CREMOPHOR EL REVERSED MULTIDRUG-RESISTANCE IN-VITRO BUT NOT IN TUMOR-BEARING MOUSE MODELS

Cremophor EL (CreEL), a polyethylene castor oil used as a vehicle for cyclosporin A and taxol, reverses P-glycoprotein-mediated drug resista nce. The vehicle in an i.v. dosage form of PSC 833, [3'-keto-Bmt(1)]-[ Val(2)]-cyclosporin, contains CreEL and has been presumed to have the potentiation of the reversal activity of PSC 833. To examine this poss ibility, we compared reversal activities of CreEL and PSC 833 against multidrug resistance (MDR) in vitro and in vivo, Both CreEL and PSC 83 3 inhibited P-glycoprotein-mediated efflux of [H-3]vincristine from ad riamycin-resistant myelogenous leukemia K562. The sensitization of mul tidrug-resistant cell lines to anticancer drugs by CreEL and PSC 833 w as selective to MDR-related agents, suggesting a specific interference of the P-glycoprotein function by the two MDR modulators. The concent ration-dependent activity of the modulators demonstrated that CreEL is at least 100 times less potent than PSC 833. The in vivo reversal eff ects of CreEL alone and PSC 833 in the vehicle were investigated in mu ltidrug-resistant tumor-bearing mouse models. In vincristine-resistant P388 leukemia-bearing mice, neither i.v. nor i.p, administration of C reEL even at 1440 mg/kg enhanced the antitumor activity of adriamycin. The in vivo negligible activity of CreEL was confirmed in an HCT-15-b earing athymic mouse model. In contrast, PSC 833 significantly enhance d the antitumor activity of adriamycin in the in vivo models, The reve rsal activity of CreEL restricted to in vitro leads us to conclude tha t the vehicle containing CreEL did not potentiate the activity of PSC 833 in the tumor-bearing mouse models.