Abstract

PSC 833, a nonimmunosuppressive cyclosporin, is able to inhibit the efflux of antitumor drugs mediated by P-glycoprotein (P-gp). The purpose of the present study is to compare the effect of PSC 833 on the tumor disposition of [³H]vincristine ([³H]VCR) and [³H]vinblastine ([³H]VBL) in in vitro and in vivo experiments from a pharmacokinetic point of view. Inin vitro experiments, the effect of PSC 833 was investigated on the cellular uptake of [³H]VCR and [³H]VBL by HCT-15 and COLO 205, human colorectal tumor cell lines with extensive and minimal expression of P-gp, respectively. PSC 833 (2 μM) increased the cellular uptake of [³H]VCR and [³H]VBL by HCT-15 cells, but not that by COLO 205 cells, 8- and 6-fold, respectively, without affecting the initial influx rates. In addition, 2 μM PSC 833 reduced the efflux of [³H]VCR from HCT-15 cells to a level comparable with that from COLO 205 cells. Furthermore, the effect of PSC 833 on the tumor disposition of intravenously administered [³H]VCR and [³H]VBL was studied in tumor inoculated mice. Infusion of PSC 833 (10 μg/hr/mouse) increased the HCT-15 tumor disposition of [³H]VBL and [³H]VCR in vivoto a level comparable with that observed in vitro. These findings demonstrate that PSC 833 enhances the tumor disposition of vinca alkaloids by inhibition of P-gp-mediated efflux not onlyin vitro but also in vivo in a solid tumor model.