Skip to main content
SpringerLink
Log in

Modulation of multidrug resistance in cancer by immunosuppresive agents

Preclinical studies

  • Article
  • Published:
Pathology & Oncology Research

Abstract

This is a brief summary of the status of known immunosuppressive drugs describing their potential and mode of action to reverse the function of the MDR1 gene product, the P glycoprotein. Different aspects of these immunosuppressors have been reviewed in the recent literature. This summary will focus only on those studies which relate to the effect of these drugs on the P-glycoprotein. In addition, studies which may explain the mode of action, but do not deal directly with P-glycoprotein, are also summarized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gros P, Croop J and Housman DE: Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47:371–380. 1986.

    Article  PubMed  CAS  Google Scholar 

  2. Chen Cj, Chin JF, Ueda K, Clask D and Pastan I: Internal duplication and homology with bacterial transport proteins in the mdrl (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47:381–389, 1986.

    Article  PubMed  CAS  Google Scholar 

  3. Dano K: Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochem Biophys Acta 323:466–468. 1973.

    Article  PubMed  CAS  Google Scholar 

  4. Skovsgaard T: Mechanism of cross-resistance between vincristine and daunorubicin in Ehrlich ascites tumor cells. Cancer Res 38:4722–4727. 1978.

    PubMed  CAS  Google Scholar 

  5. Fojo A, Al yama SI, Gottesman MM, Pastan I: Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Res 45:3002–3007, 1985.

    PubMed  CAS  Google Scholar 

  6. Van Kalken CK, Van des Valk P, Hadisaputro MM, Pieters R, Broxterman HJ, Kuiper CM, Scheffer GL, Veerman AJ, Meyer CJ and Scheper RJ: Ann Oncology 2:55–62, 1981.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Burty RK, Garfield S, Johnson K and Thorgeirsson SS: Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione- S-transferase-P and increased resistance to cytotoxiy chemicals. Carcinogenesis 9:2329–2332, 1988.

    Article  Google Scholar 

  9. Weinstein RS, Jakate SM, Dominguez JM, Lebowitz MD, Koukoulis GK, Kuszak JR, Kluskens LF, Grogan TM, Saclarides TJ, Roninson IB and Coon JS: Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res 51:2720–2726, 1991.

    PubMed  CAS  Google Scholar 

  10. Pirker R, Wallner J, Geissler K, Linkesch W, Haas OA, Bettelkeim P, Hapfer M, Ludwig H and Lechner K: MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst 83:708–712, 1991

    Article  PubMed  CAS  Google Scholar 

  11. Ozols RF, Cunnion RE, Klecker RW, Hamilton TC, Ostchega Y, Parrillo JF and Young RC: Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients. J Clin Oncol 5:641–647, 1987.

    PubMed  CAS  Google Scholar 

  12. Miller TP, Grogan TM, Dalton WS, Spie CM, Schepar RJ and Salmon SE: P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil. J Clin Oncol 9:17–24, 1991.

    PubMed  CAS  Google Scholar 

  13. Safa AR, Glover CJ, Sewell JE, Meyers MB, Biedles JL and Fedsted RL: Identification of the multidrug resistance-related membrane glycoprotein in a an acceptor for calcium channel blockers. J Biol Chem 262:7884–7888, 1987.

    PubMed  CAS  Google Scholar 

  14. Hofman J, Wolf A, Spitaler M, Bock M, Draeh J, Ludescher C and Grunieke H: Reversal of multidrug resistance by B859-35. a metabolite of 859–35. niguldipine. verapamil and nitrendipine. J Cancer Res Clin Oncol 118:361–366, 1992.

    Article  Google Scholar 

  15. Foster BJ, Grotzinger KR, McKoy WM, Rubinstein LV and Hamilton TC: Modulation of indeced resistance to adriamycin in two human breast cancer cell lines with tamoxifen or perhexiline maleate. Cancer Chemother Pharmacol 22:147–152, 1988.

    Article  PubMed  CAS  Google Scholar 

  16. Weaver JL, Szabo G jr,Pine PS, Gottesman MM, Goldenberg S and Aszalos A: The effect of ion channel blockers, immunosuppressive agents, and other drugs on the activity of the multi-drug transporter. Int J Cancer 54:456–461, 1993.

    Article  PubMed  CAS  Google Scholar 

  17. Weaver JL, Pine PS and Aszalos A: Comparison of the in vitro and biophysical effects of eyclosporin A. FK-506. and mycophenolic acid on human peripheral blood lymphocytes. Immunopharmacol Immunotoxicol 13:563–576, 1991.

    Article  PubMed  CAS  Google Scholar 

  18. Damjanovich S, Aszalos A, Mulhern S, Bcdazs M and Matyus L: Cytoplasmic membrane potential of mouse lymphocytes is decreased by cyclosporine. Mol Immunol 23:175–180, 1986.

    Article  PubMed  CAS  Google Scholar 

  19. Vayuvegula B, Slater L, Meador J and Gupta S: Correction of altered plasma membrane potentials. A possible mechanism of eyclosporin A and verapamil reversal of pleiotropic drug resistance in neoplasia. Cancer Chemother Pharmacol 22:163–168, 1988.

    Article  PubMed  CAS  Google Scholar 

  20. Sweet P, Chan PK and Slater LM: Cyclosporin A and verapamil enhancement of daunorubicin produced nucleolar protein B23 translocation in daunorubicin-resistant and-sensitive human and murine tumor cells. Cancer Res 49:677–680, 1989.

    PubMed  CAS  Google Scholar 

  21. Boscoboinik D, Gupta RS and Epand RM: Investigation of the relationship between altered intracellular pH and multidrug resistance in mammalian cells. Br J Cancer 61:568–572 1990.

    PubMed  CAS  Google Scholar 

  22. Walker RJ, Lazzaro VA, Duggin GG, Horvath JS and Tiller DJ: Cyclosporin A inhibits protein kinase C activity: a contributing mechanism in the development of nephrotoxicity. Biochem Biophys Res Commun 160:409–415, 1989.

    Article  PubMed  CAS  Google Scholar 

  23. Valverde MA, Diaz M, Sepulveda FV, Gill DR, Hyde SC and Higgens CF: Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature 355.830–833, 1992.

    Article  PubMed  CAS  Google Scholar 

  24. Weaver JL, McKinney L, Schoenlein PV, Goldenberg S, Gottesman MM, Aszalos A: MDRI/P-glycoprotein function in MDRI-transfected cell lines: I-effect of hypotonicity and inhibitors rhodamine 123 exclusion Am J Physiol (in press)

  25. Cornwell MM, Safa AR, Felsted RE, Gettesman MM and Pastan I: Membrane vesicles from multidrug resistant human cancer cells contain a specific 150- to 170 kDa protein detected by photoaffinity labeling. Proc Natl Acad Sci 83:3847–3856, 1986.

    Article  PubMed  CAS  Google Scholar 

  26. Greenberger LM, Eisanti CJ, Silva JF and Honvitz SB: Domain mapping of the photoaffinity drug binding sites in P-glycoprotein encoded by mouse mdrlb. J Biol Chem 226:20744–20751, 1991.

    Google Scholar 

  27. Morris DI, Speieher LA, Ruohe AF, Few KD and Seaman KB: Interaction of forskolin with the P-glycoprotein multidrug transporter. Biochemistry 30:8371–8379, 1991.

    Article  PubMed  CAS  Google Scholar 

  28. Slater EM, Sweet P, Stupeeky M and Gupta S: Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J Clin Invest 77:405–1408, 1986.

    Article  Google Scholar 

  29. Hait WN, Stem JM, Koletsky AJ, Harding MW and Handschumacher RE: Activity of cyclosporin A and a non-immuno-suppressive cyclosporin against multidrug resistant leukemic cell lines. Cancer Comm 1:35–43, 1989.

    CAS  Google Scholar 

  30. Coley HM, Twentyman PR and Workman P: Identification of anthracyclines and related agents that retain preferential activity over adriamycin in multidrug-resistant cell lines, and further resistance modification by verapamil and cyclosporin A. Cancer Chemother Pharmocol 24:284–290, 1989.

    Article  CAS  Google Scholar 

  31. Schuurhuis GJ, Broxterman HJ, Cervantes A, Van Heijningen THM, de Lunge JHM, Baak JPA, Pineds HM and Lankelma J: Quantitative determination of factors contributing to doxorubicin resistance in multidrug resistant cells. J Natl Cancer Inst 81:887–1892, 1989.

    Article  Google Scholar 

  32. Weaver JL, Pine PS, Aszalos A, Schoenlein PV, Currier SJ, Padmanabhan R and Gottesman MM: Laser scanning and confocal microscopy of daunorubicin, doxorubicin and rhodamine 123 in multidrug resistant cells. Exp Cell Res 196:323 329, 1991.

    Article  PubMed  Google Scholar 

  33. Damjanovich S, Aszalos A, Mulhern, SA, Szollosi J, Balazs M, Tron L and Fulwyler NJ: Cyclosporin depolarizes human lymphocytes: earliest observed effect on cell metabolism. Eur J Immunol 17:763–768, 1987.

    Article  PubMed  CAS  Google Scholar 

  34. Aszalos A: Cyclosporin: some aspects of its mode of action. A review. Medicine 19:297–316, 1988.

    CAS  Google Scholar 

  35. Mizuno K, Furokashi Y, Misawa T, Iwata M, Kawai M, Kikkawa F, Kano T and Tomoda Y: Modulation of multidrug resistance by immunosuppressive agents: cyclosporin analogues, FK506 and mizoribine. Anticancer Res 12:21–26, 1992.

    PubMed  CAS  Google Scholar 

  36. Twentyman PR, Fox NE and White DJG: Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multidrug resistant human lung cancer cell line. Br J Cancer 56:55–57, 1987.

    PubMed  CAS  Google Scholar 

  37. Twentynum PR: Modification of cytotoxic drug resistance by non-immunosuppressive cyclosporins. Br J Cancer 57:254–258, 1988.

    Google Scholar 

  38. Foxwell BMJ, Mackie A, Ling V and Riffel B: Identification of the multidrug resistance related P-glycoprotein as a cyclosporine binding protein. Mol Pharmacol 36:543–546, 1989.

    PubMed  CAS  Google Scholar 

  39. Goldberg H, Ling V, Wong PY and Skoreeki D: Reduced cyclosporin accumulation in multidrug resistant cells. Biochem Biophys Res Commun 152:552–558, 1988.

    Article  PubMed  CAS  Google Scholar 

  40. Loe DW and Sharom FJ: Interaction of multidrug resistant Chinase hamster ovary cells with amphiphiles. Br J Cancer 68:342–351, 1993.

    PubMed  CAS  Google Scholar 

  41. Gaveriaux, D., Boesch, D., Tachez, B., Bollinger, P. Payne, T. and Loor, F. J.: Cell Pharmacol 2, 225–234, 1991.

    CAS  Google Scholar 

  42. Twentyman PR and Bleehen NM: Resistance modification by PSC 833, a novel non-immunosuppressive cyclosporine. Eur J Cancer 27:1639–1642, 1991.

    Article  PubMed  CAS  Google Scholar 

  43. Boesch D, Huller K, Pourtier-Manzanedo A and Loor F: Restoration of daunomycin retention in multidrug resistant P388 cells by submicromolar concentrations of SDZ PSC 833, a nonimmunosuppressive cyclosporine derivative. Exp Cell Res 196:26–32, 1991.

    Article  PubMed  CAS  Google Scholar 

  44. Natazuka T: FK506 reverses adriamycin resistance in a multidrug-resistant human leukemia cell line. Kobe J Med Sci 38:347–363, 1992.

    PubMed  CAS  Google Scholar 

  45. Hoof T, Demmer A, Christian U and Tummler B: Reversal of multidrug resistance in Chinase hamster ovary cells by the immunosuppressive agent rapamycin. Eur J Pharmacol 246:53–58, 1993.

    Article  PubMed  CAS  Google Scholar 

  46. Takeguchi N, Koike M, Matsui W, Kashiwagura T and Kawahara K: Inhibition of the multidrug efflux pump in isolated hepatocyte couplets by immunosuppressants FK506 and cyclosporine. Transplantation 55:646–650, 1993.

    Article  PubMed  CAS  Google Scholar 

  47. Heitman J, Roller A, Kunz J, Henriquez R, Schmidt A, Mowa NR and Hall MN: The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae. Mol Cell Biol 13:5010–5019, 1993.

    PubMed  CAS  Google Scholar 

  48. Slater LM, Sweet P, Stupecky M, Wetzel MW and Gupta S: Cyclosporin A corrects daunorubicin resistance in Ehrlich ascites carcinoma. Br J Cancer 54:235–238, 1986.

    PubMed  CAS  Google Scholar 

  49. Boesch D, Gaveriaux 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  CAS  Google Scholar 

  50. Keller RP, Altermatt HJ, Donatsch P, Zihmann H, Loissue JA and Hiestand PC: Pharmacologic interactions between the resistance modifying cyclosporine SDZ PSC 833 and etoposide (VP 16–213) enhance in vivo cytostatic activity and toxicity. Int J Cancer 51:433–438, 1992.

    Article  PubMed  CAS  Google Scholar 

  51. Keller RP, Altermatt HJ, Nooter K, Poschnann G, Laissue JA, Bollinger P and Hiestand PC: SDZ PSC 833, a non-immunosuppressivve cyclosporine: its potency in overcoming P-glycoprotein mediated multidrug resistance of murine leukemia. Int J Cancer 50:593–597, 1992.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Health, Education and Welfare, Food and Drug Administration, 200 C Street SW, 20204, Washington DC, USA

    Adorjan Aszalos

Authors
  1. Adorjan Aszalos
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aszalos, A. Modulation of multidrug resistance in cancer by immunosuppresive agents. Pathol. Oncol. Res. 1, 64–70 (1995). https://doi.org/10.1007/BF02893586

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02893586

Key words

Search

Navigation