Mechanisms of resistance to camptothecins.
Camptothecins are broad-spectrum anticancer drugs that specifically target DNA topoisomerase I. Although the availability of camptothecins has had a significant impact on cancer therapeutics, de novo or acquired clinical resistance to camptothecins is common. Studies of camptothecin resistance using yeast and mammalian cell culture models suggest three general mechanisms of resistance: (1) reduced cellular accumulation of camptothecins, (2) alteration in the structure or location of topoisomerase I, and (3) alterations in the cellular response to camptothecin-DNA-ternary complex formation. The relevance of these mechanisms to clinical drug resistance is not yet known, but evaluation of these models in clinical specimens should enhance the use of camptothecins both as single agents and in combination with other anticancer drugs.
Saleem
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Departments of Medicine and Pharmacology, Cancer Institute of New Jersey, RWJMS-UMDNJ, New Brunswick, New Jersey 08901, USA.
Edwards
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Rasheed
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Rubin
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D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin