Gynecologic Oncology. 2009 Jan;112(1):275-81. Epub 2008 Oct 31.
Platinum compounds 30 years after the introduction of cisplatin: implications for the treatment of ovarian cancer.
Muggia F.
Division of Medical Oncology, NYU Langone Cancer Institute, New York, NY 10016, USA. franco.muggia@nyumc.org
Significance:
The anti-tumor activity of cisplatin was discovered in the late 1960s by Barnett Rosenberg, a Professor of Microbiology at Michigan State University, who observed that bacterial DNA replication, was inhibited in the presence of platinum electrodes, and stimulated the National Cancer Institute to introduce it into its screening systems designed to identify promising chemotherapeutic compounds. Clinical trials showed striking efficacy against germ cell tumors and ovarian cancer, but the mechanism(s) underlying such effects remained obscure. Animal models and clinical observations now point to enhanced effects of platinum drugs in tumors that lack homologous recombination to repair DNA (such as in BRCA mutations). In addition, reduction of toxicities through anti-emetics, pharmacologic-based dosing, and the development of the less nephrotoxic and neurotoxic carboplatin continue to enhance the clinical utility of these compounds.
Abstract:
Cisplatin and carboplatin have dominated the drug therapy of ovarian cancer and other gynecologic malignancies during the past three decades. This review, based on a recent international conference on metal coordination compounds, highlights advances in our understanding of their mechanisms of action and resistance. Two emerging areas are of special importance: 1) the role of transporters and exporters (first identified in the regulation of copper) in imparting the special selectivity of platinum drugs (also including oxaliplatin) for specific tumors; and 2) the relevance of inactivated DNA repair pathways, and in particular those related to BRCA genes in determining sensitivity of tumors to platinum drugs. The status of DNA repair pathways may become relevant to response to platinums and to the treatment of ovarian cancer in general: repair inhibitors are under testing alone or in combination with cytotoxic drugs for cancer.
PMID: 18977023
