MODULATION OF ADRIAMYCIN RESISTANCE IN HUMAN BREAST-CARCINOMA MCF-7 CELLS IN-VITRO AND IN-VIVO BY MEDROXYPROGESTERONE ACETATE

The combination effect of adriamycin (ADM) and medroxyprogesterone ace tate (R-IPA) was examined in vitro against human breast carcinoma MCF- 7 and its ADM-resistant line (MCF-7/ADM). MCF-7 cells, which are posit ive for estrogen receptors, progesterone receptors and high-affinity M PA-binding activity, were more susceptible to the growth-inhibitory ac tivity of ADM or MPA than MCF-7/ADM cells. A combination effect of ADM and MPA was observed against MCF-7/ADM cells, which are negative for steroid receptors, and furthermore against human nasopharynx carcinoma KB and its ADM-resistant line KB-A1. This combination effect of ADM a nd R IPA against MCF-7/ADM cells was demonstrated to be synergistic by using the median effect plot method. The activity of R-IPA H as almos t equivalent to that of chlormadinone acetate or tamoxifen, greater th an that of progesterone, and less than that of verapamil. The accumula tion of ADM in MCF-7/ADM cells was enhanced by treatment with 10 mu M MPA as Hell as 10 mu M verapamil. The efflux of accumulated ADR I from MCF-7/ADM cells was also partially inhibited by treatment with MPA or verapamil. MPA augmented the growth-inhibitory activity of ADM agains t MCF-7/ADM tumors inoculated into nude mice, although statistical sig nificance was not observed. It is suggested that the clinical advantag e of the combination of R-IPA with ADM against advanced breast cancers may be partly explained by the modulation of ADM resistance by MPA.