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.
Footnotes
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Send reprint requests to: Dr. Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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↵1 This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan, and Core Research for Evolutional Sciences and Technology of Japan Science and Technology Corporation.
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↵2 Present address: Faculty of Pharmaceutical Sciences, Tohoku University, Aramaki-aza aoba, Aoba-ku, Sendai 980-77, Miyagi, Japan.
- Abbreviations:
- MDR
- multidrug resistance
- P-gp
- P-glycoprotein
- VCR
- vincristine
- VBL
- vinblastine
- ADR
- adriamycin
- CsA
- cyclosporin A
- Kp
- tissue-to-plasma concentration ratio
- KZI
- Konsentrat Zuer Infusion
- HPLC
- high-performance liquid chromatography
- Received February 2, 1998.
- Accepted July 7, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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