Sequential α-interferon and tamoxifen: in-vitro reversal of MDR-1 mediated multidrug resistance in the MCF-7 cell line

Abstract

Abstract Chemotherapy drug resistance in breast cancer is mediated in part by the MDR-1 gene product, P-glycoprotein (PGP). Tamoxifen (TMX) is able to modulate the MDR-1 phenotype in vitro. Interferons modulate other biologic effects of TMX and may enhance the effect of TMX on PGP function. We have investigated the effects of combinations of α-interferon (IFN) and TMX on the MDR-1 phenotype and function in MCF-7 cells. IFN and TMX were both growth inhibitory to MCF-7 cells. Preincubation with IFN potentiated the antiproliferative effect of TMX even at low concentrations. Immunocytochemically detected staining for the external domain of PGP was increased by both TMX and IFN and the effect of the two agents appeared to be synergistic. Despite the increased expression of the external domain of PGP, in functional studies, as assessed by inhibition of 3 H vinblastine (VBL) efflux, TMX partially reversed the MDR-1 phenotype in both parental MCF-7 and a multidrug resistant subline MCF-7 mdr . Prolonged exposure to IFN during culture, followed by TMX + IFN resulted in a further and significant decrease of VBL efflux in this cell line as compared to after TMX alone. TMX and IFN both have antiproliferative as well as anti-PGP functional effects in this model. Further studies with these two agents in combination, in the setting of clinical drug resistance, appear to be warranted.