Emerson D L, Besterman J M, Brown H R, Evans M G, Leitner P P, Luzzio M J, Shaffer J E, Sternbach D D, Uehling D, Vuong A
Department of Pharmacology, Glaxo Research Institute, Research Triangle Park, North Carolina 27709.
Cancer Res. 1995 Feb 1;55(3):603-9.
The development of camptothecin-like compounds as inhibitors of topoisomerase I for the treatment of resistant tumors has generated clinical excitement in this new class of drugs. We have developed two novel water-soluble camptothecin analogues which are specific inhibitors of topoisomerase I and are potent cytotoxins with significant antitumor activity. We added water-solubilizing groups off position 7 in the B ring of either 10,11-ethylenedioxy- or 10,11-methylenedioxy-20(S)-camptothecin. These water-soluble camptothecin analogues were demonstrated to be nanamolar inhibitors of the topoisomerase I enzyme in the cleavable complex assay. The compounds, GI147211 [7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camp tot hecin], and GI149893 [7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-cam pto thecin], were compared to topotecan, a known water-soluble inhibitor of topoisomerase I. Both GI compounds were found to be slightly more potent than topotecan as inhibitors of topoisomerase I in the cleavable complex assay and were 1.5-2 times more soluble. Tumor cell cytotoxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5-10 times more potent than topotecan, although by comparison all three topoisomerase I inhibitors were unaffected by the multidrug resistance P-glycoprotein. The antitumor activity of all three topoisomerase I inhibitors was compared concomitantly in two human colon xenograft models. In both models, GI147211 and GI149893 were able to induce regression of established HT-29 and SW-48 colon tumors by as much as 60%. The antitumor activity of both compounds were also demonstrated in the MX-1 and PC-3 xenografts. Microscopic examination of selected tissues indicated that drug-induced toxicity was primarily limited to the gastrointestinal tract and was comparable among the three compounds. Further clinical development of this class of compounds is ongoing.
喜树碱类化合物作为拓扑异构酶I抑制剂用于治疗耐药肿瘤的研发，已在这类新型药物领域引发了临床关注。我们研发了两种新型水溶性喜树碱类似物，它们是拓扑异构酶I的特异性抑制剂，也是具有显著抗肿瘤活性的强效细胞毒素。我们在10,11-亚乙二氧基-或10,11-亚甲二氧基-20(S)-喜树碱的B环7位上引入了水溶性基团。在可裂解复合物测定中，这些水溶性喜树碱类似物被证明是拓扑异构酶I酶的纳摩尔级抑制剂。化合物GI147211 [7-(4-甲基哌嗪亚甲基)-10,11-亚乙二氧基-20(S)-喜树碱]和GI149893 [7-(4-甲基哌嗪亚甲基)-10,11-亚甲二氧基-20(S)-喜树碱]与拓扑替康（一种已知的水溶性拓扑异构酶I抑制剂）进行了比较。在可裂解复合物测定中，发现这两种GI化合物作为拓扑异构酶I抑制剂的效力略高于拓扑替康，且溶解度高1.5至2倍。使用5种不同细胞系进行的肿瘤细胞细胞毒性测定表明，这两种GI化合物的效力比拓扑替康高5至10倍，不过相比之下，所有三种拓扑异构酶I抑制剂均不受多药耐药P-糖蛋白的影响。在两个人类结肠异种移植模型中同时比较了所有三种拓扑异构酶I抑制剂的抗肿瘤活性。在这两个模型中，GI147211和GI149893能够使已形成的HT-29和SW-48结肠肿瘤消退多达60%。这两种化合物在MX-1和PC-3异种移植模型中也显示出抗肿瘤活性。对选定组织的显微镜检查表明，药物诱导的毒性主要局限于胃肠道，且三种化合物的毒性相当。这类化合物的进一步临床研发正在进行中。
