BIPHASIC STEROIDOGENIC EFFECTS OF TAXOL AND CREMOPHOR EL

Cremophor is a polyoxyethylated castor oil intended as an inert vehicle for delivery of lipophilic drugs including taxol, a promising anticancer drug. Cremophor has been implicated in some undesirable side effects, e.g., hypersensitivity reactions which nearly resulted in premature termination of taxol phase I clinical trials. We have shown previously that clinical concentrations of purified taxol inhibit steroid secretion by cultured granulosa cells. Since cremophor has also been shown to effect steroidogenic pathways, dose-response studies were conducted 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 in a clinical dose of taxol, induced drastic morphologic alterations in granulosa cells and abolished progesterone production, while a low dose enhanced progesterone production. Likewise, high doses of taxol suppressed, while low doses stimulated progesterone output, presumably through separate mechanisms. These results show that therapeutic doses of both agents irreversibly suppress granulosa cell function, while low concentrations of both are potent stimulators of progesterone production.