Chen A Y, Liu L F
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854, USA.
Adv Pharmacol. 1994;29B:245-56. doi: 10.1016/s1054-3589(08)61141-2.
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.
已知人结肠肿瘤异种移植物对大多数化疗抗癌药物具有耐药性。最近的研究表明，一类拓扑异构酶I抑制剂——喜树碱，对裸鼠体内的人结肠肿瘤异种移植物表现出前所未有的抗肿瘤活性（乔瓦内拉等人，1989年；波特梅西尔等人，1991年）。喜树碱克服多药耐药蛋白1（MDR1）介导的耐药性的能力可能是其显著活性的一个重要促成因素（陈等人，1991年）。如果这种解释正确，那么开发能够克服MDR1介导的耐药性的新药来治疗某些人类实体瘤将很有前景。诚然，MDR1介导的耐药性只是肿瘤细胞耐药的众多机制之一。为各种耐药肿瘤设计新药将需要有关各种耐药机制的基础信息。最终将有可能为特定的耐药肿瘤量身定制药物。利用拓扑异构酶抑制剂，我们已经开始了解一些在合理药物设计中可能需要考虑的参数。
