Cremophor EL (CreEL), a polyethylene castor oil used as a vehicle for cyclosporin A and taxol, reverses P-glycoprotein-mediated drug resistance. The vehicle in an i.v. dosage form of PSC 833, [3'-keto-Bmt1]-[Val2]-cyclosporin, contains CreEL and has been presumed to have the potentiation of the reversal activity of PSC 833. To examine this possibility, we compared reversal activities of CreEL and PSC 833 against multidrug resistance (MDR) in vitro and in vivo. Both CreEL and PSC 833 inhibited P-glycoprotein-mediated efflux of [3H]vincristine from adriamycin-resistant myelogenous leukemia K562. The sensitization of multidrug-resistant cell lines to anticancer drugs by CreEL and PSC 833 was selective to MDR-related agents, suggesting a specific interference of the P-glycoprotein function by the two MDR modulators. The concentration-dependent activity of the modulators demonstrated that CreEL is at least 100 times less potent than PSC 833. The in vivo reversal effects of CreEL alone and PSC 833 in the vehicle were investigated in multidrug-resistant tumor-bearing mouse models. In vincristine-resistant P388 leukemia-bearing mice, neither i.v. nor i.p. administration of CreEL even at 1440 mg/kg enhanced the antitumor activity of adriamycin. The in vivo negligible activity of CreEL was confirmed in an HCT-15-bearing athymic mouse model. In contrast, PSC 833 significantly enhanced the antitumor activity of adriamycin in the in vivo models. The reversal activity of CreEL restricted to in vitro leads us to conclude that the vehicle containing CreEL did not potentiate the activity of PSC 833 in the tumor-bearing mouse models.