Maarten C. Bosland, Ph.D.

L-methionine-induced alterations in molecular signatures in MCF-7 and LNCaP cancer cells
Benavides, Maximo A; Hu, Dong; Baraoidan, Marie Kristine; Bruno, Annette; Du, Pan; Lin, Simon; Yang, Wancai; Bland, Kirby I; Grizzle, William E; Bosland, Maarten C
2011 Mar;137(3):441-453, Journal of cancer research & clinical oncology
BACKGROUND: Methionine inhibits proliferation of breast and prostate cancer cells. Here, we determined the influence of L-methionine on functional molecular signatures in these cell lines. METHODS: MCF-7 and LNCaP cells were treated with L-methionine (5 mg/ml) for 72 h. Changes in molecular signatures of these cells were examined by microarray analysis of 15,814 probes in triplicate experiments. RESULTS: In LNCaP cells, 325 genes were up-regulated by methionine, and 517 genes down-regulated. In MCF-7 cells, 86 genes were up-regulated and 135 genes down-regulated. Ninety-eight genes were regulated in the same direction by methionine in both cells lines, and five other genes were changed in expression in opposite directions. CONCLUSION: Several of the up-regulated genes encode proteins involved in cellular redox regulation, suggesting that methionine may enhance antioxidant mechanisms. Many of the down-regulated genes belong to protein kinase families that may be related to the anti-proliferative effects of methionine on breast and prostate cancer cells
— id: 138151, year: 2011, vol: 137, page: 441, stat: Journal Article,

Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer
Wu, Jing; Omene, Coral; Karkoszka, Jerzy; Bosland, Maarten; Eckard, Jonathan; Klein, Catherine B; Frenkel, Krystyna
2011 Sep 1;308(1):43-53, Cancer letters
Breast cancer (BC) patients use alternative and natural remedies more than patients with other malignancies. Specifically, 63-83% use at least one type of alternative medicine and 25-63% use herbals and vitamins. Propolis is a naturopathic honeybee product, and CAPE (caffeic acid phenethyl ester), is a major medicinal component of propolis. CAPE, in a concentration dependent fashion, inhibits MCF-7 (hormone receptor positive, HR+) and MDA-231 (a model of triple negative BC (TNBC) tumor growth, both in vitro and in vivo without much effect on normal mammary cells and strongly influences gene and protein expression. It induces cell cycle arrest, apoptosis and reduces expression of growth and transcription factors, including NF-kappaB. Notably, CAPE down-regulates mdr-1 gene, considered responsible for the resistance of cancer cells to chemotherapeutic agents. Further, CAPE dose-dependently suppresses VEGF formation by MDA-231 cells and formation of capillary-like tubes by endothelial cells, implicating inhibitory effects on angiogenesis. In conclusion, our results strongly suggest that CAPE inhibits MDA-231 and MCF-7 human breast cancer growth via its apoptotic effects, and modulation of NF-kappaB, the cell cycle, and angiogenesis
— id: 134448, year: 2011, vol: 308, page: 43, stat: Journal Article,

Suppression by L-methionine of cell cycle progression in LNCaP and MCF-7 cells but not benign cells
Benavides, Maximo A; Hagen, Karen L; Fang, Wenfeng; Du, Pan; Lin, Simon; Moyer, Mary P; Yang, Wancai; Bland, Kirby I; Grizzle, William E; Bosland, Maarten C
2010 Jun;30(6):1881-1885, Anticancer research
BACKGROUND/AIM: Methionine inhibits proliferation of breast and prostate cancer cells. This study aimed to determine cell cycle effects of methionine and selectivity for cancer cells. MATERIALS AND METHODS: MCF-7 (breast), LNCaP (prostate), and LS-174 (colon) cancer cells (wild-type p53), DU-145 (prostate) and SW480 (colon) cancer cells (mutated p53), and immortalized, non-tumorigenic MCF-10A (breast), BPH-1 (prostate), and NCM-460 (colon) epithelial cells were used. Cell cycle effects were assessed by flow cytometry and cell cycle-related gene expression by microarray analysis and QRT-PCR. RESULTS: L-Methionine at 5 mg/ml for 72 hours (non-apoptotic) arrested cell cycle in LNCaP, DU145, and MCF-7 cells, but not in untransformed cells, nor in LS-174 cells. LNCaP and MCF-7 cells were arrested at G(1), but DU-145 at S. Methionine up-regulated CDKIs and down-regulated CDKs. CONCLUSION: L-Methionine selectively inhibits proliferation of breast and prostate cancer cells, but not non-tumorigenic cells, and may thus have therapeutic benefits. p53 status appeared to determine the cell cycle stage at which methionine acts
— id: 116265, year: 2010, vol: 30, page: 1881, stat: Journal Article,

Words of wisdom. Re: effect of dutasteride on the risk of prostate cancer
Bosland, Maarten C; Cremers, Ruben G H M; Kiemeney, Lambertus A
2010 Oct;58(4):631-632, European urology
— id: 116263, year: 2010, vol: 58, page: 631, stat: Journal Article,

Dutasteride and prostate cancer
Kiemeney, Lambertus A; Bosland, Maarten C
2010 Aug 19;363(8):793-793, New England journal of medicine
— id: 116264, year: 2010, vol: 363, page: 793, stat: Journal Article,

Null activity of selenium and vitamin e as cancer chemopreventive agents in the rat prostate
McCormick, David L; Rao, K V N; Johnson, William D; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E
2010 Mar;3(3):381-392, Cancer prevention research (Philadelphia, Pa.)
To evaluate the potential efficacy of selenium and vitamin E as inhibitors of prostate carcinogenesis, four chemoprevention studies using a common protocol were done in a rat model of androgen-dependent prostate cancer. After stimulation of prostate epithelial cell proliferation by a sequential regimen of cyproterone acetate followed by testosterone propionate, male Wistar-Unilever rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU) followed by chronic androgen stimulation via subcutaneous implantation of testosterone pellets. At 1 week post-MNU, groups of carcinogen-treated rats (39-44/group) were fed either a basal diet or a basal diet supplemented with l-selenomethionine (3 or 1.5 mg/kg diet; study 1), dl-alpha-tocopherol (vitamin E, 4,000 or 2,000 mg/kg diet; study 2), l-selenomethionine + vitamin E (3 + 2,000 mg/kg diet or 3 + 500 mg/kg diet; study 3), or selenized yeast (target selenium levels of 9 or 3 mg/kg diet; study 4). Each chemoprevention study was terminated at 13 months post-MNU, and prostate cancer incidence was determined by histopathologic evaluation. No statistically significant reductions in prostate cancer incidence were identified in any group receiving dietary supplementation with selenium and/or vitamin E. These data do not support the hypotheses that selenium and vitamin E are potent cancer chemopreventive agents in the prostate, and when considered with the recent clinical data reported in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), show the predictive nature of this animal model for human prostate cancer chemoprevention
— id: 116267, year: 2010, vol: 3, page: 381, stat: Journal Article,

Selenomethionine and alpha-tocopherol do not inhibit prostate carcinogenesis in the testosterone plus estradiol-treated NBL rat model
Ozten, Nur; Horton, Lori; Lasano, Salamia; Bosland, Maarten C
2010 Mar;3(3):371-380, Cancer prevention research (Philadelphia, Pa.)
Previous studies with selenium and/or vitamin E in prostate carcinogenesis animal models have been negative, but these models may not involve oxidative stress mechanisms. In this study, we examined the potential of selenomethionine and alpha-tocopherol to modulate prostate cancer development in the testosterone plus estradiol-treated NBL rat, a model that does involve sex hormone-induced oxidative stress mechanisms and prostatic inflammation. One week following the implantation with hormone-filled Silastic implants, rats were fed diets containing l-selenomethionine (1.5 or 3.0 mg/kg), DL-alpha-tocopherol acetate (2,000 or 4,000 mg/kg), or a natural ingredient control diet (NIH-07). The development of prostate carcinomas was not affected by dietary treatment with either agent. Food intake, body weight, and mortality were also not affected. The high dose of selenomethionine reduced the severity of epithelial dysplasia in the lateral prostate that was not associated with inflammation, and alpha-tocopherol reduced in a dose-related fashion the incidence of marked inflammation and marked epithelial dysplasia in the lateral prostate, regardless of whether these lesions were associated with inflammation. alpha-Tocopherol significantly increased the incidence of adenocarcinomas of the mammary glands at both dietary concentrations. Collectively, our findings suggest that selenomethionine and alpha-tocopherol supplementation does not prevent prostate cancer in rats fed diets with nutritionally adequate levels of selenium and vitamin E. Importantly, the results of the current animal studies and those reported previously were fully predictive of the outcome of the Selenium and Vitamin E Cancer Prevention Trial
— id: 116266, year: 2010, vol: 3, page: 371, stat: Journal Article,

Soy consumption and colorectal cancer risk in humans: a meta-analysis
Yan, Lin; Spitznagel, Edward L; Bosland, Maarten C
2010 Jan;19(1):148-158, Cancer epidemiology biomarkers & prevention
The purpose of the present study was to determine the relationship between soy consumption and colorectal cancer risk in humans by conducting a meta-analysis of available epidemiologic studies. We systematically reviewed publications obtained through a Medline literature search and identified four cohort and seven case-control studies on soy and colorectal cancer risk that met the inclusion criteria. We extracted the risk estimate (hazard ratio, relative risk, or odds ratio) of the highest and the lowest reported categories of intake from each study and conducted this analysis using a random-effects model. Our analysis did not find that soy consumption was associated with colorectal cancer risk [combined risk estimate, 0.90; 95% confidence interval (95% CI), 0.79-1.03] nor did the separate analyses on colon cancer (combined risk estimate, 0.88; 95% CI, 0.74-1.06) and rectal cancer (combined risk estimate, 0.88; 95% CI, 0.67-1.14). However, when separately analyzed on the basis of gender, we found that soy was associated with an approximately 21% reduction in colorectal cancer risk in women (combined risk estimate, 0.79; 95% CI, 0.65-0.97; P = 0.026), but not in men (combined risk estimate, 1.10; 95% CI, 0.90-1.33). Thus, consumption of soy foods may be associated with a reduction in colorectal cancer risk in women, but not in men
— id: 116268, year: 2010, vol: 19, page: 148, stat: Journal Article,

Antioxidant supplementation and cancer prevention
Bosland, Maarten C; McCormick, David L
2009 May 13;301(18):1877-1878, JAMA
— id: 116269, year: 2009, vol: 301, page: 1877, stat: Journal Article,

Strain-dependent differences in susceptibility to lung cancer in inbred mice exposed to mainstream cigarette smoke
Gordon, Terry; Bosland, Maarten
2009 Mar 18;275(2):213-220, Cancer letters
It is becoming increasingly clear that genetic susceptibility is an important host factor determining the effects of exposure to a number of airborne particles and gases. Although numerous studies have identified a genetic component for spontaneous pulmonary tumor development and for chemically induced lung cancer (e.g., urethane) in mice, a systematic examination of murine inter-strain differences in response to cigarette smoke inhalation has not been conducted. We addressed this research gap by examining the strain distribution pattern of lung cancer in nine inbred strains of mice exposed to 258 mg/m(3) mainstream cigarette smoke for 5 months followed by 4 months of rest. Lung tumors were enumerated on fixed lungs visualized at low magnification and on serial step sections examined microscopically. With the low magnification examination, we observed statistically significant increases in the number of lung tumors in cigarette smoke-exposed A/J and the genetically-related A/HeJ mice (p<0.05). While fewer tumors were identified by the microscopic enumeration method, it confirmed that significant increases in lung tumors occurred only in A/J and A/HeJ mice exposed to cigarette smoke (p<0.05). Thus, as predicted by epidemiologic studies and animal experiments using chemically induced lung cancer models, these findings suggest that genetic host factors play a significant role in the pulmonary tumorigenic response of mice to mainstream cigarette smoke
— id: 93226, year: 2009, vol: 275, page: 213, stat: Journal Article,

Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations
Kandas, Nur Ozten; Randolph, Carla; Bosland, Maarten C
2009 ;61(2):251-264, Nutrition & cancer
We examined the hypothesis that nontoxic concentrations of selenium induce apoptosis and growth inhibition selectively in prostate cancer cells but not in benign prostate cells. Nontumorigenic BPH-1 prostate epithelial cells, androgen-sensitive LNCaP, and androgen-independent PC-3 prostate cancer cells were exposed to sodium selenite at 1 to 10 micromol/l for 24 to 72 h. Cell proliferation, viability, and apoptosis were assessed by MTT assay, trypan blue exclusion, flow cytometry, DNA laddering, and caspase activation. BPH-1 cells were more sensitive for cytotoxic selenium effects than malignant prostate cells, whereas LNCaP cells were more sensitive than PC-3 cells. At noncytotoxic selenium concentrations, there was no apoptosis in BPH-1 and PC-3 cells and no growth inhibition of LNCaP and BPH-1 cells. PC-3 cells were refractory to apoptosis induction but were growth inhibited at noncytotoxic concentrations. LNCaP cells were growth stimulated at 1 micromol/l and sensitive to apoptosis induction at higher noncytotoxic concentrations. Thus, noncytotoxic selenite concentrations did not induce growth inhibition or apoptosis selectively in prostate cancer cells. Growth stimulation of LNCaP cells by low concentrations suggests the possibility of adverse effects of selenium supplementation on hormone sensitive prostate cancer, whereas inhibition of PC-3 cell proliferation at noncytotoxic concentrations suggests potential benefit of selenium in advanced prostate cancer
— id: 95186, year: 2009, vol: 61, page: 251, stat: Journal Article,

Inflammatory processes of prostate tissue microenvironment drive rat prostate carcinogenesis: preventive effects of celecoxib
Narayanan, Narayanan K; Nargi, Dominick; Horton, Lori; Reddy, Bandaru S; Bosland, Maarten C; Narayanan, Bhagavathi A
2009 Feb 1;69(2):133-141, Prostate
BACKGROUND: Prostate tissue microenvironment is susceptible to several risk factors including carcinogens, dietary factors, hormones, cytokines and growth factors that could induce chronic inflammation. Because of the difference in the serum levels and the intrinsic ability of monocytes/macrophages to cause harm, the transcriptional responses triggered by inflammatory stimuli must be controlled. Unfortunately, an in-depth association between prostate cancer and potential mediators of inflammation has not been completely investigated. METHODS: To determine whether activated macrophage (infiltrating monocytes), iNOS and NF-kappaB are primary mediators of inflammation, besides COX-2, in prostate carcinogenesis, we examined tissue sections of rat prostate tumor induced by N-methyl-N-nitrosourea (MNU) plus testosterone in a follow-up study. We performed H&E and immunohsitochemical staining of the prostate tissue to detect specific markers of inflammation. RESULTS: We report an increase in infiltrating monocyte, iNOS, NF-kappaBp65, VEGF and TNF-alpha at the early and advanced stages of tumor growth in MNU plus testosterone treated rats. Monocyte infiltration was often found in the stromal and perivascular regions of the DL prostate. We conclude for the first time that prostate cancer induced by MNU plus testosterone partly involves mediators of inflammation which could trigger the process of carcinogenesis and cause loss of apoptosis. Selective COX-2 inhibitor celecoxib at a dose of 500 mg/kg/bw administered for 52 weeks reduced infiltrating monocytes, inhibited iNOS, NF-kappaB p65 expression, induced apoptosis and tumor growth inhibition. CONCLUSION: Carcinogen plus testosterone induced prostate carcinogenesis showing activation of macrophage, iNOS and NF-kappaBp65 could be prevented by celecoxib or related anti-inflammatory agents
— id: 91973, year: 2009, vol: 69, page: 133, stat: Journal Article,

Histopathological evidence for an association of inflammation with ductal pin-like lesions but not with ductal adenocarcinoma in the prostate of the noble rat
Bernoulli, Jenni; Yatkin, Emrah; Laakso, Arto; Anttinen, Mikael; Bosland, Maarten; Vega, Katherine; Kallajoki, Markku; Santti, Risto; Pylkkanen, Liisa
2008 May 15;68(7):728-739, Prostate
BACKGROUND: Chronic inflammation may contribute to the development of prostate cancer. The goal of this study was to determine the possible association of prostatic inflammation, prostatic intraepithelial neoplasia (PIN)-like lesion, and prostate cancer, and to assess the androgen and estrogen dependency of the early steps of carcinogenesis. METHODS: Noble rats were treated with testosterone and estradiol implants for 13, 18, or 26 weeks. Hormone dependency of the lesions was studied in a subset of animals by removing hormone implants for 3 weeks after 15 weeks treatment time. RESULTS: After treatment for 13 weeks, acute and chronic inflammation was found in the dorsolateral prostate lobes and both inflammation and PIN-like lesions were present in the periurethal area of the prostate in all animals (n = 8). Following hormone exposure for 18 and 26 weeks, inflammation in the prostate remained, and adenocarcinomas in the periurethal prostate area with no adjacent inflammation were observed in all 18 animals studied. When both hormone implants were removed after 15 weeks, PIN-like lesions progressed further to adenocarcinoma only in two of seven animals. When only the estradiol implants were removed, three of five animals developed adenocarcinomas. CONCLUSIONS: Even though adenocarcinomas were not morphologically associated with inflammation, PIN-like lesions preceding adenocarcinoma were found in close association with inflammation, pointing towards a possible initiator role of inflammation in the early steps of prostatic carcinogenesis. Further, these results indicate that both androgens and estrogens together play a significant role in the induction of inflammation and prostatic cancer in this model
— id: 116270, year: 2008, vol: 68, page: 728, stat: Journal Article,

Roles of hormone replacement therapy and iron in proliferation of breast epithelial cells with different estrogen and progesterone receptor status
Dai, Jisen; Jian, Jinlong; Bosland, Maarten; Frenkel, Krystyna; Bernhardt, Guenther; Huang, Xi
2008 Apr;17(2):172-179, Breast
Estrogen and iron play critical roles in a female body development and were investigated in the present study in relation to in vitro cell proliferation. Prempro, a hormone replacement therapy drug, and 17beta-estradiol (E2) were shown to increase cell proliferations in estrogen receptor positive (ER+) cells independent of progesterone receptor (PR) status. For example, increased cell proliferation was observed in ER+/PR+ human breast cancer MCF-7, its matching non-cancerous human breast epithelial MCF-12A, and ER+/PR+ murine mammary cancer MXT+ cells, but not in ER-/PR- MDA-MB-231, its matching non-cancerous MCF-10A, and MXT- (ER-/PR+) cells. By mimicking post-menopausal conditions of high estrogen in local breast tissue and increased iron levels due to cessation of menstrual periods, E2 and iron were shown to exert synergistic effects on proliferation of MCF-7 cells and significantly increased Ki67 and proliferating cell nuclear antigen. Western blotting of E2-treated ER+ but not ER- cells showed that E2 also increased transferrin receptor (TfR). Further studies are needed to assess the mitogenic effects of iron and estrogen in normal post-menopausal breast
— id: 80282, year: 2008, vol: 17, page: 172, stat: Journal Article,

Disruption of growth hormone signaling retards prostate carcinogenesis in the Probasin/TAg rat
Wang, Zhuohua; Luque, Raul M; Kineman, Rhonda D; Ray, Vera H; Christov, Konstantin T; Lantvit, Daniel D; Shirai, Tomoyuki; Hedayat, Samad; Unterman, Terry G; Bosland, Maarten C; Prins, Gail S; Swanson, Steven M
2008 Mar;149(3):1366-1376, Endocrinology
We asked whether down-regulation of GH signaling could block carcinogenesis in the Probasin/TAg rat, a model of aggressive prostate cancer. The Spontaneous Dwarf rat, which lacks GH due to a mutation (dr) in its GH gene, was crossed with the Probasin/TAg rat, which develops prostate carcinomas at 100% incidence by 15 wk of age. Progeny were heterozygous for the TAg oncogene and homozygous for either the wild-type GH gene (TAg/Gh(+/+)) or the dr mutation (TAg/Gh(dr/dr)). Prostate tumor incidence and burden were significantly reduced, and tumor latency was delayed in TAg/Gh(dr/dr) rats relative to TAg/Gh(+/+) controls. At 25 wk of age, loss of GH resulted in a 20 and 80% decrease in the area of microinvasive carcinoma in the dorsal and lateral lobes, respectively. By 52 wk of age, invasive prostate adenocarcinomas were observed in all TAg/Gh(+/+) rats, whereas the majority of TAg/Gh(dr/dr) did not develop invasive tumors. Suppression of carcinogenesis could not be attributed to alterations in prostate expression of TAg or androgen receptor or changes in serum testosterone levels. As carcinogenesis progressed in TAg/Gh(+/+) rats, prostate GHR mRNA and protein expression increased significantly, but prostate IGF-I receptor mRNA and protein levels dropped. Furthermore, serum IGF-I and prostate IGF-I levels did not change significantly over the course of carcinogenesis. These findings suggest that GH plays a dominant role in progression from latent to malignant prostate cancer driven by the powerful probasin/TAg fusion gene in rats and suggest that GH antagonists may be effective at treating human prostate cancer
— id: 95187, year: 2008, vol: 149, page: 1366, stat: Journal Article,

Combined estrogen-progestogen contraceptives
Anderson G.L.; Autier P.; Beral V.; Bosland M.C.; Fernandez E.; Haslam S.Z.; Kaufman D.G.; La Vecchia C.; Molinolo A.A.; Newcomb P.A.; Parl F.F.; Peto J.; Rosano G.; Roy D.; Stanczyk F.Z.; Thomas D.B.; Vatten L.; Junghans T.; Olin S.; Shapiro S.; Stafford R.S.; Jameson C.W.; Meyer J.U.; Baan R.; Berthiller J.; Cogliano V.J.; Dresler C.; El Ghissassi F.; Franceschi S.; Goncalves M.-A.G.; Grosse Y.; Guha N.; Marron M.; Mitchell J.; Napalkov N.; Secretan B.; Straif K.; Ullrich A.; Egraz S.; Kajo B.; Lezere M.; Lorenzen-Augros H.
2007 ;91:41-202, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
— id: 83351, year: 2007, vol: 91, page: 41, stat: Journal Article,

Combined estrogen-progestogen menopausal therapy
Anderson G.L.; Autier P.; Beral V.; Bosland M.C.; Fernandez E.; Haslam S.Z.; Kaufman D.G.; La Vecchia C.; Molinolo A.A.; Newcomb P.A.; Parl F.F.; Peto J.; Rosano G.; Roy D.; Stanczyk F.Z.; Thomas D.B.; Vatten L.; Junghans T.; Olin S.; Shapiro S.; Stafford R.S.; Jameson C.W.; Meyer J.U.; Baan R.; Berthiller J.; Cogliano V.J.; Dresler C.; El Ghissassi F.; Franceschi S.; Goncalves M.-A.G.; Grosse Y.; Guha N.; Marron M.; Mitchell J.; Napalkov N.; Secretan B.; Straif K.; Ullrich A.; Egraz S.; Kajo B.; Lezere M.; Lorenzen-Augros H.
2007 ;91:205-372, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
— id: 83350, year: 2007, vol: 91, page: 205, stat: Journal Article,

General remarks
Anderson G.L.; Autier P.; Beral V.; Bosland M.C.; Fernandez E.; Haslam S.Z.; Kaufman D.G.; La Vecchia C.; Molinolo A.A.; Newcomb P.A.; Parl F.F.; Peto J.; Rosano G.; Roy D.; Stanczyk F.Z.; Thomas D.B.; Vatten L.; Junghans T.; Olin S.; Shapiro S.; Stafford R.S.; Jameson C.W.; Meyer J.U.; Baan R.; Berthiller J.; Cogliano V.J.; Dresler C.; El Ghissassi F.; Franceschi S.; Goncalves M.-A.G.; Grosse Y.; Guha N.; Marron M.; Mitchell J.; Napalkov N.; Secretan B.; Straif K.; Ullrich A.; Egraz S.; Kajo B.; Lezere M.; Lorenzen-Augros H.
2007 ;91:33-35, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
— id: 83352, year: 2007, vol: 91, page: 33, stat: Journal Article,

IARC monographs programme on the evaluation of carcinogenic risks to humans
Anderson G.L.; Autier P.; Beral V.; Bosland M.C.; Fernandez E.; Haslam S.Z.; Kaufman D.G.; La Vecchia C.; Molinolo A.A.; Newcomb P.A.; Parl F.F.; Peto J.; Rosano G.; Roy D.; Stanczyk F.Z.; Thomas D.B.; Vatten L.; Junghans T.; Olin S.; Shapiro S.; Stafford R.S.; Jameson C.W.; Meyer J.U.; Baan R.; Berthiller J.; Cogliano V.J.; Dresler C.; El Ghissassi F.; Franceschi S.; Goncalves M.-A.G.; Grosse Y.; Guha N.; Marron M.; Mitchell J.; Napalkov N.; Secretan B.; Straif K.; Ullrich A.; Egraz S.; Kajo B.; Lezere M.; Lorenzen-Augros H.
2007 ;91:9-31, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
— id: 83353, year: 2007, vol: 91, page: 9, stat: Journal Article,

Soy isoflavone consumption is not associated with increased risk of advanced prostate cancer
Bosland, Maarten C; Gann, Peter H
2007 Oct;16(10):2169-2169, Cancer epidemiology biomarkers & prevention
— id: 95188, year: 2007, vol: 16, page: 2169, stat: Journal Article,

Radiographic determination of tissue thickness in paraffin blocks: application to the construction of tissue microarrays
Kong, Xiangtian; Zhao, Yan; Ksionsk, Marti; Zhou, Meisheng; Walden, Paul; Bosland, Maarten; Pei, Zhiheng; Lee, Peng; Melamed, Jonathan
2007 Mar;15(1):108-112, Applied immunohistochemistry & molecular morphology
The determination of tissue thickness in paraffin blocks in the histology laboratory has been largely based on visual estimates. More accurate methods are required for the construction of tissue microarrays (TMAs) to assure a greater yield of cores in sections through the TMA block. We describe an accurate radiographic method to determine tissue thickness in donor paraffin blocks and have validated its application to TMA construction. Individual radiographic analysis was performed on paraffin donor blocks used for the construction of TMAs for determination of donor block tissue thickness. Consecutive numbered slide sections through the TMA block were then examined for the presence or loss of cores in the 150th TMA slide (from the final third of the TMA block) and correlated with the thickness of the individual donor blocks determined radiographically. At the 150th TMA slide, 202 of 1340 cores (15.1%) were depleted. Radiographic measurement showed a greater thickness of the donor paraffin block tissue (2.02 mm) corresponding to the retained cores as compared with the donor tissue (1.54 mm) of the depleted cores (P < 0.001). With progressive slide sections through a TMA block, the retention of tissue cores shows a significant correlation with donor block tissue thickness. Radiographic determination of tissue thickness in donor paraffin blocks can be used in TMA construction. Prior knowledge of tissue thickness in TMA construction can prompt compensatory steps that can enhance the yield of valuable samples and assure sufficient numbers of adequate cores for statistical analysis in biomarker evaluations
— id: 73238, year: 2007, vol: 15, page: 108, stat: Journal Article,

Chemoprevention of rat prostate carcinogenesis by soy isoflavones and by Bowman-Birk inhibitor
McCormick, David L; Johnson, William D; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E
2007 ;57(2):184-193, Nutrition & cancer
Epidemiology studies suggest that soy consumption confers protection against human prostate cancer. To identify the soy component(s) that may be responsible for this chemopreventive activity, studies were conducted to determine the influence of a soy isoflavone mixture (PTI G-2535; 45% genistein, 22% daidzein, 2% glycitein) and a soy-derived protease inhibitor (Bowman-Birk Inhibitor Concentrate; BBIC) on prostate carcinogenesis in rats. Prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single intravenous injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In separate studies, PTI G-2535 and BBIC were administered continuously at 0 (control), 200, or 2000 mg/kg diet, beginning 1 wk post-MNU. PTI G-2535 and BBIC both conferred modest, but statistically significant and dose-related protection against carcinogenesis in the dorsolateral+anterior prostate. These data demonstrate that both the isoflavone and protein (protease inhibitor) components of soy can inhibit prostate carcinogenesis in the rat. However, the modest individual activities of soy isoflavones and BBIC suggest that while both components may contribute to the chemopreventive activity of soy, combination administration (or exposure to whole soy) may be more effective in prostate cancer prevention than is administration of either component alone
— id: 95190, year: 2007, vol: 57, page: 184, stat: Journal Article,

Null effect of dietary restriction on prostate carcinogenesis in the Wistar-Unilever rat
McCormick, David L; Johnson, William D; Haryu, Todd M; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E
2007 ;57(2):194-200, Nutrition & cancer
Chronic dietary restriction inhibits carcinogenesis in several sites in laboratory animals. To determine the effects of dietary restriction on prostate carcinogenesis, prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate (50 mg/day; 21 days); testosterone propionate (100 mg/kg/day; 3 days); N-methyl-N-nitrosourea [MNU; 30 mg/kg; single dose]; and testosterone (subcutaneous implants of 2 pellets containing 40 mg each). Dietary restriction (0% [ad libitum control], 15%, or 30%) was initiated 2 wk post-MNU, and continued until study termination at 12 mo. Dietary restriction induced a rapid suppression of body weight gain but conferred no protection against prostate carcinogenesis. 74% of carcinogen-treated ad libitum controls developed accessory sex gland cancers, versus cancer incidences of 64% and 72% in groups restricted by 15% and 30%, respectively. Similarly, 44% of dietary controls developed cancers limited to the dorsolateral/prostate, versus incidences of 45% and 53% in groups restricted by 15% and 30%. The results of the present study do not support the hypothesis that prostate carcinogenesis can be prevented by reducing caloric intake. Reducing mean body weight by up to 25% through chronic dietary restriction has no effect on the induction of prostate cancers in the Wistar-Unilever rat model
— id: 95189, year: 2007, vol: 57, page: 194, stat: Journal Article,

Chemoprevention of rat prostate carcinogenesis by dietary 16alpha-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone
McCormick, David L; Johnson, William D; Kozub, Nicole M; Rao, K V N; Lubet, Ronald A; Steele, Vernon E; Bosland, Maarten C
2007 Feb;28(2):398-403, Carcinogenesis
Dehydroepiandrosterone (DHEA) is a potent inhibitor of prostate carcinogenesis in rats. However, concerns related to the possible androgenicity of DHEA may preclude its use for chemoprevention of human prostate cancer. Studies were performed to compare the androgenicity of DHEA and a fluorinated DHEA analog, 16alpha-fluoro-5-androsten-17-one (fluasterone), and to determine the chemopreventive activity of fluasterone in the rat prostate. Comparisons of accessory sex gland weight and histology in gonadectomized male rats demonstrated that fluasterone is less androgenic than is DHEA. Fluasterone conferred significant protection against prostate carcinogenesis induced in Wistar-Unilever rats by a sequential regimen of N-methyl-N-nitrosourea+testosterone. Chronic administration of fluasterone at levels of 2000 and 1000 mg/kg diet reduced the incidence of adenocarcinoma in the dorsolateral/anterior prostate from 64% in dietary controls to 28 and 31%, respectively. Other than a dose-related suppression of body weight gain, chronic exposure to fluasterone induced no clinical evidence of toxicity; suppression of body weight gain may be either a pharmacological effect or a minimally toxic effect of the compound. These data demonstrate that a minimally androgenic analog of DHEA protects against prostate carcinogenesis induced in rats by a chemical carcinogen + androgen. The reduced androgenicity of fluasterone may obviate toxicities associated with the androgenicity of the parent compound. On this basis, fluasterone merits consideration for evaluation in clinical trials for prostate cancer prevention. The chemopreventive activity of a non-androgenic DHEA analog suggests that at least a portion of the chemopreventive activity of DHEA in the rat prostate is unrelated to hormonal effects
— id: 72096, year: 2007, vol: 28, page: 398, stat: Journal Article,

Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence
Narayanan, Bhagavathi A; Reddy, Bandaru S; Bosland, Maarten C; Nargi, Dominick; Horton, Lori; Randolph, Carla; Narayanan, Narayanan K
2007 Oct 1;13(19):5965-5973, Clinical cancer research
PURPOSE: Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer. EXPERIMENTAL DESIGN: We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-alpha levels were determined using enzyme immunoassay/ELISA assays. RESULTS: The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-alpha indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr(992) and Tyr(845)) and Akt (Ser(473)) was significant in rats given with these agents in combination. CONCLUSIONS: In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events
— id: 75385, year: 2007, vol: 13, page: 5965, stat: Journal Article,

Sex steroids and prostate carcinogenesis: integrated, multifactorial working hypothesis
Bosland, Maarten C
2006 Nov;1089:168-176, Annals of the New York Academy of Sciences
Androgens are thought to cause prostate cancer, but there is little epidemiological support for this notion. Animal studies, however, demonstrate that androgens are very strong tumor promotors for prostate carcinogenesis after tumor-initiating events. Even treatment with low doses of testosterone alone can induce prostate cancer in rodents. Because testosterone can be converted to estradiol-17beta by the enzyme aromatase, expressed in human and rodent prostate, estrogen may be involved in prostate cancer induction by testosterone. When estradiol is added to testosterone treatment of rats, prostate cancer incidence is markedly increased and even a short course of estrogen treatment results in a high incidence of prostate cancer. The active testosterone metabolite 5alpha-dihydrotestosterone cannot be aromatized to estrogen and hardly induces prostate cancer, supporting a critical role of estrogen in prostate carcinogenesis. Estrogen receptors are expressed in the prostate and may mediate some or all of the effects of estrogen. However, there is also evidence that in the rodent and human prostate conversion occurs of estrogens to catecholestrogens. These can be converted to reactive intermediates that can adduct to DNA and cause generation of reactive oxygen species, and thus estradiol can be a weak DNA damaging (genotoxic) carcinogen. In the rat prostate DNA damage can result from estrogen treatment; this occurs prior to cancer development and at exactly the same location. Inflammation may be associated with prostate cancer risk, but no environmental carcinogenic risk factors have been definitively identified. We postulate that endogenous factors present in every man, sex steroids, are responsible for the high prevalence of prostate cancer in aging men, androgens acting as strong tumor promoters in the presence of a weak, but continuously present genotoxic carcinogen, estradiol-17beta
— id: 72094, year: 2006, vol: 1089, page: 168, stat: Journal Article,

Docosahexaenoic acid in combination with celecoxib modulates HSP70 and p53 proteins in prostate cancer cells
Narayanan, Narayanan K; Narayanan, Bhagavathi A; Bosland, Maarten; Condon, Mark S; Nargi, Dominick
2006 Oct 1;119(7):1586-1598, International journal of cancer
The role of cyclooxygenase-2 (COX-2) and the mechanism by which it influences the development and behavior of prostate cancer is unclear. Selective COX-2 inhibitors may be effective against prostate cancer via COX-2-independent mechanisms. But administration of high doses of COX-2 inhibitors over longer period of time may not be devoid of side effects. There is increasing interest in using COX-2 inhibitors in combination with other chemopreventive agents to overcome the issue of toxicity. However, the molecular mechanisms underlying their combined actions are not well understood. Therefore, the present study was designed to determine the effects of low doses of docosahexaenoic acid (DHA) in combination with celecoxib on the molecular targets at the proteins level in rat prostate cancer cells. Two-dimensional gel electrophoresis, in combination with mass spectrometry analysis, was used for protein identification. Western blot analysis confirmed the proteins identified. Paraffin-embedded tissue sections from the rat prostate tumor were used to detect base level expression of heat shock protein 70 (HSP70) and p53. The rate of cancer cell growth was inhibited more effectively (p < 0.01) by DHA in combination with celecoxib at lower doses (2.5 muM each). A total number of twelve proteins were differentially expressed by the combined action of DHA and celecoxib at low doses. It was interesting to note that these agents activated both HSP70 and p53 proteins. Activation of HSP70 by the combined actions of DHA and celecoxib in the presence of wild-type p53 reveals a unique COX-2 independent mode of action against prostate cancer. (c) 2006 Wiley-Liss, Inc
— id: 64745, year: 2006, vol: 119, page: 1586, stat: Journal Article,

The parity-related protection against breast cancer is compromised by cigarette smoke during rat pregnancy: observations on tumorigenesis and immunological defenses of the neonate
Steinetz, Bernard G; Gordon, Terry; Lasano, Salamia; Horton, Lori; Ng, Sheung Pui; Zelikoff, Judith T; Nadas, Arthur; Bosland, Maarten C
2006 Jun;27(6):1146-1152, Carcinogenesis
Early pregnancy is a powerful negative risk factor for breast cancer (BCa) in women. Pregnancy also protects rats against induction of BCa by carcinogens such as N-methyl-N-nitrosourea (MNU), making the parous rat a useful model for studying this phenomenon. Smoking during early pregnancy may lead to an increased risk of BCa in later life, possibly attributable to carcinogens in cigarette smoke (CS), or to reversal of the parity-related protection against BCa. To investigate these possibilities, 50-day-old timed first-pregnancy rats were exposed to standardized mainstream CS (particle concentration = 50 mg/m3) or to filtered air (FA) 4 h/day, Day 2-20 of gestation. Age-matched virgin rats were similarly exposed to CS or FA. At age 100 days, the CS or FA-exposed, parous and virgin rats were injected s.c. with MNU (50 mg/kg body wt), or with MNU vehicle. Mammary tumors (MTs) first appeared in virgin rats 9 weeks post-MNU injection. While no MTs were detected in FA-exposed parous rats until 18 weeks post-MNU, MTs appeared in the CS-exposed parous rats as early as 10 wks (P < 0.02). As no MTs developed in CS-exposed rats not injected with MNU, CS did not act as a direct mammary carcinogen. Serum prolactin concentration on Day 19 of pregnancy in CS-exposed dams was reduced by 50% compared with FA-exposed dams (P < 0.005). CS exposure during a pregnancy may thus 'deprotect' rats, enhancing their vulnerability to MNU-induced BCa. Prenatal CS exposure had no detectable effect on the immune responses of the pups examined at 3, 8 or 19 weeks of age. However, prolactin concentration in stomach contents (milk) of 3-day-old pups suckled by CS-exposed dams was decreased when compared with that of FA-exposed dams (P < 0.032). As milk-borne prolactin modulates development of the central nervous and immune systems of neonatal rats, CS exposure of the dams could adversely affect later maturation of these systems by reducing milk prolactin
— id: 66151, year: 2006, vol: 27, page: 1146, stat: Journal Article,

The role of estrogens in prostate carcinogenesis: a rationale for chemoprevention
Bosland, Maarten C
2005 ;7 Suppl 3:S4-S10, Reviews in urology
Estrogens as hormonal therapy, particularly diethylstilbestrol, are effective against androgen-dependent prostate cancer, but paradoxically estrogens might also be involved in the causation of this malignancy. Therefore, antiestrogens have been suggested as both a chemopreventive and chemotherapeutic treatment, thereby inhibiting the development and progression of prostate cancer. This review addresses the role of estrogens in prostate carcinogenesis and prostate cancer progression and examines the rationale for using antiestrogenic agents in chemoprevention of prostate cancer
— id: 72095, year: 2005, vol: 7 Suppl 3, page: S4, stat: Journal Article,

Prostate cancer in patients with screening serum prostate specific antigen values less than 4.0 ng/dl: results from the cooperative prostate cancer tissue resource
Datta, Milton W; Dhir, Rajiv; Dobbin, Kevin; Bosland, Maarten C; Melamed, Jonathan; Becich, Michael J; Orenstein, Jan M; Kajdacsy-Balla, Andre A; Patel, Ashok; Macias, Virgilia; Berman, Jules J
2005 May;173(5):1546-1551, Journal of urology
PURPOSE: Prostate cancer can occur in patients with low screening serum prostate specific antigen (PSA) values (less than 4.0 ng/ml). It is currently unclear whether these tumors are different from prostate cancer in patients with high PSA levels (greater than 4.0 ng/ml). MATERIALS AND METHODS: From the Cooperative Prostate Cancer Tissue Resource database through March 2004, 3,416 patients with screening PSA less than 16.0 ng/ml diagnosed with prostate cancer between 1993 and 2004 were stratified in groups based on screening serum PSA. These subsets were compared for race, age at diagnosis, clinical and pathological stage, Gleason score, positive surgical margins, posttreatment recurrent disease, and vital status. RESULTS: We identified 468 (14%) patients with screening PSA less than 4.0 ng/ml, 142 (4.2%) of whom had a PSA of less than 2.0 ng/ml. This group included 40 black and 376 white patients. Men with low screening PSA treated with radical prostatectomy had smaller cancers, lower Gleason scores, lower pathological tumor (T) stage and lower PSA recurrence rates than men with high PSA levels (4 ng/ml or greater). These differences held true for men who were younger than 62 years or were white, whereas older or black men had tumor characteristics and outcomes similar to those with higher PSA levels. CONCLUSIONS: Young (younger than 62 years) or white patients with screening serum PSA less than 4.0 ng/ml had smaller, lower grade tumors and lower recurrence rates than patients with PSA 4.0 ng/ml or greater. This was not true for those older than 62 years and for black men
— id: 51790, year: 2005, vol: 173, page: 1546, stat: Journal Article,

Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement
Liang, Feng-Xia; Bosland, Maarten C; Huang, Hongying; Romih, Rok; Baptiste, Solange; Deng, Fang-Ming; Wu, Xue-Ru; Shapiro, Ellen; Sun, Tung-Tien
2005 Dec 5;171(5):835-844, Journal of cell biology
Although the epithelial lining of much of the mammalian urinary tract is known simply as the urothelium, this epithelium can be divided into at least three lineages of renal pelvis/ureter, bladder/trigone, and proximal urethra based on their embryonic origin, uroplakin content, keratin expression pattern, in vitro growth potential, and propensity to keratinize during vitamin A deficiency. Moreover, these cells remain phenotypically distinct even after they have been serially passaged under identical culture conditions, thus ruling out local mesenchymal influence as the sole cause of their in vivo differences. During vitamin A deficiency, mouse urothelium form multiple keratinized foci in proximal urethra probably originating from scattered K14-positive basal cells, and the keratinized epithelium expands horizontally to replace the surrounding normal urothelium. These data suggest that the urothelium consists of multiple cell lineages, that trigone urothelium is closely related to the urothelium covering the rest of the bladder, and that lineage heterogeneity coupled with cell migration/replacement form the cellular basis for urothelial squamous metaplasia
— id: 59934, year: 2005, vol: 171, page: 835, stat: Journal Article,

Anti-inflammatory effects of omega-3 fatty acid promote differentiation in prostate cancer cells: Role of prohibitin, a highly conserved protein modulated by DHA
Narayanan, NK; Narayanan, BA; Bosland, MC; Nargi, D; Reddy, BS
2005 NOV ;14(11):2722S-2723S, Cancer epidemiology biomarkers & prevention
— id: 61899, year: 2005, vol: 14, page: 2722S, stat: Journal Article,

The development of common data elements for a multi-institute prostate cancer tissue bank: The Cooperative Prostate Cancer Tissue Resource (CPCTR) experience
Patel, Ashokkumar A; Kajdacsy-Balla, Andre; Berman, Jules J; Bosland, Maarten; Datta, Milton W; Dhir, Rajiv; Gilbertson, John; Melamed, Jonathan; Orenstein, Jan; Tai, Kuei-Fang; Becich, Michael J
2005 Aug 21;5(1):108-108, BMC cancer
BACKGROUND: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a consortium of four geographically dispersed institutions that are funded by the U.S. National Cancer Institute (NCI) to provide clinically annotated prostate cancer tissue samples to researchers. To facilitate this effort, it was critical to arrive at agreed upon common data elements (CDEs) that could be used to collect demographic, pathologic, treatment and clinical outcome data. METHODS: The CPCTR investigators convened a CDE curation subcommittee to develop and implement CDEs for the annotation of collected prostate tissues. The draft CDEs were refined and progressively annotated to make them ISO 11179 compliant. The CDEs were implemented in the CPCTR database and tested using software query tools developed by the investigators. RESULTS: By collaborative consensus the CPCTR CDE subcommittee developed 145 data elements to annotate the tissue samples collected. These included for each case: 1) demographic data, 2) clinical history, 3) pathology specimen level elements to describe the staging, grading and other characteristics of individual surgical pathology cases, 4) tissue block level annotation critical to managing a virtual inventory of cases and facilitating case selection, and 5) clinical outcome data including treatment, recurrence and vital status. These elements have been used successfully to respond to over 60 requests by end-users for tissue, including paraffin blocks from cases with 5 to 10 years of follow up, tissue microarrays (TMAs), as well as frozen tissue collected prospectively for genomic profiling and genetic studies. The CPCTR CDEs have been fully implemented in two major tissue banks and have been shared with dozens of other tissue banking efforts. CONCLUSION: The freely available CDEs developed by the CPCTR are robust, based on 'best practices' for tissue resources, and are ISO 11179 compliant. The process for CDE development described in this manuscript provides a framework model for other organ sites and has been used as a model for breast and melanoma tissue banking efforts
— id: 57729, year: 2005, vol: 5, page: 108, stat: Journal Article,

An accurate method for determination of tissue thickness in paraffin blocks by Faxitron analysis: Application to tissue microarray construction
Zhao, Y; Kong, X; Ksionsk, M; Walden, PD; Bosland, MC; Melamed, J
2005 ;18(Suppl 1):337A-337A, Modern pathology
— id: 50449, year: 2005, vol: 18, page: 337A, stat: Journal Article,

An accurate method for determination of tissue thickness in paraffin blocks by faxitron analysis: Application to tissue microarray construction
Zhao, Y; Kong, X; Ksionsk, M; Walden, PD; Bosland, MC; Melamed, J
2005 ;85(Suppl 1):337A-337A, Laboratory investigation
— id: 50479, year: 2005, vol: 85, page: 337A, stat: Journal Article,

"A randomized, controlled 6-Mo intervention with soy protein isolate in men with biochemical recurrence after radical prostatectomy"
Bosland, MC; Zeleniuch-Jacquotte, A; Melamed, J; Lepor, H; Taneja, SS; Schmoll, J; Watanabe, H; Levinson, B; Randolph, C; Walden, PD
2004 MAY ;134(5):1259S-1259S, Journal of nutrition
— id: 46488, year: 2004, vol: 134, page: 1259S, stat: Journal Article,

Synthetic luteinizing hormone releasing hormone (LHRH) vaccine for effective androgen deprivation and its application to prostate cancer immunotherapy
Finstad, Connie L; Wang, Chang Yi; Kowalski, Jacek; Zhang, Meilun; Li, Ming Lie; Li, Xuan Mao; Xia, Wei Guo; Bosland, Maarten C; Murthy, Krishna K; Walfield, Alan M; Koff, Wayne C; Zamb, Timothy J
2004 Mar 12;22(9-10):1300-1313, Vaccine
We have designed a peptide-based immunotherapeutic vaccine for treatment of androgen-responsive prostate cancer. The vaccine targets the luteinizing hormone-releasing hormone (LHRH) decapeptide that results in an androgen-deprivation immunotherapy. The design elements of the peptide immunogens are the LHRH peptide or B cell epitope synthetically linked to different promiscuous helper T cell (Th) sequences, the UBITh epitopes, derived from four natural pathogens for effective immunogenicity in outbred populations, and in some cases, also linked to an adjuvanting peptide from Yersinia invasin (Inv) protein. The UBITh LHRH immunogens are adsorbed on Alhydrogel or formulated as several different oil-based emulsions and tested in rodents, dogs, and a non-human primate, baboons. The immunogens generate an anti-LHRH antibody response specific to the LHRH decapeptide element in contrast to LHRH conjugate-carrier protein vaccines where only a small portion of the antibody response is directed to the target epitope and epitopic suppression is noted. Individual UBITh peptide domains, but not the LHRH and Inv peptide domains, are stimulatory in lymphocyte cultures. The UBITh LHRH immunogens in a clinically applicable formulation, controlled the growth of Dunning R3327-H androgen-responsive prostate tumor cells in rats. The results demonstrate universal responsiveness and long duration of androgen deprivation from three diverse species, and thus vaccine efficacy
— id: 44709, year: 2004, vol: 22, page: 1300, stat: Journal Article,

Adherence to a low-fat diet in men with prostate cancer
Link, Lilli B; Thompson, Seth M; Bosland, Maarten C; Lumey, L H
2004 Nov;64(5):970-975, Urology
OBJECTIVES: To evaluate, in a feasibility study, the adherence to a low-fat diet by men with prostate cancer. Evidence is growing that a low-fat diet affects the development and course of prostate cancer. To design preventive and therapeutic interventions, it is important to know whether men will adhere to these nutritional recommendations, particularly when motivated by the diagnosis of prostate cancer. METHODS: Men with elevated prostate-specific antigen levels, most of whom were recently treated for prostate cancer, were randomized to one of four dietary regimens for which they received nutritional counseling: a low-fat diet (15% fat or less) with supplements (vitamin E and selenium), a low-fat diet (15% fat or less) without the supplements, the supplements alone, and a control group. Adherence was evaluated by the change in weight, fat intake, free fatty acids, cholesterol, high-density and low-density lipoproteins, and triglycerides during a 12-month period. RESULTS: The mean age of the 48 participants was 66 years. For those counseled about a low-fat diet, the mean change in the percentage of energy (kilocalories) in the diet from fat was greater after 3 months (-8.6% versus +2.1%, P <0.001) and 12 months (-9.8% versus -1.6%, P = 0.001). Three months after starting the intervention, those randomized to low-fat dietary counseling had lost 2 kg, on average, compared with 0.8 kg lost by those who did not receive this counseling (P = 0.09). At 12 months, those receiving low-fat counseling had lost 2.8 kg, on average, compared with 0.5 kg gained among the other groups (P = 0.02). CONCLUSIONS: With appropriate counseling, men with prostate cancer can adhere to a low-fat dietary intervention for a 12-month period
— id: 62121, year: 2004, vol: 64, page: 970, stat: Journal Article,

The cooperative prostate cancer tissue resource: a specimen and data resource for cancer researchers
Melamed, Jonathan; Datta, Milton W; Becich, Michael J; Orenstein, Jan M; Dhir, Rajiv; Silver, Sylvia; Fidelia-Lambert, Marie; Kadjacsy-Balla, Andre; Macias, Virgilia; Patel, Ashokkumar; Walden, Paul D; Bosland, Maarten C; Berman, Jules J
2004 Jul 15;10(14):4614-4621, Clinical cancer research
PURPOSE: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a National Cancer Institute-supported tissue bank that provides large numbers of clinically annotated prostate cancer specimens to investigators. This communication describes the CPCTR to investigators interested in obtaining prostate cancer tissue samples. EXPERIMENTAL DESIGN: The CPCTR, through its four participating institutions, has collected specimens and clinical data for prostate cancer cases diagnosed from 1989 onward. These specimens include paraffin blocks and frozen tissue from radical prostatectomy specimens and paraffin blocks from prostate needle biopsies. Standardized histopathological characterization and clinical data extraction are performed for all cases. Information on histopathology, demography (including ethnicity), laboratory data (prostate-specific antigen values), and clinical outcome related to prostate cancer are entered into the CPCTR database for all cases. Materials in the CPCTR are available in multiple tissue formats, including tissue microarray sections, paraffin-embedded tissue sections, serum, and frozen tissue specimens. These are available for research purposes following an application process that is described on the CPCTR web site (www.prostatetissues.org). RESULTS: The CPCTR currently (as of October 2003) contains 5135 prostate cancer cases including 4723 radical prostatectomy cases. Frozen tissues, in some instances including patient serum samples, are available for 1226 cases. Biochemical recurrence data allow identification of cases with residual disease, cases with recurrence, and recurrence-free cases. CONCLUSIONS: The CPCTR offers large numbers of highly characterized prostate cancer tissue specimens, including tissue microarrays, with associated clinical data for biomarker studies. Interested investigators are encouraged to apply for use of this material (www.prostatetissues.org)
— id: 44707, year: 2004, vol: 10, page: 4614, stat: Journal Article,

Immuno-neutralization of circulating relaxin does not alter the breast cancer-protective action of parity in MNU-treated rats
Steinetz, Bernard G; Sherwood, O David; Lasano, Sally; Horton, Lori; Bosland, Maarten C
2004 Apr;4(1):59-68, Journal of experiemental therapeutics & oncology
Early pregnancy and childbirth protects women against future development of breast cancer by an unknown mechanism. Parity likewise reduces mammary cancer incidence in rats exposed to the carcinogen, N-methyl-N-nitrosourea (MNU), providing a model for the human phenomenon. We hypothesized that relaxin, a 6KD luteal mammotropic hormone of pregnancy, might be the anti-cancer pregnancy factor, and that induced relaxin deficiency during rat gestation would restore carcinogen sensitivity. Forty-one pregnant (age 50 days) and 25 age-matched virgin Sprague-Dawley rats were used. Relaxin deficiency was induced by injecting mouse monoclonal anti-rat relaxin antibody (MCA1) days 12-18 of gestation. Pregnant controls were injected with vehicle or mouse IgG on the same schedule. Because MCA1 disrupts parturition, all rats underwent cesarean section on day 22. At age 100 days, all rats were injected i.v. with MNU (50mg/Kg) and examined daily for tumors until euthanized at age 240 days.Mammary tumor incidence and frequency were significantly (p<0.01) reduced and tumor latency was increased (p<0.001) in primiparous as compared with virgin rats. However, tumor incidence, type, size and latency were similar in MCA1-treated and control primiparous rats. Thus, luteal relaxin does not appear to be the factor responsible for resistance to breast cancer
— id: 44708, year: 2004, vol: 4, page: 59, stat: Journal Article,

The parity-related protection against breast cancer is compromized by cigarette smoke during rat pregnancy
Steinetz, BG; Gordon, T; Lasano, S; Horton, L; Bosland, MC
2004 SEP 2 ;5(4):114-115, Biology of reproduction
— id: 46508, year: 2004, vol: 5, page: 114, stat: Journal Article,

A randomized, controlled six-month intervention study soy protein isolate in men with biochemical recurrence after radical prostatectomy
Bosland, MC; Zeleniuch-Jacquotte, A; Melamed, J; Lepor, H; Taneja, SS; Schmoll, J; Watanabe, H; Levinson, B; Walden, PD
2003 NOV ;12(11):1327S-1328S, Cancer epidemiology biomarkers & prevention
— id: 55376, year: 2003, vol: 12, page: 1327S, stat: Journal Article,

Ethnicity based analysis of prostatectomy specimens and PSA outcomes: Results of the NCI cooperative prostate cancer tissue resource
Datta, MW; Becich, MJ; Bosland, MC; Dhir, R; Kajdacsy-Balla, A; Melamed, J; Orenstein, J; Silveer, S; Berman, J
2003 ;83(Suppl 1):147A-147A, Laboratory investigation
— id: 37154, year: 2003, vol: 83, page: 147A, stat: Journal Article,

Ethnicity based analysis of prostatectomy specimens and PSA outcomes: Results of the NCI cooperative prostate cancer tissue resource
Datta, MW; Becich, MJ; Bosland, MC; Dhir, R; Kajdacsy-Balla, A; Melamed, J; Orenstein, J; Silver, S; Berman, J
2003 ;16(Suppl 1):147A-147A, Modern pathology
— id: 38525, year: 2003, vol: 16, page: 147A, stat: Journal Article,

Lack of chemopreventive activity of selenium compounds in the Wistar-Unilever rat prostate cancer model
McCormick, DL; Johnson, WD; Lubet, RA; Steele, VE; Bosland, MC
2003 NOV ;12(11):1327S-1327S, Cancer epidemiology biomarkers & prevention
— id: 55375, year: 2003, vol: 12, page: 1327S, stat: Journal Article,

Prostate cancer pathologic parameters and clinical outcome: Results from the cooperative prostate cancer tissue resource (CPCTR)
Melamed, J; Datta, MW; Becich, MJ; Bosland, M; Dhir, R; Kajdacsy-Balla, A; Orenstein, J; Silver, S; Berman, JJ
2003 ;16(Suppl 1):162A-162A, Modern pathology
— id: 38526, year: 2003, vol: 16, page: 162A, stat: Journal Article,

Prostate cancer pathologic parameters and clinical outcome: Results from the cooperative prostate cancer tissue resource (CPCTR)
Melarned, J; Datta, MW; Becich, MJ; Bosland, M; Dhir, R; Kajdacsy-Balla, A; Orenstein, J; Silver, S; Berman, JJ
2003 ;83(Suppl 1):162A-162A, Laboratory investigation
— id: 37155, year: 2003, vol: 83, page: 162A, stat: Journal Article,

Suppression of N-methyl-N-nitrosourea/testosterone-induced rat prostate cancer growth by celecoxib: effects on cyclooxygenase-2, cell cycle regulation, and apoptosis mechanism(s)
Narayanan, Bhagavathi A; Condon, Mark S; Bosland, Maarten C; Narayanan, Narayanan K; Reddy, Bandaru S
2003 Aug 15;9(9):3503-3513, Clinical cancer research
PURPOSE: This study was aimed at examining the mechanisms underlying the chemopreventive effect of celecoxib against prostate cancer. We focused our attention on events at the cellular level to show the ability of celecoxib to inhibit prostate cancer growth, by inducing cell cycle arrest and apoptosis. Moreover, we attempted to demonstrate the expression of genes involved in the downstream events related to cyclooxygenase-2 (COX-2) regulation and apoptosis. EXPERIMENTAL DESIGN: To determine the level of COX-2 expression, we used paraffin-embedded tumor tissue sections and cancer cells (I-26) derived from N-methyl-N-nitroso-urea/testosterone-induced rat dorsolateral prostate, and we used immunofluorescence detection and Western blot analyses with anti-COX-2 monoclonal antibodies. We conducted clonogenic cell survival assays to demonstrate cell growth inhibition at very low doses of celecoxib. Flow cytometric analysis demonstrated the effects on the cell cycle. Reverse transcription-PCR and Western blot analyses were performed to show the effect of celecoxib on the downstream events of COX-2 and apoptosis-related targets. RESULTS: The summary of our findings indicates that (a). these cells from chemically induced rat prostate tumors express COX-2 at both the mRNA and the protein level; (b). celecoxib significantly reduces COX-2 expression in these cancer cells; and (c). celecoxib induces cell cycle arrest at the G(1)-S phase transition point and modifies cell cycle regulatory proteins such as cyclin D1, retinoblastoma (Rb), and phosphorylated Rb, cyclin E, p27(KIP1), and p21(WAF1/CIP1). Furthermore, celecoxib inhibits DNA synthesis and induces apoptosis. Most importantly, celecoxib-induced apoptosis was associated with down-regulation of COX-2, nuclear factor kappaBp65, and with activation of peroxisome proliferator-activated receptor gamma, apoptosis activating factor-1, and caspase-3. CONCLUSION: Results from the present study clearly indicate that celecoxib exerts its anticancer effect partly through COX-2-independent mechanisms in addition to the known primary function of COX-2 inhibition
— id: 44710, year: 2003, vol: 9, page: 3503, stat: Journal Article,

Does arsenic require a carcinogenic partner?
Rossman TG; Uddin AN; Burns FJ; Bosland MC
Arsenic exposure and health effects V : proceeding of the Fifth International Conference on Arsenic Exposure and Health Effects New York : Elsevier, 2003,
— id: 3329, year: 2003, vol: , page: 197, stat: Chapter,

Chemoprevention strategies for prostate cancer
Bosland, Maarten C; McCormick, David L; Melamed, Jonathan; Walden, Paul D; Zeleniuch-Jacquotte, Anne; Lumey, L H
2002 Aug;11 Suppl 2(2):S18-S27, European journal of cancer prevention
Prostate cancer is the most common male malignancy in western countries. Although primary prevention of prostate cancer is not possible, screening using prostate-specific antigen (PSA) may eliminate prostate cancers by definitive treatments. Prevention of clinically detectable prostate cancer requires earlier chemoprevention interventions. Because prostate cancer is histologically present in 30-50% of 30- to 50-year-old men, effective chemoprevention needs to inhibit not only prostate carcinogenesis but also growth and progression of these cancers. A prostate carcinogenesis animal model has been used to screen chemopreventive agents; inhibitory effects were found with 9-cis-retinoic acid, dehydroepiandrosterone, fluasterone, and the Bowman-Birk inhibitor and an isoflavone mixture which both occur in soy. Such results can be used to select agents for clinical trials. Besides large-scale long-duration prevention trials, trials of short/intermediate duration using smaller cohorts prior to or following radical prostatectomy may provide excellent and cost-effective approaches for chemopreventive agent efficacy testing. Intervention prior to surgery allows measurements of intervention agents and intermediate end-points in the prostate. These peri-surgical trials only assess inhibition of growth and progression of preexisting cancer, not real preventive effects, but they focus on clinically significant cancers. Such trials are an essential step in the development of antiprostate cancer chemoprevention agents
— id: 34748, year: 2002, vol: 11 Suppl 2, page: S18, stat: Journal Article,

Endocrine disruptors. Anthropogenic compounds
Bosland, Maarten C; Metzler, Manfred
Berlin : Springer, 2002,
— id: 2096, year: 2002, vol: , page: , stat: ,

Efficacy testing of chemoprevention agents in the MNU plus testosterone WU rat prostate carcinogenesis model
Bosland, MC; Johnson, WD; Luber, RA; Steele, VE; McCormick, DL
2002 OCT ;11(10):B111-41, Cancer epidemiology biomarkers & prevention
— id: 34088, year: 2002, vol: 11, page: B111, stat: Journal Article,

Catechol estrogen metabolites and conjugates in different regions of the prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer
Cavalieri, Ercole L; Devanesan, Prabu; Bosland, Maarten C; Badawi, Alaa F; Rogan, Eleanor G
2002 Feb;23(2):329-333, Carcinogenesis
Prostate carcinomas arise in 100% of Noble rats treated with estradiol and testosterone. We hypothesize that estrogens initiate prostate cancer mainly by formation of 4-catechol estrogens (CE), followed by their oxidation to catechol estrogen-3,4-quinones (CE-3,4-Q), which can react with DNA. To avoid cancer initiation, CE can be detoxified by catechol-O-methyltransferase (COMT), and CE-3,4-Q by conjugation with glutathione (GSH) or by reduction to CE, catalyzed by quinone reductase and/or cytochrome P450 reductase. To investigate the prostatic metabolism of estrogens, Noble rats were treated with the CE 4-hydroxyestradiol (4-OHE2) or estradiol-3,4-quinone (E2-3,4-Q), and CE metabolites and conjugates were analyzed in the four regions of the prostate, which differ in susceptibility to carcinoma formation. Following treatment of rats with 4-OHE2 (6 micromol/100 g body weight in 200 microl of trioctanoin/dimethylsulfoxide (4:1) by intraperitoneal injection) for 90 min, the non-susceptible ventral (VP) and anterior (AP) prostate had higher levels of 4-methoxyCE and GSH conjugates than the susceptible dorsolateral prostate (DLP) and periurethral prostate (PUP). After treatment with the same molar amount of E2-3,4-Q, the VP and AP contained more GSH conjugates, 4-CE and 4-methoxyCE than the susceptible DLP and PUP. These results suggest that prostate areas susceptible to carcinoma induction have less protection by COMT, GSH, and quinone reductase and/or cytochrome P450 reductase, favoring reaction of CE-3,4-Q with DNA, presumably to initiate cancer
— id: 34897, year: 2002, vol: 23, page: 329, stat: Journal Article,

Evaluation of the adequacy of published studies of low-dose effects of bisphenol A on the rodent prostate for use in human risk assessment
Milman, Harry A; Bosland, Maarten C; Walden, Paul D; Heinze, John E
2002 Jun;35(3):338-346, Regulatory toxicology & pharmacology
Studies conducted in our laboratories and by others found no consistent correlation between prostate size, prostate pathology, or the development of prostate cancer under a variety of experimental conditions. Furthermore, an evaluation of eight published studies that were conducted in mice and rats following in utero exposure by oral treatment of dams with low levels of bisphenol A (BPA) and that focused on the prostate identified several discrepancies that affect their adequacy for use in human risk assessment. For example, there was inadequate reporting of the purity of BPA and the animal supplier used, and housing of offspring was not the same among the studies. In addition, there were differences between studies with mice and rats in exposure regimen, route of exposure, and numbers of dams or pups used per BPA dose group. Poor inter- and intraspecies correlation (i.e., mouse to rat or between mouse or rat strains) further complicates the ability to use results from these studies to predict potential prostate effects in humans. Thus, we conclude that a finding of increased prostate weight in rodent studies with perinatal exposure in the absence of associated pathologic and/or functional changes is meaningless and not indicative of a potential adverse effect in humans
— id: 34896, year: 2002, vol: 35, page: 338, stat: Journal Article,

Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies
Rossman, Toby G; Uddin, Ahmed N; Burns, Fredric J; Bosland, Maarten C
2002 Oct;110 Suppl 5(4):749-752, Environmental health perspectives
Although epidemiologic evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung, and bladder cancers, no animal model for arsenic carcinogenesis has been successful. This lack has hindered mechanistic studies of arsenic carcinogenesis. Previously, we and others found that low concentrations (< or =5 microm) of arsenite (the likely environmental carcinogen), which are not mutagenic, can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR) and alkylating agents. This enhancing effect appears to result from inhibition of DNA repair by arsenite, but not via inhibition of DNA repair enzymes. Rather, low concentrations of arsenite disrupt p53 function and upregulate cyclin D1. Failure to find an animal model for arsenic carcinogenesis might be because arsenite is not a carcinogen per se but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice were given 10 mg/L sodium arsenite in drinking water (or not) and irradiated with 1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no tumors appeared in any organs in control mice or in mice given arsenite alone. After 26 weeks irradiated mice given arsenite had a 2.4-fold increase in skin tumor yield compared with mice given UVR alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite were much larger and more invasive. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling. Skin cancers in populations drinking water containing arsenic may be caused by the enhancement by arsenic compounds of carcinogenesis induced by UVR (or other environmental agents). It is possible that lung and bladder cancers associated with arsenic in drinking water may also require a carcinogenic partner
— id: 34894, year: 2002, vol: 110 Suppl 5, page: 749, stat: Journal Article,

Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells
Tyagi, Alpana; Bhatia, Neehar; Condon, Mark S; Bosland, Maarten C; Agarwal, Chapla; Agarwal, Rajesh
2002 Nov 1;53(3):211-217, Prostate
BACKGROUND: The tremendous impact of prostate cancer (PCA) on the US male population has led to an increased attention on its prevention and on therapeutic intervention. Short-term models are needed to quickly screen the efficacy of promising agents against PCA. We have established recently several rat PCA cell lines from primary PCA in rats induced by a MNU-testosterone protocol, but their usefulness as a model for screening PCA preventive and therapeutic agents remains to be established. With the rationale that agents found effective in these cells could be promising for efficacy testing in long-term in vivo experiments, e.g., with MNU-testosterone-induced PCA in rats, the major goal of our study was to assess the antiproliferative and apoptotic efficacy in rat PCA cell lines of silibinin, a major active flavonoid component of silymarin, which consists of a group of flavonoid antioxidants occurring in milk thistle (Silybum marianum). METHODS: Three rat PCA cell lines, namely H-7, I-8, and I-26, were treated with silibinin or silymarin, a crude silibinin-containing preparation, at various doses for varying lengths of time. Cell growth and viability studies were carried out by using hemocytometer and Trypan blue dye exclusion methods. Cell cycle distribution studies were conducted by using PI staining and flow cytometry analysis, and DNA synthesis was assessed by bromodeoxyuridine incorporation. Apoptotic cell death was assessed as DNA damage by using an enzyme-linked immunosorbent assay method and by annexin V and PI staining followed by flow cytometry analysis. RESULTS: Silibinin resulted in a significant growth inhibition and reduction in cell viability in each cell line studied in both a dose- and a time-dependent manner. Silibinin treatment of H-7 and I-8 cells at 100 microM dose for 12 and 24 hr resulted in a G1 arrest but caused S phase arrest after a 48-hr treatment period in each cell line studied. Similar silibinin treatment of I-26 cells resulted in a slight S phase arrest at all time points studied. Consistent with these findings, silibinin showed a strong inhibition of DNA synthesis. Silibinin also induced a substantial apoptotic death in each cell line studied. Similar to silibinin, silymarin induced growth inhibition and reduced viability in a dose- and time-dependent manner. CONCLUSION: This study demonstrates that silibinin as well as silymarin induce growth inhibition and apoptosis in rat PCA cells. These results form a strong rationale for PCA prevention and therapeutic intervention studies with silibinin and silymarin in animal models, such as the MNU-testosterone rat PCA model, to establish their efficacy and to further define their mechanisms of action under in vivo conditions
— id: 34895, year: 2002, vol: 53, page: 211, stat: Journal Article,

Chemoprevention trials in men with prostate-specific antigen failure or at high risk for recurrence after radical prostatectomy: Application to efficacy assessment of soy protein
Bosland MC; Kato I; Melamed J; Taneja S; Lepor H; Torre P; Walden P; Zeleniuch-Jacquotte A; Lumey LH
2001 Apr;57(4 Suppl 1):202-204, Urology
This article discusses the basic elements of chemoprevention trial designs using cohorts of men following radical prostatectomy who either have prostate-specific antigen (PSA) failure indicative of recurrence or are at high risk for recurrence (positive surgical margins, extracapsular extension, seminal vesicle invasion, positive lymph nodes, Gleason score of greater than or equal to 8, preoperative serum PSA less than 20 ng/mL). Two ongoing randomized, double-blind, placebo-controlled clinical trials with soy protein as intervention in these 2 populations are described. In the trial with men at high risk for recurrence, participants started intervention within 4 months after surgery and were followed for up to 2 years; primary endpoints were PSA failure rate and time-to-PSA failure. In the trial with men with PSA failure (PSA 0.1 to 2.0 ng/mL), participants received treatment for 8 months and the primary endpoint is rise in PSA over time. The strengths and limitations of these designs are discussed and interim experience using studies with soy protein as the intervention agent are summarized
— id: 18555, year: 2001, vol: 57, page: 202, stat: Journal Article,

Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: an animal model for arsenic carcinogenesis
Rossman TG; Uddin AN; Burns FJ; Bosland MC
2001 Oct 1;176(1):64-71, Toxicology & applied pharmacology
Although epidemiological evidence shows an association between arsenic in drinking water and increased risk of skin, lung, and bladder cancers, arsenic compounds are not animal carcinogens. The lack of animal models has hindered mechanistic studies of arsenic carcinogenesis. Previously, this laboratory found that low concentrations of arsenite (the likely environmental carcinogen) which are not mutagenic can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR). This enhancing effect appears to result from inhibition of DNA repair by arsenite. Recently we found that low concentrations of arsenite disrupted p53 function and upregulated cyclin D1. These results suggest that the failure to find an animal model for arsenic carcinogenesis is because arsenite is not a carcinogen per se, but rather acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR as carcinogenic stimulus in hairless Skh1 mice. Mice given 10 mg/l sodium arsenite in drinking water for 26 weeks had a 2.4-fold increase in yield of tumors after 1.7 KJ/m(2) UVR three times weekly compared with mice given UVR alone. No tumors appeared in mice given arsenite alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite appeared earlier and were much larger and more invasive than in mice given UVR alone. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling
— id: 32229, year: 2001, vol: 176, page: 64, stat: Journal Article,

The role of steroid hormones in prostate carcinogenesis [In Process Citation]
Bosland MC
2000 ;(27):39-66, Journal of the National Cancer Institute. Monographs
Carcinoma of the prostate is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the United States and in many other Western countries. Notwithstanding the importance of this malignancy, little is understood about its causes. The epidemiology of prostate cancer strongly suggests that environmental factors, particularly diet and nutrition, are major determinants of risk for this disease, and evidence is mounting that there are important genetic risk factors for prostate cancer. Human prostate carcinomas are often androgen sensitive and react to hormonal therapy by temporary remission, followed by relapse to an androgen-insensitive state. These well-established features of prostate cancer strongly suggest that steroid hormones, particularly androgens, play a major role in human prostatic carcinogenesis, but the precise mechanisms by which androgens affect this process are unknown. In addition, the possible involvement of estrogenic hormones is not entirely clear. The purpose of this overview is to summarize the literature about steroid hormonal factors, androgens and estrogens, and prostate carcinogenesis. From these literature observations, a multifactorial general hypothesis of prostate carcinogenesis emerges with androgens as strong tumor promoters acting via androgen receptor-mediated mechanisms to enhance the carcinogenic activity of strong endogenous genotoxic carcinogens, such as reactive estrogen metabolites and estrogen- and prostatitis-generated reactive oxygen species and possible weak environmental carcinogens of unknown nature. In this hypothesis, all of these processes are modulated by a variety of environmental factors such as diet and by genetic determinants such as hereditary susceptibility and polymorphic genes that encode for steroid hormone receptors and enzymes involved in the metabolism and action of steroid hormones
— id: 11526, year: 2000, vol: , page: 39, stat: Journal Article,

RESPONSE: re: dietary fat, calories, and prostate cancer risk
Bosland MC
1999 Oct 6;91(19):1692-1693, Journal of the National Cancer Institute
— id: 18556, year: 1999, vol: 91, page: 1692, stat: Journal Article,

Use of animal models in defining efficacy of chemoprevention agents against prostate cancer
Bosland MC
1999 ;35(5-6):459-463, European urology
Animal models are crucial in preclinical efficacy testing of chemoprevention agents. The most feasible, realistic, and potentially effective target for prostate cancer chemoprevention is progression from prostatic intraepithelial neoplasia (PIN) to histologic cancer and from histologic to clinically manifest cancer. There are transgenic mouse models for prostate cancer and models for PIN, but these have not yet been fully developed and evaluated for chemoprevention studies. Human prostate cancer xenografts in mice and transplantable Dunning rat prostate carcinomas can be used to assess tumor growth inhibition. Several Dunning tumors metastasize, enabling detection of inhibition of metastases. Detection of inhibitory effects on de novo prostate cancer development requires induction of a high cancer incidence and similarity of induced tumors to human prostate carcinomas. Transgenic mice with oncogenes expressed in a prostate-specific fashion, combined chronic treatment of NBL rats with estradiol-17beta and testosterone, and sequential treatment of rats with carcinogens such as N-methyl-N-nitrosourea (MNU) and chronic testosterone treatment all lead to a high incidence of prostatic adenocarcinomas. PIN occurs mostly in the former two models, and metastases are frequent in some transgenic models and the MNU-testosterone rat model. The latter model has been applied to chemoprevention agent efficacy testing. In 8 control groups, the carcinoma incidence was 77% in all accessory sex glands combined, 51% for small tumors confined to dorsolateral/anterior prostate, and 25% for large tumors of uncertain origin in the prostate area. This model was predictive of the lack of antiprostate cancer efficacy of N-(4-hydroxyphenyl)all-trans-retinamide in humans. Thus, rats given MNU and chronic testosterone represent a relevant and reliable model for efficacy testing of chemoprevention agents. In conclusion, there are now adequate animal models for prostate cancer proven to be suitable for preclinical chemoprevention studies
— id: 56436, year: 1999, vol: 35, page: 459, stat: Journal Article,

Dietary fat, calories, and prostate cancer risk
Bosland MC; Oakley-Girvan I; Whittemore AS
1999 Mar 17;91(6):489-491, Journal of the National Cancer Institute
— id: 18558, year: 1999, vol: 91, page: 489, stat: Journal Article,

The role of stromal cells in prostate cancer development and progression
Condon MS; Bosland MC
1999 Jan-Feb;13(1):61-65, In vivo
Prostate cancer is one of the most common malignancies in males, and tumor progression critically determines its clinical significance. Prostatic stromal cells may be critically involved in growth and progression of prostate cancer. There is substantial evidence that the stromal component of the embryological tissue of origin, the urogenital sinus, is essential in directing outgrowth and prostatic differentiation of the epithelial anlage of the prostate. The presence of a stromal androgen receptor is required for this effect, and humoral factors, such as keratinocyte growth factor, have been shown to be able to mediate it in a paracrine fashion. The adult prostate is also under control of multiple steroid hormone and paracrine peptide factors, and there is evidence that the prostatic stroma plays a major role in mediation of androgen effects on prostatic epithelium. Normal seminal vesicle mesenchyme can cause differentiation of the Dunning R3327H prostate carcinoma. Normal rat prostatic fibroblasts influence the in vivo and soft agar growth of epithelial cells derived from chemically/hormonally induced rat prostate carcinomas, as do fibroblasts that are isolated from these tumors. Both growth-enhancing and growth-inhibiting effects were observed, apparently depending on the stage of progression of both cell types as well as on whether fibroblasts were derived from the same or a different tumor than the epithelial cells. These findings indicate that stromal cells critically influence epithelial prostate cancer growth, and they suggest that these effects can significantly vary in different tumors as well as in different stages of tumor progression
— id: 6099, year: 1999, vol: 13, page: 61, stat: Journal Article,

Multiple pathways of prostate carcinogenesis analyzed by using cultured cells isolated from rats treated with N-methyl-N-nitrosourea and testosterone
Condon MS; Kaplan LA; Crivello JF; Horton L; Bosland MC
1999 Jul;25(3):179-186, Molecular carcinogenesis
Treatment of rats with N-methyl-N-nitrosourea (MNU) and testosterone results in a high incidence of metastasizing dorsolateral prostate tumors. In previous studies, a high frequency (> or = 70%) of a G35 --> A transition mutation at the second position of codon 12 of the Ki-ras oncogene was found in these tumors. This was confirmed in the study reported here, and the frequency of this mutation appeared similar in tumors induced in four different rat strains, regardless of differences in sensitivity among these strains to the induction of prostate cancers by MNU and testosterone: Wistar Furth (62% incidence of grossly visible prostate tumors) > Lobund Wistar (55%) > Fisher 344 (40%) > Copenhagen (37%). A method was developed to isolate and separately culture epithelial and stromal cells from these rat prostate carcinomas. Of 20 primary cell cultures established from histologically confirmed rat prostate carcinomas, 19 (95%) displayed one or more of the following characteristics: the Ki-ras mutation (17 of 20; 85%), anchorage-independent growth in soft agar at early passage (12 of 20; 60%), or tumorigenicity at later passage (eight of eight; 100%). One epithelial cell culture and all five stromal cell cultures established from prostate tumors had none of these characteristics. Epithelial cultures that had the Ki-ras mutation and grew in soft agar constitute the predominant genotype/phenotype (55%), cultures with the mutation that did not grow in soft agar were less frequent (30%), 10% of the cultures had neither characteristic, and only one grew in soft agar but did not have the mutation. These findings suggest that there are at least two and perhaps more different molecular pathways of prostate carcinogenesis in rats treated with MNU plus testosterone. Furthermore, these data suggest that these pathways and the mechanisms determining strain differences in sensitivity to prostate cancer induction are unrelated
— id: 6160, year: 1999, vol: 25, page: 179, stat: Journal Article,

Chemoprevention of rat prostate carcinogenesis by 9-cis-retinoic acid
McCormick DL; Rao KV; Steele VE; Lubet RA; Kelloff GJ; Bosland MC
1999 Feb 1;59(3):521-524, Cancer research
A chemoprevention study was conducted to evaluate the activity of 9-cis-retinoic acid (9-cis-RA) as an inhibitor of prostate carcinogenesis in male Wistar-Unilever (HsdCpb:Wu) rats. After pretreatment with a sequential regimen of cyproterone acetate (50 mg/kg/day for 21 days) and testosterone propionate (100 mg/kg/day for 3 days), groups of 40 rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU; 30 mg/kg body weight). Beginning 2 weeks after carcinogen administration, rats received chronic exposure to testosterone administered in s.c. implanted silastic capsules. The study was terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. Continuous dietary administration of 9-cis-RA at 100 mg/kg diet or 50 mg/kg diet beginning 1 week before MNU administration reduced cancer incidence in the dorsolateral + anterior prostate from 65% in dietary controls to 18 and 20%, respectively (P < 0.001 for both comparisons). Similarly, these dose levels of 9-cis-RA reduced the incidence of cancer in all accessory sex glands from 79% in dietary controls to 48 and 33% (P < 0.01 for both comparisons), respectively. Chronic dietary administration of 9-cis-RA induced no gross or organ-specific toxicity in any animal and did not suppress group mean body weight gain. The potent anticarcinogenic activity of 9-cis-RA in the rat prostate, when considered with its apparent lack of toxicity in rodents, suggests that this and other ligands for the retinoid X receptor merit consideration for evaluation in clinical prostate cancer chemoprevention trials
— id: 57053, year: 1999, vol: 59, page: 521, stat: Journal Article,

Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone
Rao KV; Johnson WD; Bosland MC; Lubet RA; Steele VE; Kelloff GJ; McCormick DL
1999 Jul 1;59(13):3084-3089, Cancer research
Two in vivo bioassays were conducted to evaluate the efficacy of dehydroepiandrosterone (DHEA) as an inhibitor of prostate carcinogenesis in rats. Prostate adenocarcinomas were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In the first experiment, DHEA (1000 or 2000 mg/kg diet) was administered continuously to rats beginning 1 week before MNU exposure. In the second experiment, continuous administration of DHEA (2000 mg/kg diet) was begun either 1 week before, 20 weeks after, or 40 weeks after MNU exposure. Controls received basal diet without added DHEA. Studies were terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. In the first study, continuous dietary administration of DHEA beginning 1 week before MNU resulted in a dose-related inhibition of prostate cancer induction. In the second experiment, comparable reductions in prostate cancer incidence were observed in groups exposed to DHEA beginning 1 week before, 20 weeks after, and 40 weeks after carcinogen exposure. These data demonstrate that nontoxic doses of DHEA confer significant protection against prostate carcinogenesis in rats. The efficacy of delayed administration of DHEA suggests that the compound confers protection against later stages of prostate cancer induction and can suppress the progression of existing preneoplastic lesions to invasive disease
— id: 18557, year: 1999, vol: 59, page: 3084, stat: Journal Article,

Workgroup I: rodent models of prostate cancer
Lucia MS; Bostwick DG; Bosland M; Cockett AT; Knapp DW; Leav I; Pollard M; Rinker-Schaeffer C; Shirai T; Watkins BA
1998 Jun 15;36(1):49-55, Prostate
— id: 57199, year: 1998, vol: 36, page: 49, stat: Journal Article,

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats
McCormick DL; Rao KV; Dooley L; Steele VE; Lubet RA; Kelloff GJ; Bosland MC
1998 Aug 1;58(15):3282-3288, Cancer research
The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats
— id: 57207, year: 1998, vol: 58, page: 3282, stat: Journal Article,

Phytoestrogens and prostate cancer: possible preventive role
Rosenthal MA; Taneja S; Bosland MC
1998 May 4;168(9):467-467, Medical journal of Australia
— id: 7770, year: 1998, vol: 168, page: 467, stat: Journal Article,

Influence of acid aerosol droplet size on structural changes in the rat lung caused by acute exposure to sulfuric acid and ozone
Kimmel TA; Chen LC; Bosland MC; Nadziejko C
1997 Jun;144(2):348-355, Toxicology & applied pharmacology
To investigate whether aerosol droplet size influences structural changes in the lung produced by short-term, concomitant exposure to ozone and sulfuric acid, groups of 10 rats were exposed 4 hr/day for 2 days to filtered air, 0.6 ppm ozone, 0.5 mg/m3 fine (aerosol mass median diameter (MMD) = 0.3 microm) or ultrafine (MMD = 0.06 microm) sulfuric acid, or a mixture of ozone and 0.5 mg/m3 fine or ultrafine sulfuric acid. The volume percentage of total parenchyma containing markedly to severely injured alveolar septae was measured morphometrically. There were no differences between the ultrafine or fine acid exposure groups and the sham group for any of the morphologic endpoints. Volume percentage of markedly to severely injured tissue was increased in the ultrafine, but not fine, mixture animals when compared with the ozone-only group. In addition, a synergistic interaction between ozone and ultrafine, but not fine, sulfuric acid was found for this endpoint. The bromodeoxyuridine cell labeling index in the periacinar region was greater in the rats exposed to the fine sulfuric acid and ozone mixture than that in rats exposed to ozone alone, and a synergistic interaction between ozone and fine sulfuric acid was found for this end point. None of the exposures produced any changes in ventilatory parameters. Thus, acid aerosol droplet size was found to influence the effect of sulfuric acid in modifying ozone-induced structural changes in the rat lung
— id: 7180, year: 1997, vol: 144, page: 348, stat: Journal Article,

Hormonal factors in carcinogenesis of the prostate and testis in humans and in animal models
Bosland MC
1996 ;394:309-352, Progress in clinical & biological research
The etiology of human testicular tumors is poorly defined. With the possible exception of prenatal estrogen exposure, no specific chemical exposures have been associated with testicular cancer risk in men. Prenatal as well as postnatal estrogen treatments induce testicular tumors in some mouse strains, but not in other mouse strains or in rats. Prenatal estrogen exposure also causes cryptorchid testes in mice and possibly rats. Cryptorchidism is a consistent risk factor for testicular cancer in men, and estrogen- or surgically-induced cryptorchidism is associated with Leydig cell tumorigenesis in mice. In rats, however, surgically induced cryptorchidism inhibits Leydig cell tumor formation. Overall, it appears that the mouse is the most appropriate species as animal model for testicular tumorigenesis in humans. Any of the following hormonal exposures can cause testicular tumor formation in rodents: 1) chronic exposure to estrogenic compounds of adult mice and hamsters; 2) prenatal exposure to estrogenic compounds of mice and possibly humans; and 3) any treatment or condition that induces cryptorchidism in mice and humans. The mechanisms whereby these treatments or conditions may cause testicular tumorigenesis are poorly understood. Undefined local testicular factors appear to be dominant in tumorigenesis in cryptorchid human and rodent testes. Pituitary factors, most likely LH and perhaps prolactin, play a critical but poorly defined role in estrogen-induced and spontaneous testicular tumorigenesis in rodents. In the mouse, estrogen receptor-mediated mechanisms seem to be involved in induction of testicular tumors by prenatal estrogen exposure, and a direct, perhaps estrogen receptor-mediated, inhibiting effect of estrogens on the action of mullerian inhibiting substance is probably central in the induction of cryptorchidism in this species
— id: 57496, year: 1996, vol: 394, page: 309, stat: Journal Article,

Initial assessment of changes in sulfotransferase expression during carcinogenesis in rat prostate
Ringer, DP; Bosland, MC; Kong, J; Templer, LA
1996 APR 30 ;10(6):836-836, FASEB journal
— id: 52907, year: 1996, vol: 10, page: 836, stat: Journal Article,

Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol
Bosland MC; Ford H; Horton L
1995 Jun;16(6):1311-1317, Carcinogenesis
This study determined the incidence of prostate adenocarcinoma following long-term treatment of NBL and Sprague-Dawley rats with estradiol-17 beta or diethylstilbestrol (DES) plus testosterone and it defined the origin of these tumors. NBL and Sprague-Dawley rats were treated with two Silastic tubing implants (i.d. 1.6 mm, o.d. 3.2 mm) containing a 2 cm long filling of testosterone and one implant containing a 1 cm long filling of estradiol-17 beta or DES. Control animals received empty implants. Treated animals were killed when moribund and controls were killed at 91 (NBL) or 75 (Sprague-Dawley) weeks after initiation of treatment and accessory sex glands were sampled for histopathological examination of multiple step sections. Prostatic adenocarcinoma occurred in 100% of NBL rats after treatment with estradiol-17 beta or DES plus testosterone for 44 and 59 weeks (group means) respectively. Adenocarcinoma incidences were lower in Sprague-Dawley rats. The adenocarcinomas were small, microscopic, invasive tumors and they were spatially closely associated with the periurethral ducts of the dorsal, lateral and/or anterior (= coagulating gland) prostate, but never with the ducts of the ventral lobe and seminal vesicles. One adenocarcinoma was of uncertain origin. Duct-acinar dysplastic lesions occurred in the periphery of the dorsal and lateral prostate of all hormone-treated NBL and many Sprague-Dawley rats, but did not appear to give rise to carcinoma. Although some adenocarcinomas were contiguous with dysplastic ducts of the peripheral dorsolateral prostate, the main mass of these neoplasms was located in the periurethral area. Also, most adenocarcinomas were only connected with the periurethral ducts, in which atypical hyperplasia occurred following hormone treatment for 36 weeks or longer. Thus atypical hyperplasia of the periurethral prostate ducts, but not peripheral duct-acinar dysplasia, appeared to be the likely precursor of the induced carcinomas. Testosterone plus DES, but not estradiol-17 beta, induced marked dysplasia-like lesions in the acini of the ventral prostate of all NBL and many Sprague-Dawley rats. These lesions had progressed to carcinoma in situ (or adenoma) in 46% of NBL rats
— id: 7892, year: 1995, vol: 16, page: 1311, stat: Journal Article,

Induction of a DNA adduct detectable by 32P-postlabeling in the dorsolateral prostate of NBL/Cr rats treated with estradiol-17 beta and testosterone
Han X; Liehr JG; Bosland MC
1995 Apr;16(4):951-954, Carcinogenesis
Treatment with estradiol-17 beta and testosterone induces epithelial dysplasia and, subsequently, adenocarcinoma in the dorsolateral prostate of NBL rats. The purpose of this study was to determine whether this carcinogenic effect is mediated by genotoxicity. Analogous to adducts produced by estrogens in the male hamster kidney, a target of estrogen carcinogenicity, induction of DNA adducts detectable by 32P-postlabeling was investigated in the prostate target tissue. NBL rats were treated with separate Silastic tubing implants containing testosterone and estradiol-17 beta. Control animals received empty implants. Animals were killed at 8, 16 and 24 weeks after initiation of treatment, and accessory sex glands were sampled for adduct analysis. DNA of the dorsolateral and ventral prostate and the coagulating gland (= anterior prostate) was isolated and analyzed by nuclease P1-enhancement of the 32P-post-labeling assay. DNA adducts were quantitated by Cerenkov counting. An adduct occurred selectively in DNA of the dorsolateral prostate of rats treated with estradiol plus testosterone for 16 or 24 weeks with relative adduct level values of approximately 10 x 10(9), but not in DNA of the ventral or anterior prostate. The adduct was not present in DNA of prostate tissue of rats treated for 8 weeks or in DNA of control tissues. This adduct was unique with respect to chromatographic location and has not been observed before in any tissue of control or hormone-treated animals. Neither the structure of the treatment-induced adduct nor the mechanism of its formation is known. However, the selective occurrence of this adduct in the tissue of origin of the carcinomas and its appearance coinciding with putative preneoplastic lesions and preceding carcinoma development suggests a causal relation between adduct formation and prostate cancer development in testosterone plus estradiol-17 beta-treated rats
— id: 7899, year: 1995, vol: 16, page: 951, stat: Journal Article,

Induction of benign prostatic hyperplasia in intact dogs by near-physiological levels of 5 alpha-dihydrotestosterone and 17 beta-estradiol
Winter ML; Bosland MC; Wade DR; Falvo RE; Nagamani M; Liehr JG
1995 Jun;26(6):325-333, Prostate
Benign prostatic hyperplasia was induced in mongrel dogs treated for 60 days with one silastic implant containing 17 beta-estradiol and four containing 5 alpha-dihydrotestosterone. The condition was characterized by (1) a marked increase of the stromal elements, particularly the stromal septa between the individual glands, (2) a slight increase in prostatic volume, and (3) a morphology that resembled spontaneous complex benign prostatic hyperplasia in the dog. Other groups of animals that remained untreated or received only 17 beta-estradiol or only 5 alpha-dihydrotestosterone did not develop this condition. Prostate volumes decreased by 14% in the estrogen-treated dogs, whereas they increased in the androgen-treated animals by 6% compared to pretreatment prostate volumes. The morphology of the epithelium of the prostates of androgen-treated animals was not different from that of controls despite the increase in prostate volume. The serum 17 beta-estradiol and 5 alpha-dihydrotestosterone concentrations were increased from 25 +/- 2 (mean +/- SEM) and 256 +/- 42 pg/mL, respectively, in control dogs to 52 +/- 37 and 562 +/- 37 pg/mL, respectively, in the dogs treated with the hormone combination. Thus, hormone concentrations were two- to three-fold higher than control values, and the ratio of estradiol-17 beta to 5 alpha-dihydrotestosterone was increased by up to 19%. These data demonstrate that treatment of dogs with low levels of estrogen and androgen may be an excellent model for the study of spontaneous complex benign prostatic hyperplasia in aging men
— id: 8295, year: 1995, vol: 26, page: 325, stat: Journal Article,

Dietary fat affects plasma prolactin in female F344 rats under conditions of ether stress
Bosland MC; Bunnik GS; Wilbrink B; de Bie BT; Floor B
1994 ;22(3):247-256, Nutrition & cancer
The influence of amount and type of dietary fat on circulating concentrations of prolactin and estradiol-17 beta in female F344 rats from which blood was sampled by decapitation under ether anesthesia was compared with that in rats from which blood was collected without anesthesia. The animals were fed isonutrient (adjusted for differences in energy density) semipurified diets containing 5% or 20% (by weight) sunflower seed oil or lard. Blood was sampled by decapitation with or without standardized ether anesthesia during the afternoon of proestrus-estrus or the morning of metestrus-diestrus, as determined by examination of vaginal smears. Plasma hormone concentrations were measured by radioimmunoassay. Prolactin levels were lower during proestrus-estrus in rats fed a low-fat diet than in animals fed a high-fat diet, statistically independent of the type of dietary fat, but only when blood was sampled by decapitation under ether anesthesia [p = 0.0384, 2-way analysis of variance (ANOVA)]. No such difference was found in rats decapitated without anesthesia. This effect of amount of dietary fat on prolactin in proestrus-estrus animals anesthetized with ether was predominantly present in animals fed polyunsaturated fat (p < 0.05, 1-way ANOVA and Tukey's test) and was statistically not significant in rats fed saturated fat diets. During metestrus-diestrus, prolactin levels were significantly lower in animals fed a high-saturated fat diet than in those fed low-saturated fat, low-unsaturated fat, or high-unsaturated fat diets, independent of the blood sampling conditions (p < 0.05, 2-way ANOVA and Tukey's test). No consistent effects on estradiol-17 beta levels were found in type or amount of dietary fat or in presence or absence of ether anesthesia before decapitation. Growth, apparent digestibility of fat, and caloric intake were similar in all four dietary groups, but food consumption was higher and food conversion efficiency was lower in animals fed low-fat diets than in those fed high-fat diets. This study confirms the hypothesis that effects of dietary fat, particularly polyunsaturated fat, on circulating prolactin occur only during (ether) stress. Because stress is a frequent and normal phenomenon, this observation implies that the mammary glands of animals with a high dietary intake of polyunsaturated fat are frequently exposed to higher circulating prolactin concentrations than rats fed a low-fat diet, which may be a major mechanism by which dietary fat enhances rat mammary carcinogenesis
— id: 7891, year: 1994, vol: 22, page: 247, stat: Journal Article,

Requirement for transcription factor IRF-1 in NO synthase induction in macrophages
Kamijo R; Harada H; Matsuyama T; Bosland M; Gerecitano J; Shapiro D; Le J; Koh SI; Kimura T; Green SJ
1994 Mar 18;263(5153):1612-1615, Science
Production of nitric oxide (NO) by macrophages is important for the killing of intracellular infectious agents. Interferon (IFN)-gamma and lipopolysaccharide stimulate NO production by transcriptionally up-regulating the inducible NO synthase (iNOS). Macrophages from mice with a targeted disruption of the IFN regulatory factor-1 (IRF-1) gene (IRF-1-/- mice) produced little or no NO and synthesized barely detectable iNOS messenger RNA in response to stimulation. Two adjacent IRF-1 response elements were identified in the iNOS promoter. Infection with Mycobacterium bovis (BCG) was more severe in IRF-1-/- mice than in wild-type mice. Thus, IRF-1 is essential for iNOS activation in murine macrophages
— id: 6417, year: 1994, vol: 263, page: 1612, stat: Journal Article,

Biological functions of IFN-gamma and IFN-alpha/beta: lessons from studies in gene knockout mice
Kamijo R; Shapiro D; Gerecitano J; Le J; Bosland M; Vilcek J
1994 Nov;69(6):1332-1338, Hokkaido igaku zasshi
Mice with a targeted disruption in the IFN-gamma receptor gene (IFN-gamma R0/0) provided a useful model to ask to what extent other cytokines could replace IFN-gamma in macrophage activation. In thioglycollate-elicited peritoneal macrophages from wild-typy (WT) mice, TNF enhanced nitric oxide (NO) release in the presence of IFN-gamma, though TNF alone was not effective. In macrophages from IFN-gamma R0/0 mice, which are not responsive to IFN-gamma, TNF completely failed to stimulate NO release. The NO inducing effects of IFN-alpha/beta were indistinguishable in IFN-gamma R0/0 and WT macrophages. The important role of IFN-gamma in the regulation of the induced expression of MHC class II antigen (Ia) was confirmed by showing that after systemic infection with the BCG strain of Mycobacterium bovis, peritoneal macrophages from IFN-gamma R0/0 mice had a lower level of Ia expression than macrophages from WT mice. BCG infection was not lethal for WT mice whereas all IFN-gamma R0/0 mice died 7-9 weeks after infection. It is well known that BCG infection greatly sensitizes mice to lethal action of LPS. Injection of LPS 2 weeks after BCG inoculation was significantly less lethal for IFN-gamma R0/0 mice than for WT mice. Reduced lethality of LPS correlated with a drastically reduced TNF-alpha production in the IFN-gamma R0/0 mice after BCG infection and LPS challenge. The greatly reduced ability of BCG-infected IFN-gamma R0/0 mice to produce TNF-alpha may be an important factor in their inability to resist BCG infection.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 12874, year: 1994, vol: 69, page: 1332, stat: Journal Article,

Mycobacterium bovis infection of mice lacking receptors for interferon-gamma or for transcription factor IRF-1
Kamijo R; Shapiro D; Gerecitano J; Le J; Bosland M; Vilcek J
1994 Oct;14(5):281-282, Journal of interferon research
— id: 7902, year: 1994, vol: 14, page: 281, stat: Journal Article,

Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guerin and subsequent challenge with lipopolysaccharide
Kamijo R; Le J; Shapiro D; Havell EA; Huang S; Aguet M; Bosland M; Vilcek J
1993 Oct 1;178(4):1435-1440, Journal of experimental medicine
Mice with a targeted disruption of the interferon gamma receptor gene (IFN-gamma R0/0 mice) and control wild-type mice were inoculated with the Bacillus Calmette-Guerin (BCG) strain of Mycobacterium bovis. BCG infection was not lethal for wild-type mice whereas all IFN-gamma R0/0 mice died approximately 7-9 wk after inoculation. Histological examination at 2 and 6 wk after BCG inoculation showed that livers of IFN-gamma R0/0 mice had higher numbers of acid-fast bacteria than wild-type mice, especially at 6 wk. In parallel, the livers of IFN-gamma R0/0 mice showed a reduction in the formation of characteristic granulomas at 2 wk after inoculation. Injection of lipopolysaccharide (LPS) 2 wk after BCG inoculation was significantly less lethal for IFN-gamma R0/0 mice than for wild-type mice. Reduced lethality of LPS correlated with a drastically reduced production of tumor necrosis factor alpha (TNF-alpha) in the IFN-gamma R0/0 mice. Interleukin 1 alpha (IL-1 alpha) and IL-6 levels in the serum were also significantly reduced in the IFN-gamma R0/0 mice after BCG infection and LPS challenge. The greatly reduced capacity of BCG-infected IFN-gamma R0/0 mice to produce TNF-alpha may be an important factor in their inability to resist BCG infection. These results show that the presence of a functional IFN-gamma receptor is essential for the recovery of mice from BCG infection, and that IFN-gamma is a key element in the complex process whereby BCG infection leads to the sensitization to endotoxin
— id: 13065, year: 1993, vol: 178, page: 1435, stat: Journal Article,

Animal models for the study of prostate carcinogenesis
Bosland MC
1992 ;16H:89-98, Journal of cellular biochemistry. Supplement
Human prostate carcinogenesis has been viewed as a multi-step process involving progression from low histologic grade, small, latent carcinoma to large, higher grade, metastasizing carcinoma. However, recent data suggest that a variety of pathogenetic pathways may exist. The precise etiology and pathogenesis of human prostate cancer remain largely undefined. It is difficult to investigate stages in the development of human prostate cancer, but some animal models provide opportunities in this regard. Short-term treatment of rats with chemical carcinogens produces a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. Chronic treatment with testosterone also produces a low prostate carcinoma incidence. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU) and 3,2'-dimethyl-4-aminobiphenyl (DMAB). Testosterone markedly enhances prostate carcinogenesis even at doses that do not measurably increase circulating testosterone. Thus, testosterone is a strong tumor promoter for the rat prostate. All such MNU- or DMAB-initiated and/or testosterone-promoted tumors are adenocarcinomas; most originate from the dorsolateral and anterior, but not ventral, prostate lobes. These tumors share a number of important characteristics with human prostate cancer. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. Another high incidence prostate carcinogenesis model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta to rats in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. While it is unknown whether testosterone is a tumor promoter in this system, preliminary studies indicate the formation of a DNA adduct in the target tissue, which suggests that estradiol-17 beta acts as a tumor initiating agent in this system. The high incidence models mentioned earlier are adequate for the study of chemoprevention of prostatic carcinogenesis. Analysis of shifts in the relative incidence of metastasizing carcinoma, grossly apparent but not-metastasizing carcinoma, microscopic-size carcinoma, and carcinoma in situ or atypical hyperplasia may allow study of the modifying effects of potential chemopreventive agents on tumor progression in these animal models of prostatic carcinogenesis
— id: 13808, year: 1992, vol: 16H, page: 89, stat: Journal Article,

Possible enhancement of prostate carcinogenesis by some chemopreventive agents
Bosland MC
1992 ;16H:135-137, Journal of cellular biochemistry. Supplement
— id: 13809, year: 1992, vol: 16H, page: 135, stat: Journal Article,

Induction of proliferative lesions of ventral prostate, seminal vesicle, and other accessory sex glands in rats by N-methyl-N-nitrosourea: effect of castration, pretreatment with cyproterone acetate and testosterone propionate and rat strain
Bosland MC; Prinsen MK; Rivenson A; Silverman J; Fiala E; Williams GM; Kroes R; Weisburger JH
1992 ;20(4):339-353, Prostate
Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate
— id: 18562, year: 1992, vol: 20, page: 339, stat: Journal Article,

Induction of skin and thyroid tumors in male rats by N-methyl-N-nitrosourea after sequential treatment with cyproterone acetate and testosterone propionate: effects of castration, rat strain and time of carcinogen injection
Bosland MC; Prinsen MK; Rivenson A; Weisburger JH
1992 Apr;13(4):669-674, Carcinogenesis
The purpose of this study was to determine the carcinogenic effect in male rats of a single i.v. injection of N-methyl-N-nitrosourea (MNU) after sequential treatment with cyproterone acetate (for 21 days) and testosterone propionate (for 3 days). This treatment has previously been shown to induce carcinomas of the prostate and other male accessory sex glands. A wide spectrum of non-melanoma skin tumors was found in 38-48% of Wistar (Cpb:WU) rats given this sequential treatment, but only in 5% of rats that received only MNU. Castration long and, particularly, early after MNU markedly reduced this skin tumor response to a 10-13% incidence. The skin tumorigenic efficacy of MNU was dependent on the time between the start of the testosterone propionate treatment and carcinogen administration: MNU injection after 48-50 or 60-63 h induced skin tumors in 17-21% of Wistar rats, whereas injection after 72-74 h induced a 48% incidence. The Fischer F344 and Sprague-Dawley strains were not very sensitive to induction of skin tumors by this approach. Thyroid follicular cell tumors were also induced by MNU only after the hormonal pretreatment, and their induction was influenced by the time of MNU injection as well. The time of MNU injection and rat strain used did not significantly influence the induction of sebaceous-squamous neoplasms of the ear-duct/Zymbal's glands or other tumors. These data indicate that endogenous androgens are critically involved in the later stages of rat skin tumorigenesis and suggest that androgen-induced cell proliferation influences the initiation stage of this process and, possibly, of thyroid tumorigenesis
— id: 18560, year: 1992, vol: 13, page: 669, stat: Journal Article,

Differential effects of diethylstilbestrol and estradiol-17 beta in combination with testosterone on rat prostate lobes
Ofner P; Bosland MC; Vena RL
1992 Feb;112(2):300-309, Toxicology & applied pharmacology
Treatment of Noble rats with separate silastic implants containing testosterone (T) and estradiol-17 beta (E2) for 16 weeks has previously been shown to induce multifocal epithelial dysplasia, a putative preneoplastic lesion, consistently in the dorsolateral prostate (DLP) but not in the ventral prostate (VP). We now studied effects of diethylstilbestrol (DES) substituted for E2 on these prostate lobes under the same conditions of exogenous androgen support. Three-week treatments with one 1-cm-long silastic implant of E2 or DES were approximately equipotent in changing target-organ weights and plasma prolactin. Accordingly, rats received for 16 weeks one 1-cm-long E2 or DES implant and two 2-cm-long T implants. In contrast to T + E2, T + DES induced widespread multifocal VP dysplasia and less or no DLP dysplasia. A serum-free explant-culture assay was used to determine uptake and metabolic disposition of 3H-labeled 5 alpha-dihydrotestosterone (DHT), T, and E2. Dysplastic VP explants incubated with 1.7 microM 1 beta-3H-labeled DHT and T accumulated more 3H-labeled steroid, metabolized 69 and 50% less substrate to terminal hydroxylated metabolites, and thereby formed and retained up to eight times as much estrogenic metabolite 5 alpha-androstane-3 beta,17 beta-diol (3 beta-androstanediol) and its lipoidal derivative than control VP. Experimental DLP explants did not form or retain more 3 beta-[3H]androstanediol than control DLP irrespective of treatments. Control VP metabolized [2-3H]E2 more actively to estrone than DLP. Dysplastic VP, however, metabolized one-half and accumulated five times as much E2 as VP and did not release more 3H as a marker of the 2,3-catechol estrogen pathway. These data suggest that differential target-tissue bioavailability of the estrogen component of the protracted dual-hormone stimulus determines in which prostate lobe dysplasia develops
— id: 18561, year: 1992, vol: 112, page: 300, stat: Journal Article,

Long-term intermittent exposure to sulfuric acid aerosol, ozone, and their combination: alterations in tracheobronchial mucociliary clearance and epithelial secretory cells
Schlesinger RB; Gorczynski JE; Dennison J; Richards L; Kinney PL; Bosland MC
1992 Jul-Aug;18(4):505-534, Experimental lung research
Understanding the effects from long-term exposure to individual ambient air pollutants and mixtures of pollutants is necessary for adequate assessment of health risk. This study examined quantitative and temporal alterations in tracheobronchial mucociliary clearance function and bronchial epithelial secretory cells in rabbits exposed to sulfuric acid (125 micrograms/m3), ozone (0.1 ppm), and their combination for 2 h/d, 5 d/wk for up to 1 yr; some animals were allowed a 6-month post-exposure period. Clearance times were altered during exposure to sulfuric acid or to the mixture, and became progressively slower following the end of exposures to each of the pollutant atmospheres. There was no indication of any interaction in terms of clearance response between the acid and ozone in the group exposed to the mixture. Histological examination of intrapulmonary conducting airways was performed after 4, 8, or 12 months of exposure, and after the post-exposure period. Sulfuric acid resulted in an increase in the number of secretory cells in small airways by 12 months of exposure. Ozone and the mixture resulted in an increase in secretory cell number by 4 months, but the response became attenuated with continued exposure. There was evidence for synergistic interaction between ozone and acid at 4 months, and antagonistic interaction at subsequent times. No inflammation or other biologically significant histological effects were found in any of the animals
— id: 13537, year: 1992, vol: 18, page: 505, stat: Journal Article,

SUBCHRONIC TOXICITY STUDY OF LACTITOL IN DOGS
TIL, HP; BOSLAND, MC; HOLLANDERS, VMH; BAR, A
1992 APR ;11(2):219-232, Journal of the American College of Toxicology
The subchronic oral toxicity of lactitol was examined by feeding the test substance at dietary levels of 0, 5, 10, and 15% to groups of 6 male and 6 female dogs for 26 weeks. A comparison group received a diet containing 15% lactose. Although the dogs gradually were adapted to the high doses of the test compounds, diarrhea was observed in the dogs fed 10 and 15% lactitol, and 15% lactose. The diarrhea in the lactose group was less severe than in the 10% lactitol group. Body weight did not show treatment-related differences between the groups. Food intake was slightly higher in the lactitol groups than in the controls. Hemoglobin content (Hb), packed cell volume (PCV), and red blood cell counts (RBC) were slightly lower in dogs of the 15% lactitol group and the 15% lactose group. No other hematological parameters exhibited differences between the various treatment groups. Plasma glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (G
— id: 51886, year: 1992, vol: 11, page: 219, stat: Journal Article,

Pathogenesis of blood-filled cavities in estrogen-induced anterior pituitary tumors in male Sprague-Dawley rats
van Nesselrooij JH; Hendriksen GJ; Feron VJ; Bosland MC
1992 ;20(1):71-80, Toxicology pathology
The formation of blood-filled cavities in developing tumors of the anterior pituitary of estrogen-treated male Sprague-Dawley rats was studied in a serial sacrifice experiment. Two treated and 2 control rats were killed at each of 15 time points ranging from 7-272 days after sc implantation of an estradiol-17 beta pellet. The pituitaries were examined using light and electron microscopy. Changes at 7-9 days after implantation included epithelial cell swelling and trabecular arrangement. At 11-13 days, epithelial cells were further enlarged. Arrangement of epithelial cells in islands and endothelial degeneration were first seen at this interval. Also, any sinusoids were distended, whereas some were compressed by swollen epithelial cells. At 16-81 days, scattered necrotic and immature epithelial cells were present, and cell size decreased. Endothelial degeneration and both distended as well as compressed sinusoids were more prominent at this time. Loss of basement membrane was first seen during this interval. At 114-133 days, small hemorrhagic areas partially lined by epithelium were first seen; sinusoidal compression, endothelial necrosis, and loss of basement membrane were more frequent, but there was less sinusoidal distention. Between 150 and 272 days, epithelial cells were increasingly pleomorphic and arranged in nodules, and there was an increase in number and size of the hemorrhagic areas. Sinusoidal compression, endothelial necrosis, and loss of basement membrane were abundant, whereas sinusoidal distention had almost disappeared at this interval. Local compression of sinusoids and perhaps compression of pituitary surface veins due to epithelial cell swelling, were thought to play a primary role in the development of ischemic endothelial damage leading to loss of endothelial lining and basement membrane, and eventually to the formation of blood-filled spaces partially lined by epithelial cells
— id: 18563, year: 1992, vol: 20, page: 71, stat: Journal Article,

Correlations between presence of spontaneous lesions of the pituitary (adenohypophysis) and plasma prolactin concentration in aged Wistar rats
van Nesselrooij JH; Kuper CF; Bosland MC
1992 Jul;29(4):288-300, Veterinary pathology
The predictive value of elevated plasma prolactin concentrations for the presence of spontaneous pituitary lesions was studied in 40 male and 38 female Wistar (Cpb:WU) rats, all 30 months old. The pituitaries were examined light microscopically and stained for prolactin using immunohistochemical methods. Plasma prolactin concentrations were measured by radioimmunoassay. Pituitary lesions were classified on the basis of their morphology in hematoxylin and eosin-stained sections as foci of hypertrophic or hyperplastic cells and hemorrhagic, pleomorphic, or spongiocytic adenomas; no carcinomas were found. There were significantly (P = 0.001) more female than male rats with pituitary adenomas (58% females, 33% males) or without any pituitary lesions (21% females, 5% males); however, there were less female (21%) than male rats (63%) with foci of hyperplastic and/or hypertrophic cells but no adenomas in the pituitary (P = 0.001). Elevation of plasma prolactin concentration above the upper 99th percentile value in age-matched rats without lesions was predictive, but not conclusively, of the presence of pituitary hemorrhagic adenomas in both sexes. It was, however, not predictive of the presence of foci of hypertrophic or hyperplastic cells. Elevation of plasma prolactin concentration above 10 ng/ml in male and 60 ng/ml in female rats was conclusive for the presence of hemorrhagic adenomas. Using multivariate analysis, significant positive correlations (P less than 0.01) were found between plasma prolactin concentration and presence and size of hemorrhagic adenomas and their prolactin staining intensity (correlation coefficients between 0.392 and 0.652). Foci of hyperplastic cells stained positively for prolactin, whereas hypertrophic cell foci and pleomorphic and spongiocytic adenomas did not stain for prolactin. There were no correlations (coefficients of less than +/- 0.189) between plasma prolactin concentration and the presence of hypertrophic or hyperplastic cell foci and pleomorphic or spongiocytic adenomas in the pituitary. The morphologic criteria developed to distinguish spontaneous hypertrophic, hyperplastic, and neoplastic lesions of the rat pituitary corresponded well with their prolactin immunoreactivity and/or ability to elevate plasma prolactin concentration. These criteria constitute a biologically meaningful classification system for these rat pituitary lesions
— id: 18559, year: 1992, vol: 29, page: 288, stat: Journal Article,

Multistage prostate carcinogenesis: the role of hormones
Bosland MC; Dreef-Van Der Meulen HC; Sukumar S; Ofner P; Leav I; Han X; Liehr JG
1991 ;22:109-123, Princess Takamatsu symposia
Prostate cancer is the most frequently occurring non-skin cancer in men in the U.S.A. and other Western countries, but its etiology is poorly understood. Human prostate carcinogenesis has been viewed as a multi-step process involving progression from low histologic grade, small latent carcinoma, to large, higher grade, metastasizing carcinoma. However, recent data suggest that a variety of pathogenetic pathways exist. The precise role of hormones in the genesis of human prostate cancer remains largely undefined. It is difficult to investigate stages in the development of human prostate cancer, but some animal models provide opportunities in this regard. Short-term treatment of rats with chemical carcinogens will produce a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU). Testosterone markedly enhances prostate carcinogenesis even at doses that do not measurably increase circulating testosterone. Thus, testosterone is a strong tumor promoter for the rat prostate. All such MNU-initiated, testosterone-promoted tumors are adenocarcinomas mostly originating from the dorsolateral and anterior, but not ventral, prostate lobes. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. A variable frequency of activation of H-ras and K-ras genes occurs in human prostate carcinomas. Another rat model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. We recently found a major adduct by 32P postlabeling analysis in the tissue region that includes these ducts, but not in, e.g., the ventral prostate, of rats treated for 16-24 weeks. While it is unknown whether testosterone is a tumor promoter in this system, the presence of a DNA adduct suggests that estradiol-17 beta acts as a tumor-initiating agent in this system
— id: 14202, year: 1991, vol: 22, page: 109, stat: Journal Article,

Frequent activation of the Ki-ras oncogene at codon 12 in N-methyl-N-nitrosourea-induced rat prostate adenocarcinomas and neurogenic sarcomas
Sukumar S; Armstrong B; Bruyntjes JP; Leav I; Bosland MC
1991 ;4(5):362-368, Molecular carcinogenesis
Rat neoplasms induced by methylating carcinogens frequently contain ras genes activated by a single point mutation. Rat prostatic tumors induced by a combination of a single injection of N-methyl-N-nitrosourea (MNU) and long-term treatment with testosterone were examined for the presence of such activating point mutations in ras genes. These tumors, which arose exclusively in the dorsolateral prostate, included both adenocarcinomas and sarcomas. Activating mutations in codon 12 of the Ki-ras gene were found in 7 of 10 carcinomas and 4 of 5 sarcomas, using selective oligonucleotide hybridization analysis of DNA amplified by the polymerase chain reaction (PCR). However, no mutated Ha-ras oncogenes were detected. The presence of PCR-engineered Hphl restriction sites created by the existence of a G35----A mutation in the rat Ki-ras oncogene identified the mutation as a GC----AT transition at the second position of codon 12. Production of O6-methylguanine adducts in the Ki-ras codon 12 followed by base mispairing during replicative DNA synthesis is thus the likely molecular mechanism of initiation of prostatic carcinogenesis by MNU in the rat. Three of the four sarcomas positive for the Ki-ras G35----A mutation were immunohistochemically defined as of Schwann cell origin, indicating that involvement of the ras gene family is possible in tumorigenesis of this cell lineage. Loss of the wild-type Ki-ras allele was also observed in all four of these sarcomas
— id: 18564, year: 1991, vol: 4, page: 362, stat: Journal Article,

Papilloma and carcinoma production in DMBA-initiated, onion oil-promoted mouse skin
Belman S; Sellakumar A; Bosland MC; Savarese K; Estensen RD
1990 ;14(2):141-148, Nutrition & cancer
Groups of 20 females Ha/ICR mice were initiated with 25 micrograms 7,12-dimethylbenz[a]anthracene (DMBA) and promoted one week later with topical treatments three times per week of 5 micrograms phorbol myristate acetate (PMA) and/or onion oil or garlic oil. Promotion was continued for 49 weeks in most experiments. Promotion was continued for 60 weeks in the experiment that evaluated the effect of time intervals between PMA and garlic oil. All experiments were conducted with 0.2 ml acetone solutions of agents. Onion oil, but not garlic oil, was a weak promoter in mouse skin. A 1-mg dose produced five papillomas in three mice and one carcinoma in 330 days (18 survivors). The 10-mg dose was more effective; it produced cumulative yields of 56 papillomas in 14 mice and 7 carcinomas in 4 mice in 345 days (14 survivors). Onion oil is neither an initiator nor a whole carcinogen. The effects of intervals between PMA and a 1-mg dose of onion or garlic oil were determined. These intervals were -2 hrs, -1 hr, -0.5 hr, +0.5 hr, +1 hr, and +2 hrs with respect to time of PMA application. Maximal inhibition of papillomas by onion oil was observed at the +0.5-hr interval and was similar to that previously reported. Garlic oil is not a promoter. It inhibited papillomas at the +0.5-hr, +1.0-hr, and +2.0-hr intervals but did not appear to affect carcinoma production
— id: 18568, year: 1990, vol: 14, page: 141, stat: Journal Article,

Induction of dorsolateral prostate adenocarcinomas and other accessory sex gland lesions in male Wistar rats by a single administration of N-methyl-N-nitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2'-dimethyl-4-aminobiphenyl after sequential treatment with cyproterone acetate and testosterone propionate
Bosland MC; Prinsen MK
1990 Feb 1;50(3):691-699, Cancer research
Groups of 20-25 male Wistar rats (Cpb:WU), nine groups of 4-week-old rats, and nine groups of 8-week-old rats, were given cyproterone acetate (CA) s.c. or by gavage daily for 18 days at a dose of 50 mg/kg/day. Directly following CA treatment, the rats received 3 daily s.c. injections with testosterone propionate (TP) at a dose of 100 mg/kg/day. On the day after the last TP administration, a single dose of one of the following carcinogens was given to 3 groups: N-methyl-N-nitrosourea (MNU), 50 mg/kg i.v.; 7,12-dimethylbenz(a)anthracene, 30 mg/kg i.v.; 3,2'-dimethyl-4-aminobiphenyl, 250 mg/kg s.c. Three other groups received the same carcinogen treatments after 7 days of recovery from the CA administration. The last 3 groups received carcinogen without TP treatment, but immediately after CA pretreatment was stopped. A 25% incidence of invasively growing, metastasizing adenocarcinomas was found in the dorsolateral prostate region of 8-week-old rats that had received MNU after treatment with CA plus TP. In addition, this group had a 5% incidence of carcinoma in situ and a 5% incidence of atypical hyperplasia in the dorsolateral prostate. Lower incidences of adenocarcinoma of the dorsolateral prostate region and of carcinoma in situ and atypical hyperplasia of the dorsolateral prostate were found in other groups that were treated with MNU or 7,12-dimethylbenz(a)anthracene after pretreatment with CA, followed by TP or recovery, but never in rats that had been treated with CA only. In the groups treated with 3,2'-dimethyl-4-aminobiphenyl, which is slowly metabolized, these lesions were also found in groups that were pretreated with only CA. The carcinomas seemed to originate from the dorsolateral prostate and their average latency time was approximately 61 weeks. The 8-week-old rat given a MNU injection after sequential treatment with CA and TP may provide a relevant animal model for human prostatic cancer
— id: 18566, year: 1990, vol: 50, page: 691, stat: Journal Article,

Characterization of adenocarcinomas of the dorsolateral prostate induced in Wistar rats by N-methyl-N-nitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2'-dimethyl-4-aminobiphenyl, following sequential treatment with cyproterone acetate and testosterone propionate
Bosland MC; Prinsen MK; Dirksen TJ; Spit BJ
1990 Feb 1;50(3):700-709, Cancer research
Carcinomas of the rat prostate induced by a single injection of N-methyl-N-nitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2'-dimethyl-4-aminobiphenyl, after sequential treatment with cyproterone acetate and testosterone propionate, were evaluated as potential animal models for prostatic cancer. All ten carcinomas examined were located in the dorsolateral prostate region and did not involve the distal parts of the seminal vesicles and coagulating glands. The incidence of urinary obstruction leading to the animals' death was 6 of 10 rats, and metastases in the lung, abdominal lymph nodes, and/or liver also occurred in 6 of 10 rats. The tumors were invasive adenocarcinomas, showing frequent perineural invasion and a variable degree of differentiation. There were ultrastructural similarities with human prostatic carcinomas, such as intracellular lumina. Plasma acid phosphatase was increased. Enzyme histochemical analysis revealed similarities with the Dunning R3327H and -HI prostatic carcinomas but was not helpful in determining the site of origin of the tumors. The gross and microscopic appearance of the tumors and the observation of preneoplastic lesions exclusively located in the dorsolateral prostate suggest this lobe as site of origin of the carcinomas. Preneoplastic lesions (n = 9) included atypical hyperplasias (n = 5) and lesions with all histological characteristics of carcinoma except for local invasion and metastases, which were classified as carcinoma in situ (n = 4). Although androgen sensitivity could not be assessed, the observed characteristics of the tumors [their long latency time (46-80 weeks), the presence of preneoplastic lesions, and the short duration of the treatment, leaving the animals intact] all indicate that the present approach is a valid animal model for the study of prostatic carcinogenesis
— id: 18567, year: 1990, vol: 50, page: 700, stat: Journal Article,

Interactive effects of dietary wheat bran and lard on N-methyl-N'-nitro-N-nitrosoguanidine-induced colon carcinogenesis in rats
Sinkeldam EJ; Kuper CF; Bosland MC; Hollanders VM; Vedder DM
1990 Feb 15;50(4):1092-1096, Cancer research
A 3 x 3 factorial experiment was conducted to examine how dietary fiber (wheat bran) and fat (lard) interactively affect the genesis of N-methyl-N'-nitro-N-nitrosoguanidine-induced colon cancer in rats. Groups of 30 male 4-week-old Wistar rats were fed ad libitum one of nine experimental diets containing either 15 (low), 27.5 (medium), or 40% (high) energy as fat in combination with 0.7 (low), 2.2 (medium), or 3.8 g (high) fiber/100 kcal for a period of 37 weeks. After 4 weeks, each rat received a total of five weekly intrarectal instillations of 6 mg N-methyl-N'-nitro-N-nitrosoguanidine/kg. The highest colon carcinoma incidence and the highest total number of carcinomas of the colon were observed in the animals fed the medium-fat/medium-fiber diet. The highest number of polyps and a relatively high polyp incidence occurred in the animals on the high-fat/low-fiber diet. An enhancing effect of fat on both the tumor incidence and tumor multiplicity was clearly present for the low-fiber diets, whereas fat had no effect when the fiber content of the diet was high. In general, the results showed a nonlinear dose-response relationship for fiber and fat. These results indicate that both dietary fiber and fat affect colon carcinogenesis in a complex, interactive manner
— id: 18565, year: 1990, vol: 50, page: 1092, stat: Journal Article,

Prostatic carcinogenesis : a new method for induction of cancer the rat prostate : a model of human prostatic carcinogenesis = Het ontstaan van prostaakanker
Bosland, Maarten C
[S.l. : s.n.], 1989,
Disseration (Utrecht), 1989
— id: 2097, year: 1989, vol: , page: , stat: ,

Nasal carcinogenesis in rodents : relevance to human health risk : proceedings of the TNO-CIVO
Feron, V. J.; Bosland, M. C
Wageningen, Netherlands : Pudoc Wageningen, 1989,
— id: 377, year: 1989, vol: , page: , stat: ,

The etiopathogenesis of prostatic cancer with special reference to environmental factors
Bosland MC
1988 ;51:1-106, Advances in cancer research
— id: 11265, year: 1988, vol: 51, page: 1, stat: Journal Article,

PROSTATIC CELL-PROLIFERATION AND INDUCTION OF PROSTATE CARCINOMAS IN RATS BY METHYLNITROSOUREA
Bosland, MC
1988 Mar;29(5):254-254, Proceedings (American Association for Cancer Research)
— id: 31486, year: 1988, vol: 29, page: 254, stat: Journal Article,

INTERACTIVE EFFECTS OF AMOUNT OF FAT AND OF LINOLEIC-ACID IN THE DIET ON INDUCTION OF MAMMARY-CANCER BY NMU IN RATS
Bunnik, GSJ; Bosland, MC; Debie, ATJ
1987 Mar;28(3):158-158, Proceedings (American Association for Cancer Research)
— id: 31220, year: 1987, vol: 28, page: 158, stat: Journal Article,

THE ROLE OF CELL-PROLIFERATION IN PROSTATIC CARCINOGENESIS IN THE RAT
BOSLAND, MC; DIRKSEN, TJ; PRINSEN, MK
1986 MAR ;27(2):92-92, Proceedings (American Association for Cancer Research)
— id: 41423, year: 1986, vol: 27, page: 92, stat: Journal Article,

Nutritional factors in lung, colon, and prostate carcinogenesis in animal models
Kroes R; Beems RB; Bosland MC; Bunnik GS; Sinkeldam EJ
1986 Feb;45(2):136-141, Federation Proceedings (Federation of American Societies for Experimental Biology)
Dietary factors are now considered to be among the most important environmental risk determinants for cancer. In addition to epidemiological studies, experimental animal studies are an important tool to investigate dietary modulation in carcinogenesis. Results of recent experimental studies on the effect of some nutrients indicate that vitamin A did show an inverse relation with the occurrence of preneoplastic respiratory lesions but not with respiratory tract tumors in benzo[a]pyrene-induced respiratory carcinogenesis. Dietary fat increases respiratory tract tumors and preneoplastic lesions. In colon carcinogenesis, a fat-fiber interrelation was noticed in 1,2-dimethyl-hydrazine- and N-methyl-N'-nitro-N-nitrosoguanidine-induced tumors. Preliminary results in prostate carcinogenesis indicate that dietary fat did not influence the incidence of prostate cancer in a recently developed rat model. Some possible mechanisms in colon and prostate carcinogenesis are discussed
— id: 18569, year: 1986, vol: 45, page: 136, stat: Journal Article,

Effects of feeding stannous chloride on different parts of the gastrointestinal tract of the rat
Janssen PJ; Bosland MC; van Hees JP; Spit BJ; Willems MI; Kuper CF
1985 Mar 30;78(1):19-28, Toxicology & applied pharmacology
The effects of feeding inorganic tin on the gastrointestinal tract were examined in rats. Three groups of male weanling Wistar rats were fed a diet to which 0, 250, or 500 ppm Sn2+ had been added as SnCl2. A fourth group was subjected to feed restriction by pair feeding with the 500-ppm group. Comparison of the data from the tin-fed groups with both the control and the reduced diet groups allowed discrimination between effects of reduced feed intake and Sn2+ effects. Independent of the reduced feed intake, Sn2+ affected hemoglobin concentration in the blood and several small intestine parameters. Total length of the small intestine, as well as absolute and relative weights, was increased. An increase was also observed in the migration of epithelial cells along the villus, as revealed by [3H]thymidine incorporation and autoradiography in rats fed 900 ppm Sn2+ for 4 weeks. Stereo-light microscopy and scanning electron microscopy revealed the formation of ridge-like villi due to Sn2+ feeding and a decreased number of villi per unit surface. These data suggest that an increase in cell turnover in the small intestine, due to Sn2+, was responsible for these changes
— id: 18570, year: 1985, vol: 78, page: 19, stat: Journal Article,

Some functional characteristics of adrenal medullary tumors in aged male Wistar rats
Bosland MC; Bar A
1984 Mar;21(2):129-140, Veterinary pathology
Neither analysis of the urinary catecholamine metabolites vanillymandelic acid and 4-hydroxy-3-methoxyphenylglycol nor blood pressure measurements allowed the detection of adrenal medullary tumors or hyperplasia in 115 aged male Wistar rats (70 rats, 24 months of age and 45 rats, 30 months of age). Histochemical examination of the adrenal glands demonstrated that the 55 hyperplastic and 25 neoplastic lesions of the medulla usually had little or no chromaffinity. Chromaffinity was found comparable to normal medulla in only three tumors examined histochemically. Of these tumors, two were partially and one completely chromaffin-positive, but all three were small and did not result in elevated blood pressure or catecholamine metabolite excretion values. These observations indicate that excessive catecholamine synthesis and release is not a feature of adrenomedullary tumors and hyperplasia occurring spontaneously in aged male Wistar rats
— id: 18571, year: 1984, vol: 21, page: 129, stat: Journal Article,

Adenocarcinomas of the prostate induced by N-nitroso-N-methylurea in rats pretreated with cyproterone acetate and testosterone
Bosland MC; Prinsen MK; Kroes R
1983 Feb;18(1):69-78, Cancer letters
Prostatic adenocarcinomas were induced in 5 out of 20 Wistar rats upon a single administration of 50 mg/kg N-nitroso-N-methylurea (NMU). The rats were pretreated with a daily dose of 50 mg/kg cyproterone acetate for 3 weeks followed by 3 daily injections of 100 mg/kg testosterone. All tumours developed in the dorsolateral prostate and were invasively growing. In 2 cases distant metastases were found. Three proliferative lesions classified as carcinomas in situ were also found in the dorsolateral prostate. A total of 7/20 animals (35%) carried an adenocarcinoma and/or a carcinoma in situ. In addition, 6 epithelial hyperplasias were observed in the dorsolateral and 1 in the ventral prostate of non-tumour-bearing rats. The method described may provide a good animal model for cancer of the prostate and lead to a better understanding of prostatic carcinogenesis
— id: 18572, year: 1983, vol: 18, page: 69, stat: Journal Article,

Effect of depletion of spinal noradrenaline by 6-hydroxydopamine on the development of renal hypertension in rats
Bosland MC; Versteeg DH; van Put J; de Jong W
1981 Jan;8(1):67-77, Clinical & experimental pharmacology & physiology
1. A single injection in rats of 250 microgram of 6-hydroxydopamine HCl (6-OHDA) into the subarachnoidal space of the spinal cord of rats resulted in a lasting, selective depletion of spinal noradrenaline. Dopamine levels in the spinal cord and catecholamine levels in various brain regions were not markedly affected. 2. When ether anesthesia was used spinal noradrenaline was found to be almost completely depleted by the administration of 6-OHDA. Only partial depletion was achieved when pentobarbitone anaesthesia or neuroleptic analgesia was used. 3. The blood pressure rise caused by electrical stimulation of the posterior hypothalamus was not affected by 6-OHDA treatment 7 days previously. 4. 6-OHDA administration did not influence the development of two-kidney Goldblatt hypertension. When 6-OHDA was administered 7 days before clipping, a slight delay of the development was observed, but this did not occur when 6-OHDA treatment was given 3--4 h before clipping. 5. It is concluded that intact spinal noradrenergic neurotransmission is neither a prerequisite for the development of two-kidney Goldblatt hypertension, nor for the pressor response to hypothalamic stimulation
— id: 18573, year: 1981, vol: 8, page: 67, stat: Journal Article,

Selective depletion of spinal noradrenaline inhibits post-decapitation convulsions in rats
Bosland MC; Versteeg DH; de Jong W
1980 Feb 15;36(2):224-224, Experientia
Local administration of 6-hydroxydopamine in the subarachnoidal space of the spinal cord in rats resulted in a selective long-lasting depletion of spinal noradrenaline, but not of dopamine, and prevented the occurrence of post-decapitation convulsions
— id: 18574, year: 1980, vol: 36, page: 224, stat: Journal Article,