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

Derick H Lau, G. E. Duran, A. D. Lewis, B. I. Sikic

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)79-84
Number of pages6
JournalBritish Journal of Cancer
Volume70
Issue number1
StatePublished - Jul 1994

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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