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Modulation of doxorubicin concentration by cyclosporin A in brain and testicular barrier tissues expressing P-glycoprotein in rats

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Abstract

P-glycoprotein (Pgp) is an inducible transmembrane protein that functions as an ATP-dependent efflux pump. Pgp is normally expressed in two types of cells: specialized epithelial cells with secretory/excretory functions (e.g., proximal renal tubules) and specialized endothelial cells (e.g., the capillary endothelial cells of the blood-brain barrier). In normal tissues, Pgp could exert a cytoprotective effect by facilitating excretion of drugs. It follows that inhibition of Pgp would alter the pharmacokinetics of drugs, like doxorubicin, in cells that express Pgp. The purpose of this study was to determine whether or not inhibition of Pgp by cyclosporin A (CsA) facilitated the transport of certain drugs across the blood tissue barriers of the brain and testes (barriers tissues expressing Pgp). 120 retired male breeder CD Fisher rats were randomly assigned to groups of 4 rats each. They were given either CsA, CsA vehicle, or saline followed by doxorubicin (Dox), cisplatin (CDDP), Evan's blue (EB), sodium fluorescein (NaF), or horseradish peroxidase (HRP). There was a CsA dose dependent increase in the tissue concentration of doxorubicin in brain and testes, but platinum (Pt) concentrations, derived from CDDP, were unaffected. Unlike CDDP, Dox, can be effluxed by Pgp. These increases in Dox concentrations were not due to altered vascular permeability as a result of CsA treatment as determined by lack of EB, NaF, or HRP in brain parenchyma. Modulation of Pgp function may prove to be useful for improving chemotherapy efficacy for patients with malignancies affecting tissues with blood-tissue barriers.

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References

  1. Holzmayer TA, Hilsenbeck S, Von Hoff DD, Roninson IB: Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas. J Natl Cancer Institute 84: 1486–1491, 1992

    Google Scholar 

  2. Ramachandran C, Sauerteig A, Sridhar KS, Thurer RJ, Krishan A: MDR-1 gene expression, anthacycline retention and cytotoxicity in human lung-tumor cells from refractory patients. Cancer Chemother Pharmacol 31: 431–441, 1993

    Google Scholar 

  3. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC: Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84: 7735–7738, 1987

    Google Scholar 

  4. Fojo AT, Ueda K, Slamon DJ, Poplack DJ, Gottesman MM, Pastan I: Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84: 265–269, 1987

    Google Scholar 

  5. Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Gruer L, Biedler JL, Melamed MR, Bertino JR: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at the blood-brain barrier sites. Proc Nat Acad Sci USA 86: 695–698, 1989

    Google Scholar 

  6. Dermietzel RKD: Molecular anatomy of the blood-brain barrier as defined by immunocytochemistry. Intern Rev Cytol 127: 57–109, 1991

    Google Scholar 

  7. Dym M, Fawcett DW: The blood-testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium. Biol Reprod 3: 308–326, 1970

    Google Scholar 

  8. Pardridge W: Peptide Drug Delivery to the Brain. Raven Press, New York, 1991

    Google Scholar 

  9. Tsuruo T, Iida H, Tsukagoshi S, Sakurai J: Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41: 1967–1972, 1981

    Google Scholar 

  10. Tsuruo T, Iida H, Kititani Y, Yokada K, Tsukagoshi S, Sakurai Y: Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug resistant tumor cells. Cancer Res 44: 4303–4307, 1984

    Google Scholar 

  11. DeGregorio GW, Ford JM, Benz CC, Wiebe VJ: Toremifene: pharmacologic and pharmacokinetic basis of reversing multi-drug resistance. J Clin Oncol 7: 1359–1364, 1989

    Google Scholar 

  12. Ramu A, Glaubiger D, Fuks Z: Reversal of acquired resistance to doxorubicin in P388 murine cell leukemia cells by tamoxifen and other triparanol analogues. Cancer Res 44: 4392–4395, 1984

    Google Scholar 

  13. Siddik ZH, Newell DR, Boxall FE, Harrap KR: The comparative pharmacokinetics of carboplatin and cisplatin in mice and rats. Biochem Pharmacol 36: 1925–1932, 1987

    Google Scholar 

  14. Yesair DW, Schwartzbach E, Shuck D, Denine EP, Asbell MA: Comparative pharmacokinetics of daunomycin and adriamycin in several animal species. Cancer Res 32: 1177–1183, 1972

    Google Scholar 

  15. Yeu-Tsu NL, Chan KK, harris PA: Tissue disposition of doxorubicin in experimental animals. Med Pediatric Oncol 10: 259–267, 1982

    Google Scholar 

  16. Hudson LC, Hughes CS, Fletcher-Bold N, Vaden SL: Cerebrospinal fluid collection in rats: modification of a previous technique. Lab Anim Sci 44: 358–361, 1994

    Google Scholar 

  17. Cox SK, Wilke AV, Frazier D: Determination of adriamycin in plasma and tissue biopsies. J Chromat Biomed Appl 564: 322–329, 1991

    Google Scholar 

  18. McGahan MC, Tyczkoska K: The determination of platinum in biological material by electrochemical atomic absorption spectroscopy. Spectrochimica Acta 42B: 665, 1987

    Google Scholar 

  19. Saria A, Lundberg JM: Evans blue fluorescence: quantitative and morphological evaluation of vascular permeability in animal tissues. J Neurosci Methods 8: 41–49, 1983

    Google Scholar 

  20. Wolman M, Klatzo I, Chui E, Wilmes F, Nishimoto K, Fujiwara K, Spatz M: Evaluation of the dye-protein tracers in pathophysiology of the blood-brain barrier. Acta Neuropathol 54: 55–61, 1981

    Google Scholar 

  21. Stewart PA, Farrell CR, Farrell CL, Hayakawa E: Horseradish peroxidase retention and washout in blood-brain barrier lesions. J Neurosci Methods 41: 75–84, 1992

    Google Scholar 

  22. Schinkel AH, Smit JJM, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CAAM, van der Valk MA, Robanus-Maandag EC, te Riele HPJ, Berns AJM, Borst P: Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77: 491–502, 1994

    Google Scholar 

  23. Shirai A, Naito M, Tatsuta T, Dong J, Hanaoka K, Mikami K, Oh-hara T, Tsuruo T: Transport of cyclosporin A across the brain capillary endothelial cell monolayer by P-glycoprotein. Biochim Biophys Acta 1222: 400–404, 1994

    Google Scholar 

  24. Chan BBK, Kern JA, Flanagan, Terry L, Kron IL, Tribble CG: Effects of in vivo cyclosporine administration on endothelium-dependent responses in isolated vascular rings. Circulation 86: II-265–II-299, 1992

    Google Scholar 

  25. Nooter K, Oostrum R, Deurloo J: Effects of verapamil on the pharmacokinetics of daunomycin in the rat. Cancer Chemother Pharmacol 20: 176–178, 1988

    Google Scholar 

  26. Schrenk D, Gant T, Silverman J, Marino P, Thorgeirsson S: Induction of mdr expression by cholestasis: P-glycoprotein function as a biliary excretion pump. In: American Association for Cancer Research Annual Meeting, San Diego, 1992, 31

  27. Trump DL, Smith DC, Ellis PG, Rogers MP, Schold SC, Winer EP, Panella TJ, Jordan VC, Fine RL: High-dose oral tamoxifen, a potential multidrug-resistance-reversal agent: phase I trial in combination with vinblastine. J Natl Cancer Inst 84: 1811–1816, 1992

    Google Scholar 

  28. Dudeja PK, Anderson KM, Harris JE, Coon JS: MDR reversal by surfactants: Relationship to membrane lipid physical state. In: Proceedings of the American Association for Cancer Research, San Francisco, Ca, 1994, 356

  29. Moynihan TJ, Grossman SA: The role of chemotherapy in the treatment of primary tumors of the central nervous system. Cancer Invest 12: 88–97, 1994

    Google Scholar 

  30. Luthert PJ: Opening of the barrier in cerebral pathology. In: Bradburu MWB (ed) Physiology and Pharmacology of the Blood Brain Barrier. Springer-Verlag, New York, 1992, pp 440–441

    Google Scholar 

  31. Donelli MG, Zucchetti M, Incalci DX: Do anticancer agents reach the tumor target in the human brain? Cancer Chemother Pharmacol 30: 251–260, 1992

    Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy, Physiological Sciences, and Radiology, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA

    Christine S. Hughes & L.C. Hudson

  2. Department of Companion Animal and Special Species Medicine, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA

    Shelly L. Vaden, Christine A. Manaugh & G. Sylvester Price

Authors
  1. Christine S. Hughes
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  2. Shelly L. Vaden
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  3. Christine A. Manaugh
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  4. G. Sylvester Price
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  5. L.C. Hudson
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Hughes, C.S., Vaden, S.L., Manaugh, C.A. et al. Modulation of doxorubicin concentration by cyclosporin A in brain and testicular barrier tissues expressing P-glycoprotein in rats. J Neurooncol 37, 45–54 (1998). https://doi.org/10.1023/A:1005900908540

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  • DOI: https://doi.org/10.1023/A:1005900908540

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