Role of oxygen free radical formation in the mechanism of menogaril resistance in multidrug resistant tumor cells.
The mechanisms of action and resistance to menogaril, a clinically active anthracycline antitumor drug, were evaluated in sensitive and doxorubicin-selected multidrug resistant human breast tumor (MCF-7) cell lines. While MCF-7/ADRR cells were highly resistant (250-500-fold) to doxorubicin, they displayed only marginal resistance (10-fold) to menogaril. In contrast to doxorubicin, the mechanism of resistance to menogaril in these cells does not involve differential inhibition of DNA synthesis as measured by thymidine incorporation. P-170-glycoprotein-dependent drug transport did not contribute to resistance as there was no difference in the accumulation and retention of menogaril by sensitive and resistant cell lines. However, there was a 2-fold decrease in oxygen free radical formation in the resistant cells, compared to sensitive cells, in the presence of menogaril. Since resistant cells contain 12-fold higher glutathione peroxidase activity than the parental sensitive cells, the detoxification of hydrogen peroxide may be responsible for the decreased free radical formation and thus, may play a role in the resistance to menogaril.
Sinha
B K
BK
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Atwell
J
J
Politi
P M
PM
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000096:biosynthesis; D003630:Daunorubicin / Q000031:analogs & derivatives*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006801:Humans; D017290:Menogaril; D009621:Nogalamycin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D005609:Free Radicals; D004317:Doxorubicin; D017290:Menogaril; D004247:DNA; D009621:Nogalamycin; D010100:Oxygen; D003630:Daunorubicin