Molecular mechanisms of resistance and toxicity associated with platinating agents

• Published in: Cancer treatment reviews Vol. 33; no. 1; pp. 9 - 23
• Main Authors: Rabik, Cara A, Dolan, M. Eileen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2007
• Subjects: Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Carboplatin - adverse effects; Carboplatin - pharmacology; Cisplatin; Cisplatin - adverse effects; Cisplatin - pharmacology; DNA Damage; DNA, Neoplasm - drug effects; Drug resistance; Drug Resistance, Neoplasm; Hematology, Oncology and Palliative Medicine; Humans; Organoplatinum Compounds - adverse effects; Organoplatinum Compounds - pharmacology; Platinum Compounds - adverse effects; Platinum Compounds - pharmacology; Signal Transduction - drug effects; inhibitor of apoptosis proteins; microsatellite instability; RAR; retinoid-X receptors; trans-DDP; cis-platinum(II) diammine dichloride; CHO; Dnmt3b, DNA methyltransferase 3b; double-strand breaks; Drug resistance; AP-1; small cell lung carcinoma; high mobility group; thioredoxin reductase; UCN-01; sodium thiosulfate; DSB; activator protein 1; STS; UPR; Trx; BSO; O 6-alkylguanine DNA alkyltransferase; MT; cyclobutane-1,1-dicarboxylic acid platinum(II); bis(aceto)amminedichloro(cyclohexylamine) platinum(IV); ER; unfolded protein response; MMR; Chinese hamster ovary; oxalate ( trans-l-1,2-diamminocyclohexane) platinum(II); ROS; IAP; satraplatin; trans-platinum(II) diammine dichloride; MNB; glutathione-S-transferase; hOCT2; thioredoxin; glutathione; DNA damage; mismatch repair; metallothionein; Grx; glutaredoxin; RXR; murine neuroblastoma; 7-hydroxystaurosporine; reactive oxygen species; oxaliplatin; hypoxia inducible factor 1α; HIF1α; GSH; buthiomine sulfoximine; TrxR; SCLC; MSI; HMG; GST; Cisplatin; human organic cation transporter 2; AGT; carboplatin; NER; retinoic acid receptors; nucleotide excision repair; endoplasmic reticulum
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2006.09.006

Summary Platinating agents, including cisplatin, carboplatin, and oxaliplatin, have been used clinically for nearly 30 years 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.