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.