 hrs (p greater than 0.1). Oral bioavailability was 22.3 +/- 7.7%. A consistent change in antiviral endpoints was not seen with intermittent IV dosing. Conclusions: IV dosing of Hy yields dose-limiting cutaneous phototoxicity of variable severity. PK data predict chronic oral dosing should achieve sustained blood levels in an anti-retroviral range. Further studies of Hypericin are planned
— id: 5991, year: 1993, vol: 1, page: 159, stat: Journal Article,

Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin
Hochster H; Liebes L; Wadler S; Oratz R; Wernz JC; Meyers M; Green M; Blum RH; Speyer JL
1992 Nov 18;84(22):1725-1730, Journal of the National Cancer Institute
BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies
— id: 57431, year: 1992, vol: 84, page: 1725, stat: Journal Article,

Modulation of monocyte functions by muramyl tripeptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma
Liebes L; Walsh CM; Chachoua A; Oratz R; Richards D; Hochster H; Peace D; Marino D; Alba S; Le Sher D; et al
1992 May 6;84(9):694-699, Journal of the National Cancer Institute
BACKGROUND: Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic analogue of muramyl dipeptide (MDP), a component of bacterial cell walls that has potent in vitro monocyte-activating properties. We conducted a phase II clinical trial of MTP-PE in 30 patients with metastatic melanoma. PURPOSE: Our purpose was to define a clinical response rate for this agent in patients with advanced melanoma and to evaluate the agent's immunomodulatory properties. METHODS: Patients were randomly assigned to 1- or 4-mg dose levels of MTP-PE and received the drug intravenously once a week for 12-24 weeks. Immunological monitoring consisted of measurement of plasma tumor necrosis factor-alpha (TNF-alpha), neopterin, interleukin-1-beta, interleukin-6 (IL-6), and beta 2-microglobulin levels; phenotyping analysis of expression of human HLA-DR, CD-14 on mononuclear cells; and measurement of in vitro monocyte cytotoxicity against SKMel28 targets cells. RESULTS: MTP-PE was well tolerated; fever and chills were the major toxic effects. Plasma TNF-alpha levels increased 16-fold 2 hours after the first MTP-PE treatment. Increases in TNF-alpha levels after MTP-PE administration continued through week 12, but changes were of a lower magnitude after week 1. Plasma neopterin levels were significantly increased 24 hours after treatment at weeks 1, 6, and 12. A marked increase in IL-6 and a modest rise in beta 2-microglobulin levels were also seen at week 1. No significant changes from baseline IL-1 beta were observed. In the cytotoxicity assay, monocyte cytotoxic activity was significantly increased at weeks 4 and 6. Surface immuno-phenotyping revealed a consistent transient reduction in the number of circulating monocytes 2 hours after MTP-PE was administered. In addition, we observed a down-regulation (i.e., a decrease) in the expression of Leu M3 and HLA-DR on monocytes, 2 hours after MTP-PE treatment, followed by a recovery 24 hours after treatment. No objective clinical responses were seen in this advanced disease population. CONCLUSIONS: We conclude that MTP-PE has pleiotropic and potentially beneficial biologic effects and that further clinical investigations of MTP-PE are justified. IMPLICATIONS: In view of the clear immunomodulatory actions seen in our study and in earlier clinical trials, we believe that MTP-PE deserves further study in the adjuvant setting
— id: 13597, year: 1992, vol: 84, page: 694, stat: Journal Article,

Glutathione depletion in chronic lymphocytic leukemia B lymphocytes
Silber R; Farber CM; Papadopoulos E; Nevrla D; Liebes L; Bruck M; Brown R; Canellakis ZN
1992 Oct 15;80(8):2038-2043, Blood
Glutathione (GSH) content may be the major determinant of a cell's sensitivity to cytotoxic alkylating agents. In the present study, the GSH concentration was determined in lymphocytes isolated from the blood of normal subjects and patients with chronic lymphocytic leukemia (CLL). Comparable levels were found in both types of cells. Incubation for 20 hours led to a decrease in GSH to 51% of baseline values in CLL B cells. Under the same conditions, normal B- or T-lymphocyte GSH content remained constant. GSH depletion was shown to be a characteristic of the B-CLL B lymphocyte. It was not found in the T cells of patients with B-CLL or in cells from patients with T-CLL. Chlorambucil (CLB) contributes to the decrease in GSH in B-CLL lymphocytes; after incubation with the drug, lower levels of GSH were found than in the normal B or T lymphocytes, B-CLL T cells, or T-CLL (CD4 or CD8) cells. GSH depletion of CLL B lymphocytes may be related to the greater therapeutic efficacy of CLB in B-CLL than in T-CLL
— id: 13396, year: 1992, vol: 80, page: 2038, stat: Journal Article,

A method for the quantitation of hypericin, an antiviral agent, in biological fluids by high-performance liquid chromatography
Liebes L; Mazur Y; Freeman D; Lavie D; Lavie G; Kudler N; Mendoza S; Levin B; Hochster H; Meruelo D
1991 May 15;195(1):77-85, Analytical biochemistry
Hypericin, a polycyclic aromatic dianthroquinone, is a natural plant product with antiviral properties. We report here the development of a methodology for the extraction and quantitation of hypericin from plasma and biological fluids and the adaptation of a sensitive and selective method for detection of the compound by high-performance liquid chromatography. The methodology offers a rapid and specific means of monitoring drug blood levels in clinical and pharmacokinetic studies. The chromatographic procedure utilizes the substantial retentive properties of hypericin on reverse-phase media and detection by the strong visible absorbance maximum at 590 nm. Verification by the fluorescence spectral properties of hypericin in organic media can also be utilized. The assay is linear over a 3 log concentration range and hypericin is consistently recovered from murine, simian, and human plasma. The methodology was applied to assess the pharmacokinetic properties of hypericin in mice receiving a single bolus injection of 350 micrograms. A distribution half-life of 2.0 h and an elimination half-life of 38.5 h were calculated. We also discuss the limitations of direct analysis of hypericin by absorbance or fluorescence measurements
— id: 14022, year: 1991, vol: 195, page: 77, stat: Journal Article,

Good tolerance of weekly oral idarubicin: (4-demethoxydaunorubicin): a phase I study with pharmacology
Hochster H; Green M; Liebes L; Speyer JL; Wernz J; Blum R; Muggia F
1990 ;26(4):297-300, Cancer chemotherapy & pharmacology
Idarubicin (4-demethoxydaunorubicin) is an orally active anthracycline. We treated 26 patients with 37 courses of the drug on a schedule of oral administration weekly x 3 followed by a 3-week rest period. The maximum tolerated dose on this schedule was 22.5 mg/m2 weekly x 3 every 6 weeks, with consistent myelosuppression being the dose-limiting toxicity; other toxicity was minimal. Pharmacologic studies showed a mean alpha half-life of 1.6 +/- 0.3 h and a beta half-life of 39 +/- 8.4 h for idarubicin. This schedule was well tolerated, with consistent toxicity patterns seen. Pharmacologic studies confirmed prolonged exposure to the drug and its active metabolite. In comparison with other schedules, this one may offer advantages in terms of consistent hematologic toxicity and prolonged exposure to both the parent compound and its active metabolite. Dose intensity was comparable with that on other schedules
— id: 35094, year: 1990, vol: 26, page: 297, stat: Journal Article,

Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group Study
Hochster, H; Dieterich, D; Bozzette, S; Reichman, R C; Connor, J D; Liebes, L; Sonke, R L; Spector, S A; Valentine, F; Pettinelli, C
1990 Jul 15;113(2):111-117, Annals of internal medicine
OBJECTIVE: To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease. DESIGN: Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history. SETTING: Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). PATIENTS: Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed. INTERVENTIONS: Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity. MEASUREMENTS AND MAIN RESULTS: Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy. CONCLUSION: The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious-CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion
— id: 101812, year: 1990, vol: 113, page: 111, stat: Journal Article,

Transfer of zidovudine (AZT) by human placenta
Liebes L; Mendoza S; Wilson D; Dancis J
1990 Feb;161(2):203-207, Journal of infectious diseases
The transfer of zidovudine (AZT) across human placenta was studied using an in vitro perfusion system with independent maternal and fetal circulations. AZT is transferred toward the fetus more rapidly than L-glucose (transfer index 1.5), a water-soluble molecule smaller than AZT (267 vs. 180 Da) that passively diffuses across the placenta. The transfer rate is proportional to the concentration in the maternal perfusate over a range of 0.03-300 microM. Transfer rate in the reverse direction, toward the maternal perfusate, also exceeds that of L-glucose and fails to show saturability. These observations are consistent with simple diffusion. The partition of AZT and glucose between perfusion buffer and octanol is 1.04 and 0.013, respectively, indicating that AZT is more lipophilic and providing a reasonable explanation for the more rapid transfer. AZT is extensively metabolized by the placenta to more polar and as yet unidentified metabolites that are not released into the perfusate. The possibility that the placental accumulation of such metabolite(s) may exert an antiviral action and may also affect placental function must be considered
— id: 43283, year: 1990, vol: 161, page: 203, stat: Journal Article,

HPLC SAMPLE PRETREATMENT AND PREPARATION
Liebes, L
1990 Feb;8(3A):28-2?, American biotechnology laboratory
— id: 32006, year: 1990, vol: 8, page: 28, stat: Journal Article,

Chlorambucil pharmacokinetics and DNA binding in chronic lymphocytic leukemia lymphocytes
Bank BB; Kanganis D; Liebes LF; Silber R
1989 Feb 1;49(3):554-559, Cancer research
Chlorambucil (CLB) uptake by chronic lymphocytic leukemia lymphocytes was studied using a radiometric and a newly developed high-performance liquid chromatography assay. CLB labeled with 14C in either the chloroethyl group or phenyl ring was used with identical results. Drug accumulation by the cells was found to peak at 30 s, was independent of temperature, and was proportional to medium CLB concentration over a wide range. Efflux from cells loaded with CLB and resuspended in drug-free medium was nearly complete at 30 s. The metabolic inhibitors 2-deoxyglucose and NaN3, the nitrogen mustard transport inhibitor hemicholinium-3, and another alkylating agent, melphalan, had no effect on drug uptake. We conclude that CLB enters and exits chronic lymphocytic leukemia lymphocytes by simple diffusion. Cells from 17 patients with all stages of chronic lymphocytic leukemia were studied including three with CLB-resistant disease, and no heterogeneity was found in the peak cell-associated CLB content or in metabolite pattern on high-performance liquid chromatography. These findings make it unlikely that transport or cellular drug metabolism are factors in drug resistance. Drug-DNA binding was found to be temperature-sensitive and increased with time of incubation. Gel filtration of DNA before and after enzymatic digestion indicated the presence of drug-DNA adducts. High-performance liquid chromatography analysis of digested DNA and DNA treated by neutral thermal hydrolysis suggested the presence of multiple adducts. Most of the radioactivity was found as purine adducts. Studies with CLB labeled at two different sites revealed the presence of the phenyl group and ethyl chains in the adducts. A survey of patients showed increased drug-DNA binding in cells from patients with clinical CLB resistance
— id: 10726, year: 1989, vol: 49, page: 554, stat: Journal Article,

Phase IB study of low-dose intraperitoneal recombinant interleukin-2 in patients with refractory advanced ovarian cancer: rationale and preliminary report
Beller U; Chachoua A; Speyer JL; Sorich J; Dugan M; Liebes L; Hayes R; Beckman EM
1989 Sep;34(3):407-412, Gynecologic oncology
The biological activity of recombinant Interleukin-2 (rIL-2) administered intraperitoneally (ip) has not been determined and may differ significantly from the maximum tolerated dose (MTD). In this trial, the pharmacokinetics, toxicity, and biologic activity of a single ip dose were studied initially followed a week later by a 5-day ip rIL-2 given for 2 weeks every 28 days. Planned dose escalation was from 2 x 10(3) to 2 x 10(7) U given in 2 liters of D5W. Drug was obtained from the NCI and was administered through an ip port. Four patients received 1 U/ml and four patients received 10 U/ml. Preliminary data demonstrate an increase in the peritoneal fluid mononuclear cell count. Mononuclear cell phenotyping tested in the first eight patients showed a modest increase in Leu 2a+, Leu 15- cells, corresponding to CTL. A similar increase in Leu 19+ cells was also demonstrated (NK cells). Soluble IL-2 receptor was elevated in peritoneal fluid. Cytotoxicity against K562 and Daudi cell lines was not observed at the first two dose levels. Toxicity of treatment was minimal and related to abdominal distention. No objective responses were seen but in one patient we documented a reduction in serum CA-125 levels. The observed biologic response and lack of toxicity is promising and justifies further exploration of this immune-modulating approach
— id: 10498, year: 1989, vol: 34, page: 407, stat: Journal Article,

Antioxidant enzymes in lymphocytes from normal subjects and patients with chronic lymphocytic leukaemia: increased glutathione peroxidase activity in CLL B lymphocytes
Farber CM; Kanganis DN; Liebes LF; Silber R
1989 May;72(1):32-35, British journal of haematology
The activities of several enzymes that protect against oxidative injury were determined in blood lymphocytes from patients with B chronic lymphocytic leukaemia (CLL) and from normal subjects. Similar glutathione reductase (GR), catalase and glucose-6-phosphate dehydrogenase (G6PD) activities were found in normal and CLL lymphocytes. Higher glutathione peroxidase (GP) activity was found in CLL lymphocytes. This activity in CLL B lymphocytes was 2-fold higher than that of normal B lymphocytes, and 3-fold higher than that of T lymphocytes from either source. Several disease processes have been associated with decreased glutathione peroxidase activity. Our finding with CLL B lymphocytes is believed to be the first example of an increased GP activity in a disease. It may reflect either the expansion of a rare type of B cell population or be an expression of the malignant process
— id: 10623, year: 1989, vol: 72, page: 32, stat: Journal Article,

DOES T-CELL ACTIVATION (TA) OCCUR DURING DIALYSIS
Neusy, AJ; Valeri, AM; Liebes, L
1989 Jan;35(1):371-371, Kidney international
— id: 31761, year: 1989, vol: 35, page: 371, stat: Journal Article,

Phase I trial of escalating dose doxorubicin administered concurrently with alpha 2-interferon
Green MD; Speyer JL; Hochster HS; Liebes LF; Dunleavy S; Widman T; Wernz JC; Blum RH; Spiegel RJ; Muggia FM
1988 May 1;48(9):2574-2578, Cancer research
The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study
— id: 11108, year: 1988, vol: 48, page: 2574, stat: Journal Article,

AZIDOTHYMIDINE GLUCURONIDATION BY HEP-G2 CELLS
LIEBES, L; HOCHSTER, H; CHACHOUA, A; JAVITT, NB
1988 APR ;36(3):A461-A461, Clinical research
— id: 41788, year: 1988, vol: 36, page: A461, stat: Journal Article,

CELLULAR PHARMACOKINETICS OF CHLORAMBUCIL (CLB) IN CHRONIC LYMPHOCYTIC-LEUKEMIA (CLL)
Bank, B; Kanganis, D; Liebes, L; Smith, I; Potmesil, M; Silber, R
1987 Apr;35(3):A628-A628, Clinical research
— id: 31375, year: 1987, vol: 35, page: A628, stat: Journal Article,

Relationship of fluorescence polarization to cell lineage in lymphocytes from normal subjects and patients with chronic lymphocytic leukemia
Glotzer TV; Liebes LF; Kanganis D; Silber R
1987 Nov;26(3):229-236, American journal of hematology
Previous investigations have shown differences in fluorescence polarization between normal and chronic lymphocytic leukemia lymphocytes following incubation with the probe 1,6-diphenyl-1,3,5-hexatriene. In the present study, we determined the fluorescence polarization of unseparated or enriched subpopulations of T and B lymphocytes from normal subjects and patients with chronic lymphocytic leukemia. As had been observed by others, the mean polarization (P) value at 25 degrees C for unseparated chronic lymphocytic leukemia lymphocytes, .240 +/- .007 (N = 22), was lower than that of unseparated normal lymphocytes, .248 +/- .005 (N = 18), P less than .001 (Student's t-test). The difference was greater when B-enriched populations were compared. The mean P value of B-cell-enriched chronic lymphocytic leukemia lymphocytes, .240 +/- .007 (N = 5), was significantly lower than that of B-cell-enriched normal preparations, .256 +/- .004 (N = 5), P less than .001. In contrast, no significant difference was found between normal and chronic lymphocytic leukemia T cells. The anomalous fluorescence polarization manifested by chronic lymphocytic leukemia lymphocytes of B-cell origin serves to distinguish this lineage from its normal counterpart and from T cells of either source
— id: 11328, year: 1987, vol: 26, page: 229, stat: Journal Article,

PHASE-I TRIAL AND PHARMACOKINETICS OF ORAL 4 DEMETHOXYDAUN- ORUBICIN (IDARUBICIN)
Green, MD; Hochster, H; Speyer, JL; Liebes, L; Wernz, JC; Blum, RH; Ward, C; London, C; Mendoza, S; Muggia, FM
1987 Mar;28(3):192-192, Proceedings (American Association for Cancer Research)
— id: 31223, year: 1987, vol: 28, page: 192, stat: Journal Article,

CELLULAR AND PLASMA PHARMACOKINETICS OF CHLORAMBUCIL IN CHRONIC LYMPHOCYTIC-LEUKEMIA
Bank, B; Liebes, LF; Potmesil, M; Silber, R
1986 Apr;34(2):A689-A689, Clinical research
— id: 31044, year: 1986, vol: 34, page: A689, stat: Journal Article,

GLUTATHIONE DEHYDROGENASE (ASCORBATE)
STAHL, RL; LIEBES, LF; SILBER, R
1986 JUN ;122(2):10-12, Methods in enzymology
— id: 41296, year: 1986, vol: 122, page: 10, stat: Journal Article,

RELATIONSHIP OF DEHYDROASCORBIC ACID TRANSPORT TO CELL LINEAGE IN LYMPHOCYTES FROM NORMAL SUBJECTS AND PATIENTS WITH CHRONIC LYMPHOCYTIC-LEUKEMIA
STAHL, RL; FARBER, CM; LIEBES, LF; SILBER, R
1985 ;45(12):6507-6512, Cancer research
— id: 41136, year: 1985, vol: 45, page: 6507, stat: Journal Article,

A REAPPRAISAL OF LEUKOCYTE DEHYDROASCORBATE REDUCTASE
STAHL, RL; LIEBES, LF; SILBER, R
1985 ;839(1):119-121, Biochimica & biophysica acta
— id: 41155, year: 1985, vol: 839, page: 119, stat: Journal Article,

LYMPHOCYTE-B H2O2 TOXICITY IS POTENTIATED BY CALCIUM AND PREVENTED BY NON-STEROIDAL ANTI-INFLAMMATORY AGENTS (NSAIA)
FARBER, CM; KANGANIS, D; LIEBES, LF; SILBER, R
1984 ;32(2):A495-A495, Clinical research
— id: 40830, year: 1984, vol: 32, page: A495, stat: Journal Article,

HUMAN LYMPHOCYTE-B SHOW GREATER SUSCEPTIBILITY TO H2O2 TOXICITY THAN LYMPHOCYTE-T
FARBER, CM; LIEBES, LF; KANGANIS, DN; SILBER, R
1984 ;132(5):2543-2546, Journal of immunology
— id: 40813, year: 1984, vol: 132, page: 2543, stat: Journal Article,

Reduced tocopherol content of B cells from patients with chronic lymphocytic leukemia
Kayden, H J; Hatam, L; Traber, M G; Conklyn, M; Liebes, L F; Silber, R
1984 Jan;63(1):213-215, Blood
The tocopherol content of lymphocytes, erythrocytes, and plasma from patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), and normal subjects was measured by a sensitive high performance liquid chromatographic method. Lymphocytes from patients with CLL had lower values of tocopherol (1.7 +/- 1.0 micrograms/10(9) cells) than lymphocytes from normal subjects (3.8 +/- 0.7 micrograms/10(9) cells). Mononuclear cells from patients with HCL had an increased tocopherol content of 6.2 +/- 1.0 micrograms/10(9) cells. Subfractionation of the lymphocytes from patients with CLL into T- and B-cell subgroups showed that the tocopherol content of T cells was the same as in normal subjects (4.1 +/- 0.5 micrograms/10(9) cells versus 3.5 +/- 1.2), but that the tocopherol content of the B cells was markedly reduced compared to normals (2.6 +/- 1.0 versus 6.0 +/- 1.3)
— id: 101185, year: 1984, vol: 63, page: 213, stat: Journal Article,

CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES - MEMBRANE ANOMALIES AND H2O2 VULNERABILITY
SILBER, R; STAHL, RL; FARBER, CM; KANGANIS, D; ASTROW, A; LIEBES, LF
1984 ;10(2-3):233-239, Blood cells
— id: 41144, year: 1984, vol: 10, page: 233, stat: Journal Article,

ANOMALOUS FUNCTION OF VIMENTIN IN CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES
STARK, RS; LIEBES, LF; SHELANSKI, ML; SILBER, R
1984 ;63(2):415-420, Blood
— id: 40856, year: 1984, vol: 63, page: 415, stat: Journal Article,

A SPECIFIC HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY ASSAY FOR DEHYDROASCORBIC ACID SHOWS AN INCREASED CONTENT IN CLL LYMPHOCYTES
FARBER, CM; KANENGISER, S; STAHL, R; LIEBES, L; SILBER, R
1983 ;134(2):355-360, Analytical biochemistry
— id: 40484, year: 1983, vol: 134, page: 355, stat: Journal Article,

Purification and characterization of actin from normal and chronic lymphocytic leukemia lymphocytes
Liebes LF; Stark R; Nevrla D; Grusky G; Zucker-Franklin D; Silber R
1983 Oct;43(10):4966-4973, Cancer research
Previous studies from this laboratory have shown actin to be a major protein of human lymphocytes (Stark, R., Liebes, L. F., Nevrla, D., and Silber, R. Biochem. Med., 27: 200-206, 1982). We now report the purification to homogeneity and characterization of actin from blood lymphocytes of normal subjects and patients with chronic lymphocytic leukemia. The recovery of the purified protein was about 20%. The properties of the lymphocyte actins were compared to each other and to those of rabbit skeletal muscle actin. Lymphocyte actin consisted of beta and gamma forms in a 2:1 ratio. The Mr 42,000 was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Normal and leukemic lymphocyte actin had similar polymerization properties as assessed by viscosity measurements at 25 degrees and 4 degrees, and the ultrastructural appearance of the filaments was the same. Similar patterns were observed between normal and chronic lymphocytic leukemia actin tryptic digests analyzed by high-performance liquid chromatography. The Vmax of the actin-activated myosin Mg2+ ATPase activity was compared using rabbit skeletal muscle heavy meromyosin and subfragment 1 preparations. The values obtained with rabbit skeletal muscle and normal lymphocyte actin were identical. The Vmax observed with chronic lymphocytic leukemia lymphocyte actin was 70% of that obtained with normal lymphocyte actin. The amount of actin needed to produce half-maximal activation (Kapparent) of heavy meromyosin and subfragment 1 were, respectively, 26 and 25 microM for normal lymphocytes and 18 and 24 microM for chronic lymphocytic leukemia lymphocytes. The anomalous ATP activation by actin did not reflect differences in B-:T-cell subpopulations between chronic lymphocytic leukemia and normal lymphocytes. The possible significance of the observed differences between the myosin Mg2+ ATPase activation by chronic lymphocytic leukemia and normal lymphocyte actin is discussed
— id: 15736, year: 1983, vol: 43, page: 4966, stat: Journal Article,

GLUTATHIONE INSTABILITY IN CHRONIC LYMPHOCYTIC-LEUKEMIA (CLL) LYMPHOCYTES
LIEBES, L; NEVRLA, D; SILBER, R
1983 ;31(2):A483-A483, Clinical research
— id: 40688, year: 1983, vol: 31, page: A483, stat: Journal Article,

RIBONUCLEOTIDE CONTENT OF MONONUCLEAR-CELLS FROM NORMAL SUBJECTS AND PATIENTS WITH CHRONIC LYMPHOCYTIC-LEUKEMIA - INCREASED NICOTINAMIDE ADENINE-DINUCLEOTIDE CONCENTRATION IN CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES
LIEBES, LF; KRIGEL, RL; CONKLYN, M; NEVRLA, DR; SILBER, R
1983 ;43(11):5608-5617, Cancer research
— id: 40489, year: 1983, vol: 43, page: 5608, stat: Journal Article,

A SPECTROPHOTOMETRIC ASSAY FOR DEHYDROASCORBATE REDUCTASE
STAHL, RL; LIEBES, LF; FARBER, CM; SILBER, R
1983 ;131(2):341-344, Analytical biochemistry
— id: 40522, year: 1983, vol: 131, page: 341, stat: Journal Article,

CHLORAMBUCIL THERAPY IN HAIRY-CELL LEUKEMIA - EFFECTS ON LIPID- COMPOSITION AND LYMPHOCYTE SUB-POPULATIONS
Krigel, R; Liebes, LF; Pelle, E; Silber, R
1982 ;60(1):272-275, Blood
— id: 30396, year: 1982, vol: 60, page: 272, stat: Journal Article,

DECREASED ACTIN CONTENT OF LYMPHOCYTES FROM PATIENTS WITH CHRONIC LYMPHOCYTIC-LEUKEMIA
Stark, R; Liebes, LF; Nevrla, D; Conklyn, M; Silber, R
1982 ;59(3):536-541, Blood
— id: 30327, year: 1982, vol: 59, page: 536, stat: Journal Article,

THE QUANTITATION OF ACTIN IN HUMAN-LYMPHOCYTES BY ISOELECTRIC- FOCUSING
Stark, R; Liebes, LF; Nevrla, D; Silber, R
1982 ;27(2):200-206, Biochemical medicine
— id: 30323, year: 1982, vol: 27, page: 200, stat: Journal Article,

DECREASED RIBONUCLEOSIDE TRIPHOSPHATE LEVELS IN CHRONIC LYMPHOCYTIC-LEUKEMIA (CLL) LYMPHOCYTES
Krigel, R; Liebes, L; Silber, R
1981 ;29(2):A548-A548, Clinical research
— id: 30266, year: 1981, vol: 29, page: A548, stat: Journal Article,

Comparison of lipid composition and 1,6-diphenyl-1,3,5-hexatriene fluorescence polarization measurements of hairy cells with monocytes and lymphocytes from normal subjects and patients with chronic lymphocytic leukemia
Liebes LF; Pelle E; Zucker-Franklin D; Silber R
1981 Oct;41(10):4050-4056, Cancer research
In this report, we compare the lipid composition and fluorescence polarization properties of hairy cells with those of monocytes and lymphocytes from normal subjects and of lymphocytes from patients with chronic lymphocytic leukemia. For hairy cells, the cholesterol content was 4.66 +/- 1.49 (S.D.) mumol/10(9) cells, and the cholesterol/phospholipid ratio was 0.60 +/- 0.09. These were significantly higher than the values of normal lymphocytes, (cholesterol content, 2.75 +/- 0.65 mumol; cholesterol/phospholipid ratio, 0.50 +/- 0.07) or of chronic lymphocytic leukemia lymphocytes (cholesterol content, 1.76 +/- 0.43 mumol; cholesterol/phospholipid ratio, 0.44 +/- 0.07). Normal monocyte values (cholesterol content, 5.81 +/- 2.08 mumol; cholesterol/phospholipid ratio, 0.59 +/- 0.06) were similar to those of hairy cells. Using the probe 1,6-diphenyl-1,3,5-hexatriene, the fluorescence polarization value at 25 degrees for hairy cells was 0.302, compared to the value of 0.259 obtained with chronic lymphocytic leukemia lymphocytes. Intermediate values (0.294) were obtained with normal lymphocytes and monocytes. Fluorescence polarization values were higher in hairy cell membranes than in chronic lymphocytic leukemia lymphocyte membranes, indicating a low fluidity in the former cell, compatible with their higher cholesterol content and cholesterol/phospholipid ratio. These studies show that two neoplastic cells, hairy cells and chronic lymphocytic leukemia lymphocytes, differ markedly in membrane fluidity and that a high membrane fluidity does not necessarily occur in neoplasia
— id: 61766, year: 1981, vol: 41, page: 4050, stat: Journal Article,

INCREASED ASCORBIC-ACID CONTENT IN CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES-B
Liebes, L; Krigel, R; Kuo, S; Nevrla, D; Pelle, E; Silber, R
1981 ;78(10):6481-6484, Proceedings of the National Academy of Sciences of the United States of America
— id: 30193, year: 1981, vol: 78, page: 6481, stat: Journal Article,

BIOCHEMICAL-CHARACTERIZATION OF ACTIN FROM NORMAL AND LEUKEMIC LYMPHOCYTES
Liebes, L; Stark, R; Nevrla, D; Unger, P; Zuckerfranklin, D; Silber, R
1981 ;33(2):A214-A214, Biophysical journal
— id: 30290, year: 1981, vol: 33, page: A214, stat: Journal Article,

CONTINUOUS-FLOW SCANNING OF SELECTED HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY PEAK COMPONENTS BY MICROPROCESSOR CONTROL - APPLICATION TO ANALYSIS OF EXTRACTS FROM HUMAN-LYMPHOCYTES
LIEBES, LF
1981 ;219(2):255-262, Journal of chromatography
— id: 40301, year: 1981, vol: 219, page: 255, stat: Journal Article,

IDENTIFICATION AND QUANTITATION OF ASCORBIC-ACID IN EXTRACTS OF HUMAN-LYMPHOCYTES BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY
Liebes, LF; Kuo, S; Krigel, R; Pelle, E; Silber, R
1981 ;118(1):53-57, Analytical biochemistry
— id: 30183, year: 1981, vol: 118, page: 53, stat: Journal Article,

ELECTROPHORETIC MOBILITY DISTRIBUTIONS DISTINGUISH HAIRY-CELLS FROM OTHER MONONUCLEAR BLOOD-CELLS AND PROVIDE EVIDENCE FOR THE HETEROGENEITY OF NORMAL MONOCYTES
PETTY, HR; WARE, BR; LIEBES, LF; PELLE, E; SILBER, R
1981 ;57(2):250-255, Blood
— id: 40352, year: 1981, vol: 57, page: 250, stat: Journal Article,

Human lymphocyte tubulin. Purification and characterization in normal and leukemic cells
Liebes LF; Fleit H; Zucker-Franklin D; Silber R
1980 Dec 1;633(2):245-257, Biochimica & biophysica acta
Tubulin has been purified from human blood and tonsil lymphocytes. Using gel filtration, the molecular weight of human lymphocyte tubulin was estimated to be 119000. The protein was shown to consist of two subunits, with molecular weights of 61000 and 58000 comparable to the alpha and beta polypeptides of human brain tubulin. A partial identity reaction was observed between lymphocyte tubulin and human tubulin when tested by double immunodiffusion against a rabbit anti-human brain tubulin antibody. In the presence of GTP, the purified protein polymerized to form microtubules. Tubulin was localized to the cell's juxtacentriolar region by immunofluorescence and electron microscopy. When assayed by a colchicine-binding assay corrected for time decay, the binding affinity was 1.50 +/- 0.86 . 10(6) M-1 and a level in normal lymphocytes of 1.21 . 10(2) +/- 0.79 g/g of soluble protein was determined. Since chronic lymphocytic leukemia lymphocytes have an anomalous capping behavior as well as an unusual susceptibility to colchicine toxicity, the properties and levels of tubulin were determined in these cells. Similar values were obtained for the level, decay rate, molecular weight, and Ka for colchicine as for normal lymphocytes. Chronic lymphocytic leukemia lymphocytes tubulin polymerized in a normal fashion. It thus appears that a decrease in the quantity for function of tubulin does not account for these anomalies in the chronic lymphocytic leukemia lymphocyte
— id: 61771, year: 1980, vol: 633, page: 245, stat: Journal Article,

PURIFICATION AND CHARACTERIZATION OF TUBULIN FROM HUMAN LEUKEMIC LYMPHOID-TISSUE
Liebes, L; Zuckerfranklin, D; Silber, R
1979 ;25(2):A35-A35, Biophysical journal
— id: 30052, year: 1979, vol: 25, page: A35, stat: Journal Article,

Differences in the behavior of the membrane and membrane-associated filamentous structures in normal and chronic lymphocytic leukemia (CLL) lymphocytes
Zucker-Franklin D; Liebes LF; Silber R
1979 Jan;122(1):97-107, Journal of immunology
— id: 61777, year: 1979, vol: 122, page: 97, stat: Journal Article,

The anomalous capping behavior of chronic lymphocytic leukemia lymphocytes: studies with an antilymphocyte antiserum
Liebes, L; Quagliata, F; Silber, R
1978 Jun;10(2):222-232, Clinical immunology & immunopathology
— id: 127510, year: 1978, vol: 10, page: 222, stat: Journal Article,

DECREASED ATP - POSSIBLE REASON FOR ANOMALOUS CAPPING BEHAVIOR OF CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES
Liebes, L; Conklyn, M; Ambady, S; Quagliata, F; Silber, R
1977 ;25(3):A477-A477, Clinical research
— id: 29598, year: 1977, vol: 25, page: A477, stat: Journal Article,

ANOMALOUS CAPPING BEHAVIOR OF CHRONIC LYMPHOCYTIC-LEUKEMIA (CLL) LYMPHOCYTES DESPITE NORMAL ANTIBODY BINDING AND TUBULIN LEVELS
Liebes, L; Fleit, H; Ambady, S; Quagliata, F; Silber, R
1977 ;36(3):711-711, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 29633, year: 1977, vol: 36, page: 711, stat: Journal Article,

LOCALIZATION OF FILAMENTOUS STRUCTURES IN NORMAL AND CHRONIC LYMPHOCYTIC-LEUKEMIA (CLL) LYMPHOCYTES EXPOSED TO ANTIBODY
Liebes, L; Silber, R; Zuckerfranklin, D
1977 ;50(5):172-172, Blood
— id: 29557, year: 1977, vol: 50, page: 172, stat: Journal Article,