ANTI-TUMOUR TREATMENTMolecular mechanisms of resistance and toxicity associated with platinating agents☆
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.).