BIPHASIC STEROIDOGENIC EFFECTS OF TAXOL AND CREMOPHOR EL

Cremophor is a polyoxyethylated castor oil intended as an inert vehicl e for delivery of lipophilic drugs including taxol, a promising antica ncer drug. Cremophor has been implicated in some undesirable side effe cts, e.g., hypersensitivity reactions which nearly resulted in prematu re termination of taxol phase I clinical trials. We have shown previou sly that clinical concentrations of purified taxol inhibit steroid sec retion by cultured granulosa cells. Since cremophor has also been show n to effect steroidogenic pathways, dose-response studies were conduct ed for both agents, and the ability of taxol- or cremophor-pretreated cells to produce progesterone was also investigated. Porcine granulosa cells were treated with therapeutic and subtherapeutic concentrations of cremophor (11-883 mu g/ well) or of taxol (0.123-10 mu g/well) for 24 h. A high concentration of cremophor, equivalent to that present i n a clinical dose of taxol, induced drastic morphologic alterations in granulosa cells and abolished progesterone production, while a low do se enhanced progesterone production. Likewise, high doses of taxol sup pressed, while low doses stimulated progesterone output, presumably th rough separate mechanisms. These results show that therapeutic doses o f both agents irreversibly suppress granulosa cell function, while low concentrations of both are potent stimulators of progesterone product ion.