Enhancement of adriamycin® cytotoxicity in a multidrug resistant Chinese hamster ovary (CHO) subline, CHO-Adrr, by toremifene and its modulation by alpha1 acid glycoprotein

Abstract

The effects of a new antioestrogen, toremifene, on multidrug resistance have been studied in a Chinese hamster ovary parental line, CHO-K1, and in a multidrug resistance subline, CHO-Adrr. Toremifene at subinhibitory concentrations increased the cytotoxic effectiveness of Adriamycin® in both cell lines. The degree of potentiation was greater in the CHO-Adrr lines for any given concentration of toremifene. Toremifene is 99.7% bound to human serum proteins (Sipila et al. Pharmacol Toxicol 1988, 63, 62–64), which includes binding to an acute phase plasma protein, alpha1 acid glycoprotein (AAG). Since AAG is normally absent from tissue culture media, we have assessed the effect of AAG on toremifene mediated potentiation of Adriamycin® cytotoxicity. In the presence of increasing concentrations of AAG, there was a dose-related reversal of the effect of toremifene on Adriamycin® cytotoxicity in both cell lines. These results show that toremifene is effective in enhancement of Adriamycin® cytotoxicity in CHO-K1 and CHO-Adrr cell lines, and this modulation can be altered by AAG. The clinical implication is that patients should be selected for such therapy by measurement of AAG levels.