Lau D H, Duran G E, Lewis A D, Sikic B I
Division of Hematology/Oncology, University of California, Davis Cancer Center, Sacramento 95817.
Br J Cancer. 1994 Jul;70(1):79-84. doi: 10.1038/bjc.1994.253.
Methoxymorpholinyl doxorubicin (MMDX) is a novel anti-cancer anthracycline that differs from doxorubicin in its mechanisms of action, pattern of resistance and metabolism. Whereas doxorubicin is primarily an inhibitor of topoisomerase II, MMDX inhibits both topoisomerases I and II, resulting in predominantly single-strand DNA cleavage and, to a lesser extent, double-strand DNA breakage. MMDX is equally cytotoxic in vitro against the doxorubicin-sensitive and -resistant uterine sarcoma cell lines, MES-SA and Dx5. Using fluorescent laser cytometry, MMDX was retained intracellularly to a similar extent in MES-SA and Dx5; the intracellular retention of MMDX was 7.5-fold higher than that of doxorubicin in Dx5. The cytotoxicity of MMDX on an ovarian carcinoma cell line, ES-2, was potentiated 50-fold by preincubating the drug with human liver microsomes and NADPH. This cytotoxic potentiation was associated with the appearance of DNA interstrand cross-links. The in vitro potentiation of MMDX was inhibited by cyclosporin A, which is a substrate for human cytochrome P450 IIIA.
甲氧基吗啉基阿霉素（MMDX）是一种新型抗癌蒽环类药物，其作用机制、耐药模式和代谢方式均与阿霉素不同。阿霉素主要是拓扑异构酶II的抑制剂，而MMDX同时抑制拓扑异构酶I和II，主要导致单链DNA断裂，在较小程度上导致双链DNA断裂。MMDX在体外对阿霉素敏感和耐药的子宫肉瘤细胞系MES-SA和Dx5具有同等的细胞毒性。使用荧光激光细胞术，MMDX在MES-SA和Dx5细胞内的保留程度相似；在Dx5细胞中，MMDX的细胞内保留量比阿霉素高7.5倍。通过将MMDX与人肝微粒体和NADPH预孵育，其对卵巢癌细胞系ES-2的细胞毒性增强了50倍。这种细胞毒性增强与DNA链间交联的出现有关。MMDX的体外增强作用被环孢素A抑制，环孢素A是人细胞色素P450 IIIA的底物。
