TY - JOUR
T1 - Metabolic conversion of methoxymorpholinyl doxorubicin
T2 - from a DNA strand breaker to a DNA cross-linker
AU - Lau, Derick H
AU - Duran, G. E.
AU - Lewis, A. D.
AU - Sikic, B. I.
PY - 1994/7
Y1 - 1994/7
N2 - 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.
AB - 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.
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M3 - Article
C2 - 8018545
AN - SCOPUS:0028200049
VL - 70
SP - 79
EP - 84
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 1
ER -