Molecular mechanisms of resistance and toxicity associated with platinating agents.
Platinating agents, including cisplatin, carboplatin, and oxaliplatin, have been used clinically for nearly 30years as part of the treatment of many types of cancers, including head and neck, testicular, ovarian, cervical, lung, colorectal and relapsed lymphoma. The cytotoxic lesion of platinating agents is thought to be the platinum intrastrand crosslink that forms on DNA, although treatment activates a number of signal transduction pathways. Treatment with these agents is characterized by resistance, both acquired and intrinsic. This resistance can be caused by a number of cellular adaptations, including reduced uptake, inactivation by glutathione and other anti-oxidants, and increased levels of DNA repair or DNA tolerance. Here we investigate the pathways that treatment with platinating agents activate, the mechanisms of resistance, potential candidate genes involved in the development of resistance, and associated clinical toxicities. Although the purpose of this review is to provide an overview of cisplatin, carboplatin, and oxaliplatin, we have focused primarily on preclinical data that has clinical relevance generated over the past five years.
Rabik
Cara A
CA
Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, 5841 S. Maryland Avenue, Box MC2115, Section of Hem-Onc, Chicago, IL 60637, United States.
Dolan
M Eileen
ME
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000494:pharmacology*; D000077150:Oxaliplatin; D017671:Platinum Compounds / Q000009:adverse effects / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin