POTENTIATION BY ESTRAMUSTINE OF THE CYTOTOXIC EFFECT OF VINBLASTINE AND DOXORUBICIN IN PROSTATIC TUMOR-CELLS

The effects of combining estramustine (EM) with vinblastine (VLB) or d oxorubicin (DOX) on cellular uptake, cellular retention and cell survi val were investigated in Dunning hormone-insensitive rat prostate AT-I tumor cells and DU-145 human prostatic tumor cells. Accumulation of V LB and DOX by AT-I cells was less than one-half of that in DU-145 cell s. Inclusion of EM or estromustine considerably increased uptake of bo th VLB and DOX in AT-I cells but not in DU-145 cells. Verapamil and ta moxifen also potentiated VLB uptake in AT-I cells. A combination of VL B and EM resulted in a considerable synergistic effect on both cytotox icity and cellular retention of VLB. The presence of P-glycoprotein (P gp) in AT-I cells could be demonstrated by both Western blots and immu nocytochemical detection. Photoaffinity labeling of Pgp by [H-3]-azido pine was clearly inhibited by VLB, verapamil and EM. Our data strongly support the argument for a combination of EM with not only VLB but al so DOX to improve the therapeutic index in patients with prostate canc er. (C) 1996 Wiley-Liss, Inc.