Hsiang Y H, Liu L F, Wall M E, Wani M C, Nicholas A W, Manikumar G, Kirschenbaum S, Silber R, Potmesil M
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Cancer Res. 1989 Aug 15;49(16):4385-9.
20(S)-Camptothecin, the 20(S)-camptothecin sodium salt, and 12 analogues with substituents on the A ring differ widely in their effectiveness in the treatment of murine L1210 lymphoblastic leukemia in vivo. The drugs were screened in the following systems: System 1, the cleavage of DNA in the presence of purified topoisomerase I; System 2, drug-induced trapping of topoisomerase I in a covalent complex with DNA; and System 3, the induction of protein-associated DNA breaks in drug-treated L1210 leukemia cells. 9-Amino-20(S), 10-amino-20(RS), and 10,11-methylenedioxy-20(RS), drugs effective against murine L1210 leukemia in vivo, stabilize topoisomerase I-DNA cleavable complexes in a purified system and in cultured L1210 cells. Other analogues, inactive against L1210 leukemia in vivo, were totally ineffective in topoisomerase I-directed screens. The rest of the analogues were intermediate in terms of their antitumor and topoisomerase I-directed activities. The study shows that the drug-induced accumulation of enzyme-DNA cleavable complexes is directly proportional to drug cytotoxicity and antitumor activity.
20(S)-喜树碱、20(S)-喜树碱钠盐以及A环带有取代基的12种类似物在体内治疗小鼠L1210淋巴细胞白血病的效果上差异很大。这些药物在以下系统中进行筛选：系统1，在纯化的拓扑异构酶I存在下DNA的裂解；系统2，药物诱导拓扑异构酶I与DNA形成共价复合物的捕获；系统3，药物处理的L1210白血病细胞中蛋白质相关DNA断裂的诱导。9-氨基-20(S)、10-氨基-20(RS)和10,11-亚甲二氧基-20(RS)，这些在体内对小鼠L1210白血病有效的药物，在纯化系统和培养的L1210细胞中稳定拓扑异构酶I-DNA可裂解复合物。其他类似物，在体内对L1210白血病无活性，在拓扑异构酶I导向的筛选中完全无效。其余类似物在抗肿瘤和拓扑异构酶I导向活性方面处于中间水平。该研究表明，药物诱导的酶-DNA可裂解复合物的积累与药物细胞毒性和抗肿瘤活性直接相关。
