ANTI-TUMOUR TREATMENT
Molecular mechanisms of resistance and toxicity associated with platinating agents

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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.

Section snippets

Background

Cisplatin [cis-diammine-dichloroplatinum(II)]4 (Fig. 1) is a commonly used chemotherapeutic agent that was discovered in 1970 as an inhibitor of growth in Eschericia coli.1 The clinical benefits of cisplatin as an anti-cancer agent have been recognized for over 30 years. Cisplatin is considered to be curative treatment for testicular cancer, when combined with bleomycin and etoposide. It is closely related to its second generation analog carboplatin; the two compounds share a mechanism of

DNA Lesions

Upon entering a cell, all platinating agents become aquated, losing chloride or oxalate ions, and gaining two water molecules. This positively charged molecule is then able to interact with nucleophilic molecules within the cell, including DNA, RNA, and proteins. It is generally agreed that DNA is the preferential and cytotoxic target for cisplatin and other platinating agents (reviewed in Ref. 6). When binding to DNA, platinating agents favor the N7 atoms of the imidazole rings of guanosine

Repair of DNA Lesions

DNA damage recognition of cisplatin and carboplatin adducts may be due to a conformational change induced by the intra- or inter-strand crosslink on DNA. In order to address this question, synthetic oligonucleotides were generated which contained one putative intrastrand binding site for cisplatin (GTG).36 Nucleotides were either exposed to cisplatin or not before being incubated with histones to generate nucleosomes. DNA that had been platinated generated a very different pattern of

Clinical utility of platinating agents

Cisplatin, carboplatin, and oxaliplatin are all commonly used intravenous platinating agents. Cisplatin is still used regularly for head and neck and germ cell tumors, while carboplatin has replaced cisplatin for most ovarian tumors and for the treatment of non-small cell lung carcinoma.90 Oxaliplatin is currently approved for treatment in colorectal cancer, but has also been shown to have activity against breast and endometrial cancers and malignant melanoma in Phase I studies (reviewed in

Resistance to platinating agents

In ovarian cancers, greater than 70% of patients initially respond to therapy with platinating agents; however, this reprieve is short-lived, as the five-year survival rate for ovarian carcinoma is less than 25%.126 Similarly, the relapse rate for small cell lung carcinomas after cisplatin or carboplatin treatment is 95%.16 Head and neck cancers, for which cisplatin is first-line therapy, have only a 20–30% response rate to platinating agents.127 Resistance can develop as a result of decreased

Summary

The platinating agents remain an important class of anti-cancer agents, with cisplatin and carboplatin used extensively in treating testicular, gynecologic, head and neck, and lung carcinomas, and oxaliplatin becoming a mainstay of colorectal cancer treatment. These agents are characterized by the ability to generate platinum lesions on DNA as their proposed major mode of cytotoxicity. However, clinical problems of tumor resistance and a number of associated toxicities limit these agents from

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    Some of the work in this review was supported by NIH/NCI grant CA81485 and Medical Scientist National Research Service Award Grant 5 T32 GM07281 (C.A.R.).

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