Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Nov;89(11):1220–1228. doi: 10.1111/j.1349-7006.1998.tb00518.x

Inhibitory Effects of a Cyclosporin Derivative, SDZ PSC 833, on Transport of Doxorubicin and Vinblastine via Human P‐Glycoprotein

Nobuya Kusunoki 1, Kohji Takara 2, Yusuke Tanigawara 2,†, Aiko Yamauchi 3, Kazumitsu Ueda 4, Fusao Komada 2, Yonson Ku 1, Yoshikazu Kuroda 1, Yohichi Saitoh 1, Katsuhiko Okumura 2,✉
PMCID: PMC5921725  PMID: 9914792

Abstract

The inhibitory effects of SDZ PSC 833 (PSC833), a non‐immunosuppressive cyclosporin derivative, on the P‐glycoprotein (P‐gp)‐mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs‐A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC‐GA5‐COL150 cells, which overexpress human P‐gp, was measured. Both PSC833 and Cs‐A inhibited P‐gp‐mediated transport of doxorubicin and vinblastine in a concentration‐dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC‐GA5‐COL150 cells. The values of the 50%‐inhibitory concentration (IC50) of PSC833 and Cs‐A for doxorubicin transport were 0.29 and 3.66 μM, respectively, and those for vinblastine transport were 1.06 and 5.10 μM, respectively. The IC50 of PSC833 for doxorubicin transport was about 4‐fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P‐gp and had higher lipophilicity than Cs‐A. These results indicated that the inhibitory effect of PSC833 on P‐gp‐mediated transport was 5‐ to 10‐fold more potent than that of Cs‐A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P‐gp and to the higher lipophilicity of PSC833.

Keywords: SDZ PSC 833, Cyclosporin A, P‐glycoprotein, Multidrug resistance

Full Text

The Full Text of this article is available as a PDF (136.8 KB).

REFERENCES

  • 1. ) Endicott , J. A. and Ling , V.The biochemistry of P‐glycoprotein‐mediated multidrug resistance . Annu. Rev. Biochem. , 58 , 137 – 171 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Gottesman , M. M. and Pastan , I.Biochemistry of multidrug resistance mediated by the multidrug transporter . Annu. Rev. Biochem. , 62 , 385 – 427 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Fisher , G. A. , Lum , B. L. , Hausdorff , J. and Sikic , B. I.Pharmacological considerations in the modulation of multidrug resistance . Eur. J. Cancer , 32A , 1082 – 1088 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Boesch , D. , Gavériaux , C. , Jachez , B. , Pourtier‐Manzanedo , A. , Bollinger , P. and Loor , F.In vivo circumvention of P‐glycoprotein‐mediated multidrug resistance of tumor cells with SDZ PSC 833 . Cancer Res. , 51 , 4226 – 4233 ( 1991. ). [PubMed] [Google Scholar]
  • 5. ) Gavériaux , C. , Boesch , D. , Jachez , B. , Bollinger , P. , Payne , T. and Loor , F.SDZ PSC 833, a non‐immunosuppressive cyclosporin analog, is a very potent multidrug‐resistance modifier . J. Cell Pharmacol. , 2 , 225 – 234 ( 1991. ). [Google Scholar]
  • 6. ) Slater , L. M. , Sweet , P. , Stupecky , M. and Gupta , S.Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro . J. Clin. Invest. , 77 , 1405 – 1408 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Twentyman , P. R.Cyclosporin as drug resistance modifiers . Biochem. Pharmacol. , 43 , 109 – 117 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Lum , B. L. , Fisher , G. A. , Brophy , N. A. , Yahanda , A. M. , Adler , K. M. , Kaubisch , S. , Halsey , J. and Sikic , B. I.Clinical trials of modulation of multidrug resistance. Pharmacokinetic and pharmacodynamic considerations . Cancer , 72 , 3502 – 3514 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Erlichman , C. , Moore , M. , Thiessen , J. , DeAngelis , C. , Goodman , P. and Manzo , J.A phase I trial of doxorubicin (D) and PSC 833, a modulator of multidrug resistance (MDR) . Proc. Am. Soc. Clin. Oncol. , 13 , 134 . Abstr 330 ( 1994. ). [Google Scholar]
  • 10. ) Giaccone , G. , Linn , S. C. , Catimel , G. , Vermorken , J. B. , Koier , I. , Welink , J. , Vijgh , J. W. F. , Eeltink , C. , Laburte , C. and Pinedo , H. M.Phase I and pharmacokinetic study of SDZ PSC 833 per os in combination with doxorubicin in patients with solid tumors . Proc. Am. Soc. Clin. Oncol. , 13 , 142 . Abstr 364 ( 1994. ). [Google Scholar]
  • 11. ) Boote , D. J. , Dennis , I. F. , Twentyman , P. R. , Osborne , R. J. , Laburte , C. , Hensel , S. , Smyth , J. F. , Brampton , M. H. and Bleehen , N. M.Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer . J. Clin. Oncol. , 14 , 610 – 618 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Sonneveld , P. , Marie , J.‐P. , Huisman , C. , Vekhoff , A. , Schoester , M. , Faussat , A. M. , Van Kapel , J. , Groenewegen , A. , Charnick , S. , Zittoun , R. and Löwenberg , B.Reversal of multidrug resistance by SDZ PSC 833, combined with VAD (vincristine, doxorubicin, dexamethasone) in refractory multiple myeloma. A phase I study . Leukemia , 10 , 1741 – 1750 ( 1996. ). [PubMed] [Google Scholar]
  • 13. ) Kornblau , S. M. , Estey , E. , Madden , T. , Tran , H. T. , Zhao , S. , Consoli , U. , Snell , V. , Shanchez‐Williams , G. , Kantarjian , H. , Keating , M. , Newman , R. A. and Andreef , M.Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC‐833 in relapsed or refractory acute myelogenous leukemia . J. Clin. Oncol. , 15 , 1796 – 1802 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Boesch , D. , Muller , K. , Pourtier‐Manzanedo , A. and Loor , F.Restoration of daunomycin retention in multidrug‐resistant P388 cells by submicromolar concentration of SDZ PSC 833, a nonimmunosuppressive cyclosporin derivative . Exp. Cell Res. , 196 , 26 – 32 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Boekhorst , P. A. W. , Van Kapel , J. , Schoester , M. and Sonneveld , P.Reversal of typical multidrug resistance by cyclosporin and its non‐immunosuppressive analogue SDZ PSC833 in Chinese hamster ovary cells expressing the mdr 1 phenotype . Cancer Chemother. Pharmacol. , 30 , 238 – 242 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Keller , R. P. , Altermatt , H. J. , Nooter , K. , Poschmann , G. , Laissue , J. A. , Bollinger , P. and Hiestand , P. C.SDZ PSC833, a non‐immunosuppressive cyclosporine: its potency in overcoming P‐glycoprotein‐mediated multidrug resistance of murine leukemia . Int. J. Cancer , 50 , 593 – 597 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Jachez , B. , Nordmann , R. and Loor , F.Restoration of taxol sensitivity of multidrug‐resistant cells by the cyclosporine SDZ PSC833 and the cyclopeptolide SDZ 280–446 . J. Natl. Cancer Inst. , 85 , 478 – 483 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Chen , G. , Jaffrezou , J. P. , Fleming , W. H. , Duran , G. E. and Sikic , B. I.Prevalence of multidrug resistance related to activation of the mdr 1 gene in human sarcoma mutants derived by single‐step doxorubicin selection . Cancer Res. , 54 , 4980 – 4987 ( 1994. ). [PubMed] [Google Scholar]
  • 19. ) Jiang , X.‐R. , Kelsey , S. M. , Wu , Y.‐L. and Newland , A. C.Circumvention of P‐glycoprotein‐mediated drug resistance in human leukaemic cells by non‐immunosuppressive cyclosporin D analogue, SDZ PSC833 . Br. J. Haematol. , 90 , 375 – 383 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Watanabe , T. , Tsuge , H. , Oh‐hara , T. , Naito , M. and Tsuruo , T.Comparative study of reversal efficacy of SDZ PSC 833, cyclosporin A and verapamil on multidrug resistance in vitro and in vivo . Acta Oncol. , 34 , 235 – 241 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Pourtier‐Manzanedo , A. , Didier , A. D. , Muller , C. D. and Loor , F.SDZ PSC 833 and SDZ 280–446 are the most active of various resistance‐modifying agents in restoring rhodamine‐123 retention within multidrug resistant P388 cells . Anti-Cancer Drugs , 3 , 419 – 425 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Tanigawara , Y. , Okamura , N. , Hirai , M. , Yasuhara , M. , Ueda , K. , Kioka , N. , Komano , T. and Hori , R.Transport of digoxin by human P‐glycoprotein expressed in a porcine kidney epithelial cell line (LLC‐PK1) . J. Pharmacol. Exp. Ther. , 263 , 840 – 845 ( 1992. ). [PubMed] [Google Scholar]
  • 23. ) Ueda , K. , Okamura , N. , Hirai , M. , Tanigawara , Y. , Saeki , T. , Kioka , N. , Komano , T. and Hori , R.Human P‐glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone . J. Biol. Chem. , 267 , 24248 – 24252 ( 1992. ). [PubMed] [Google Scholar]
  • 24. ) Okamura , N. , Hirai , M. , Tanigawara , Y. , Tanaka , K. , Yasuhara , M. , Ueda , K. , Komano , T. and Hori , R.Digoxin‐cyclosporin A interaction: modulation of the multidrug transporter P‐glycoprotein in the kidney . J. Pharmacol. Exp. Ther. , 266 , 1614 – 1619 ( 1993. ). [PubMed] [Google Scholar]
  • 25. ) Saeki , T. , Ueda , K. , Tanigawara , Y. , Hori , R. and Komano , T.Human P‐glycoprotein transports cyclosporin A and FK506 . J. Biol. Chem. , 268 , 6077 – 6080 ( 1993. ). [PubMed] [Google Scholar]
  • 26. ) Saeki , T. , Ueda , K. , Tanigawara , Y. , Hori , R. and Komano , T.P‐glycoprotein‐mediated transcellular transport of MDR‐reversing agents . FEBS Lett. , 324 , 99 – 102 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Hirai , M. , Tanaka , K. , Shimizu , T. , Tanigawara , Y. , Yasuhara , M. , Hori , R. , Kakehi , Y. , Yoshida , O. , Ueda , K. , Komano , T. and Inui , K.Cepharanthin, a multidrug resistant modifier, is a substrate for P‐glycoprotein . J. Pharmacol. Exp. Ther. , 275 , 73 – 78 ( 1995. ). [PubMed] [Google Scholar]
  • 28. ) Tanaka , K. , Hirai , M. , Tanigawara , Y. , Yasuhara , M. , Hori , R. , Ueda , K. and Inui , K.Effect of cyclosporin analogues and FK506 on transcellular transport of daunorubicin and vinblastine via P‐glycoprotein . Pharm. Res. , 13 , 1073 – 1077 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Tanaka , K. , Hirai , M. , Tanigawara , Y. , Ueda , K. , Takano , M. , Hori , R. and Inui , K.Relationship between expression level of P‐glycoprotein and daunorubicin transport in LLC‐PK1 cells transfected with human MDR1 gene . Biochem. Pharmacol. , 53 , 741 – 746 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Archinal‐Mattheis , A. , Rzepka , R. W. , Watanabe , T. , Kokubu , N. , Itoh , Y. , Combates , N. J. , Bair , K. W. and Cohen , D.Analysis of the interaction of SDZ PSC 833 ([3′‐keto‐Bmt1]‐Val2]‐cyclosporin), a multidrug resistance modulator, with P‐glycoprotein . Oncol. Res. , 7 , 603 – 610 ( 1995. ). [PubMed] [Google Scholar]
  • 31. ) Demeule , M. , Wenger , R. M. and Béliveau , R.Molecular interactions of cyclosporin A with P‐glycoprotein. Photolabeling with cyclosporin derivatives . J. Biol. Chem. , 272 , 6647 – 6652 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Bartlett , N. L. , Lum , B. L. , Fischer , G. A. , Brophy , N. A. , Ehsan , M. N. , Halsey , J. and Sikic , B. I.Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance . J. Clin. Oncol. , 12 , 835 – 842 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Lum , B. , Kaubisch , S. , Yahanda , A. M. , Adler , K. M. , Jew , L. , Ehsan , M. N. , Brophy , N. A. , Halsey , J. , Gosland , M. P. and Sikic , B. I.Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance . J. Clin. Oncol. , 10 , 1635 – 1642 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Erlichman , C. , Moore , M. , Thiessen , J. J. , Kerr , I. G. , Walker , S. , Goodman , P. , Bjarnason , G. , DeAngelis , C. and Bunting , P.Phase I pharmacokinetic study of cyclosporin A combined with doxorubicin . Cancer Res. , 53 , 4837 – 4842 ( 1993. ). [PubMed] [Google Scholar]
  • 35. ) List , A. F. , Spier , C. , Greer , J. , Wolff , S. , Hutter , J. , Dorr , R. , Salmon , S. , Futscher , B. , Baier , M. and Dalton , W.Phase I/II trial of cyclosporine as a chemotherapy‐resistance modifier in acute leukemia . J. Clin. Oncol. , 11 , 1652 – 1660 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Samuels , B. L. , Mick , R. , Vogelzang , N. J. , Williams , S. F. , Schilsky , R. L. , Safa , A. R. , O'Brien , S. M. and Ratain , M. J.Modulation of vinblastine resistance with cyclosporine: a phase I study . Clin. Pharmacol. Ther. , 54 , 421 – 429 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Rushing , D. A. , Raber , S. R. , Rodvold , K. A. , Piscitelli , S. C. , Plank , G. S. and Tewksbury , D. A.The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer . Cancer , 74 , 834 – 841 ( 1994. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES