Association of DNA cross-linking with potentiation of the morpholino derivative of doxorubicin by human liver microsomes

Derick H Lau, Alexander D. Lewis, Branimir I. Sikic

Research output: Contribution to journalArticle

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Abstract

The morpholmo analog of doxorubicin (DOX), 3'-deamino-3'-(4"-morpholinyl)-doxorubicm (MRA), is 0.5- to 10-fold more potent than DOX in vitro but 100- to 200-fold more potent in vivo, which indicated that biotransformation in vivo may generate a highly potent metabolite(s). A likely mechanism for such biotransformation is hepatic mixed-function oxidation. At a concentration of 5 μM, MRA was incubated for 30 minutes at 37 °C with 1 mg of human liver microsomes/mL and 0.45 mM of NADPH. The cytotoxicity of the microsome- and NADPH-treated MRA was 44-fold higher than that of the untreated MRA in the human ovarian carcinoma cell line ES-2. This potentiation did not occur for MRA treated with boiled microsomes and NADPH, active microsomes in the absence of NADPH, or. Tris buffer plus NADPH. No potentlation was observed with DOX or the highly potent cyanomorpholino derivative of DOX, MRA-CN, under any of the above conditions. After 2 hours of exposure of the ES-2 cells to microsome- and NADPH-treated MRA, dose-dependent DNA cross-links were observed with 5 nM or more of MRA, whereas only DNA strand breaks were detected in cells exposed to 500 nM of untreated MRA or MRA incubated under other conditions. These data indicate that MRA is biotransformed by the hepatic mixed-function oxidases to a potent DNA-alkylating metabolite(s), which may be important in the determination of the pharmacologic and toxicologic profile of MRA. The active metabolite(s) of MRA may be analogous to MRA-CN, which cross-links DNA without requiring bioactivation.

Original languageEnglish (US)
Pages (from-to)1034-1038
Number of pages5
JournalJournal of the National Cancer Institute
Volume81
Issue number13
DOIs
StatePublished - Jul 5 1989
Externally publishedYes

Fingerprint

Morpholinos
3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin
Liver Microsomes
NADP
Liver
Doxorubicin
Linking
Fold
DNA
Metabolites
Microsomes
Derivatives
Derivative
Cell
Cytotoxicity
Biotransformation
Oxidation
Buffer
Dose
Likely

ASJC Scopus subject areas

  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging
  • Oncology
  • Cancer Research

Cite this

Association of DNA cross-linking with potentiation of the morpholino derivative of doxorubicin by human liver microsomes. / Lau, Derick H; Lewis, Alexander D.; Sikic, Branimir I.

In: Journal of the National Cancer Institute, Vol. 81, No. 13, 05.07.1989, p. 1034-1038.

Research output: Contribution to journalArticle

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