Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity.
Camptothecins are broad-spectrum anticancer drugs that specifically target DNA topoisomerase I (Topo I). The formation of a cleavable drug-Topo I-DNA complex results in lethal double-strand DNA breakage and cell death. However, de novo or acquired clinical resistance to camptothecins is common. Studies of the camptothecin analog irinotecan suggest the following general mechanisms of resistance: (i) variable levels of the enzymes involved in the conversion of irinotecan; (ii) reduced cellular accumulation from active drug efflux; (iii) reduced levels of Topo I expression; (iv) alterations in the structure of Topo I from different mutations; (v) alterations in the cellular response to camptothecin-Topo I-DNA complex formation, which involves proteasome degradation of Topo I and/or enhanced DNA repair; and (vi) activation of the transcription factor nuclear factor kappa B by DNA damage and subsequent suppression of apoptosis. Multiple approaches using pharmacological and biological modulation to circumvent the above mechanisms of resistance have been incorporated into ongoing clinical trials and are expected to enhance the antitumor activity of irinotecan and reduce its systemic toxicity.
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Department of Medicine and the Experimental Therapeutics Program, Comprehensive Cancer Center, Arthur G. James Cancer Hospital, Columbus, OH, USA.
Villalona-Calero
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D059004:Topoisomerase I Inhibitors
D016328:NF-kappa B; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin