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Research ArticleArticle

Modulation of the Tumor Disposition of Vinca Alkaloids by PSC 833In Vitro and In Vivo

Saeheum Song, Hiroshi Suzuki, Tetsuya Terasaki, Michel Lemaire and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 963-968;
Saeheum Song
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Hiroshi Suzuki
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Tetsuya Terasaki
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Michel Lemaire
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Yuichi Sugiyama
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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

  • 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.

  • ↵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.

  • ↵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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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Modulation of the Tumor Disposition of Vinca Alkaloids by PSC 833In Vitro and In Vivo

Saeheum Song, Hiroshi Suzuki, Tetsuya Terasaki, Michel Lemaire and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 963-968;

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Research ArticleArticle

Modulation of the Tumor Disposition of Vinca Alkaloids by PSC 833In Vitro and In Vivo

Saeheum Song, Hiroshi Suzuki, Tetsuya Terasaki, Michel Lemaire and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 963-968;
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