Metabolic conversion of methoxymorpholinyl doxorubicin: from a DNA strand breaker to a DNA cross-linker

S_mmary 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 cytotox.ic 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. Since its introduction into clinical medicine in the early 1970s, doxorubicin has become an important anti-cancer drug in the treatment of a variety of solid tumours (Blum & Carter. 1974). However, its clinical uses are limited by car