Design of topoisomerase inhibitors to overcome MDR1-mediated drug resistance.
Human colon tumor xenografts are known to be refractory to most chemotherapeutic anticancer drugs. Recent studies have demonstrated that a class of topoisomerase I inhibitors, camptothecins, exhibits unprecedented antitumor activity against human colon tumor xenografts in nude mice (Giovanella et al., 1989; Potmesil et al., 1991). The ability of camptothecin to overcome MDR1-mediated resistance may be one important contributing factor to camptothecin's impressive activity (Chen et al., 1991). If this interpretation is correct, it will be promising to develop new drugs that can overcome MDR1-mediated resistance for treating certain human solid tumors. Admittedly, MDR1-mediated resistance is only one of the many mechanisms of drug resistance in tumor cells. Designing new drugs for various resistance tumors will require fundamental information on various drug resistance mechanisms. It will eventually be possible to tailor drugs for particular drug-resistant tumors. Using topoisomerase inhibitors, we have begun to understand some of the parameters that may have to be considered for rational drug design.
Chen
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Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854, USA.
Liu
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D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D002166:Camptothecin