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Biotherapy

, Volume 6, Issue 4, pp 291–302 | Cite as

Circumvention of chemotherapy-induced myelosuppression by transfer of themdr1 gene

  • Jan J. B. Boesen
  • Kees Nooter
  • Dinko Valerio
Research Articles

Abstract

Drug-induced myelosuppression is a frequent reason for curtailing chemotherapy in cancer patients. ‘Rescue’ of myelosuppressed patients with autologous marrow transplants is reasonably advanced and permits an increase in the dose of anticancer drugs. Despite this improvement, patients often relapse with drug resistance disease. The human multidrug resistance (mdr1) gene might make it possible to render hemopoietic stem cells resistant to anticancer drugs after transfer of this gene. By introducing resistant stem cells into patients it might be possible to treat these patients repeatedly with otherwise ablative therapy. This review explores the feasibility ofmdr1 gene therapy.

Key words

P-glycoprotein mdr1 multidrug resistance gene therapy myelosuppression chemotherapy bone marrow transplantation 

Abbreviations

MDR

multidrug resistance

ABMT

autologous bone marrow transplantation

P-gp

P-glycoprotein

RCR

replication-competent retrovirus

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References

  1. 1.
    Humblet Y, Symann M, Bosley A, Delaunois L, Francis C, Machiels J, Beauduin M, Doyen C, Weymants P, Longueville J, Prignot J. Late intensification chemotherapy with autologous bone marrow transplantation in selected small cell-carcinoma of the lung: a randomized study. J Clin Oncol 1987; 5: 1864–73.PubMedGoogle Scholar
  2. 2.
    Peters WP, Shpall EJ, Jones RB, Olsen GA, Bast RC, Gockerman JP, Moore JO. High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol 1988; 6: 1368–76.PubMedGoogle Scholar
  3. 3.
    Johnson DH, DeLeo MJ, Hande KR, Wolff SN, Hainsworth JP, Grew FA. High-dose induction chemotherapy with cyclophosphamide, etoposide, and cisplatin for extensive-stage small-cell lung cancer. J Clin Oncol 1987; 5: 703–9.PubMedGoogle Scholar
  4. 4.
    Appelbaum FR, Sullivan KM, Buckner CD. Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation. J Clin Oncol 1987; 4: 1340–7.Google Scholar
  5. 5.
    Gale RP. Myelosuppressive effects of antineoplastic chemotherapy. In: Testa NG. Gale RP, eds. Hematopoiesis: long-term effects of chemotherapy and radiation. New York: Marcel Dekker, 1988: 63–73.Google Scholar
  6. 6.
    Frei III E. Curative cancer chemotherapy. Cancer Res 1985; 45: 6523–37.PubMedGoogle Scholar
  7. 7.
    Vose JM, Armitage JO. Bone marrow transplantation. In: Perry MC, ed. The chemotherapy source book. Baltimore: Williams & Wilkins, 1992: 280–4.Google Scholar
  8. 8.
    Gabrilove JA, Jakubowski A. Biological effects and clinical applications of human colony-stimulating factors. In: Pinedo HM. Chabner BA. Longo D, eds. Cancer chemotherapy and biological response modifiers. Amsterdam: Elsevier Science Publishers, 1990: 631–62.Google Scholar
  9. 9.
    Dicke KA, Spitzer G. Evaluation of the use of high-dose cytoreduction with autologous marrow rescue in various malignancies. Transplantation 1985; 41: 4–20.Google Scholar
  10. 10.
    van der Bliek AM, Borst P. Multidrug resistance. Adv Cancer Res 1989; 52: 165–203.PubMedGoogle Scholar
  11. 11.
    Moscow JA, Cowan KH. Multidrug resistance. In: Pinedo HM. Chabner BA. Longo DL, eds. Cancer chemotherapy and biological response modifiers annual 11. Amsterdam: Elsevier Science Publishers, 1990: 97–114.Google Scholar
  12. 12.
    Nooter K, Herweijer H. Multidrug resistance (mdr) genes in human cancer. Br J Cancer 1991; 63: 663–9.PubMedGoogle Scholar
  13. 13.
    Bech-Hansen NT, Till JE, Ling V. Pleiotropic phenotype of colchicine-resistant CHO cells: cross-resistance and collateral sensitivity. J Cell Physiol 1976; 88: 23–32.PubMedGoogle Scholar
  14. 14.
    Danø K. Cross-resistance between vinca alkaloids and anthracyclines in Ehrlich ascites tumorin vivo Cancer Chemother Rep 1972; 56: 701–8.PubMedGoogle Scholar
  15. 15.
    Skovsgaard T. Mechanism of cross-resistance between vincristine and daunorubicin in Ehrlich ascites tumor cells. Cancer Res 1978; 38: 4722–7.PubMedGoogle Scholar
  16. 16.
    Chen C, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB. Internal duplication and homology with bacterial transport proteins in themdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 1986; 47: 381–9.PubMedGoogle Scholar
  17. 17.
    Gerlach JH, Endicott JA, Juranka PF, Henderson G, Sarangi PF, Deuchars KL, Ling V. Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug-resistance. Nature 1986; 324: 485.PubMedGoogle Scholar
  18. 18.
    Gros P, Croop J, Housman D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 1986; 47: 371–80.PubMedGoogle Scholar
  19. 19.
    Bradley G, Juranka PF, Ling V. Mechanism of multidrug resistance. Biochim Biophys Acta 1988; 948: 87–128.PubMedGoogle Scholar
  20. 20.
    Gill DR, Hyde SC, Higgins CF, Valverde MA, Mintenig GM, Sepulveda FV. Seperation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Cell 1992; 71: 23–32.PubMedGoogle Scholar
  21. 21.
    Ng WF, Sarangi F, Zastawny RL, Veinot-Drebot L, Ling V. Identification of members of the P-glycoprotein multigene family. Mol Cell Biol 1989; 9: 1224–32.PubMedGoogle Scholar
  22. 22.
    Roninson IB, Chin JE, Choi K, Gros P, Housman DE, Fojo A, Shen D-W, Gottesman MM, Pastan I. Isolation of human mdr DNA sequences amplified in multidrugresistant KB carcinoma cells. Proc Natl Acad Sci USA 1986; 93: 4538–42.Google Scholar
  23. 23.
    van der Bliek AM, Kooiman PH, Schneider C, Borst P. Sequence ofmdr3 cDNA encoding a human P-glycoprotein. Gene 1988; 71: 401–11.PubMedGoogle Scholar
  24. 24.
    Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 1987; 84: 265–9.PubMedGoogle Scholar
  25. 25.
    Cordon-Cardo C, O'Brien JP, Boccia L, Casals D, Bertino JR, Melamed MR. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38: 1277–87.PubMedGoogle Scholar
  26. 26.
    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 1987; 84: 7735–8.PubMedGoogle Scholar
  27. 27.
    Weinstein RS, Crogan TM, Kuszak JR, Jakate SM, Kluskens LF, Coon JS. Multidrug resistance gene product (P-glycoprotein) in normal tissue and tumors. In: Advances in pathology and laboratory medicine. MosbyYear Book, Inc 1991: 207–34.Google Scholar
  28. 28.
    Gottesman MM, Pastan I. Resistance to multiple chemotherapeutic agents in human cancer cells. Tr Pharmacol Sc 1988; 9: 54–8.Google Scholar
  29. 29.
    Van Kalken CK, Broxterman HJ, Pinedo HM, Feller N, Dekker H, Lankelma J, Giaccone G. Cortisol is transported by the multidrug resistance gene product P-glycoprotein. Br J Cancer 1993; 67: 284–9.PubMedGoogle Scholar
  30. 30.
    Drach D, Zhao S, Drach J, Mahadevia R, Gattringer C, Huber H, Andreeff M. Subpopulations of normal peripheral blood and bone marrow cells express a functional resistant phenotype. Blood 1992; 80: 2729–34.PubMedGoogle Scholar
  31. 31.
    Chaudhary PM, Roninson IB. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 1991; 66: 85–94.PubMedGoogle Scholar
  32. 32.
    Schluesener HJ, Koeppel C, Jung S. Multidrug transport in human autoimmune T line cells and peripheral blood lymphocytes. Immunopharmacol 1992; 23: 37–48.Google Scholar
  33. 33.
    Tsuruo T, Kawabata H, Nagumo N, Iida H, Kitatani Y, Tsukagoshi S, Sakurai Y. Potentiation of antitumor agents by calcium channel blockers with special reference to cross-resistance patterns. Cancer Chemoth Pharmacol 1985; 15: 16–9.Google Scholar
  34. 34.
    Ford JM, Prozialeck WC, Hait WN. Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance. Mol Pharmacol 1989; 35: 105–15.PubMedGoogle Scholar
  35. 35.
    Pearce HL, Safa AR, Bach NJ, Winter MA, Cirtain MC, Beck WT. Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance. Proc Natl Acad Sci USA 1989; 86: 5128–32.PubMedGoogle Scholar
  36. 36.
    Nooter K, Oostrum R, Jonker R, van Dekken H, Stokdijk W, van den Engh G. Effect of cyclosporin A on daunorubicin accumulation in multidrug-resistant P388 leukemia cells measured by real-time flow cytometry. Cancer Chemotherapy Pharmacol 1989; 23: 296–300.Google Scholar
  37. 37.
    Slater LM, Sweet P, Stupecky M, Gupta S. Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemiain vitro. J Clin Invest 1986; 77: 1405–8.PubMedGoogle Scholar
  38. 38.
    Twentyman PR. Modification of cytotoxic drug resistance by non-immuno-suppressive cyclosporins. Br J Cancer 1988; 57: 254–8.PubMedGoogle Scholar
  39. 39.
    Kessel D, Wilberding C. Anthracycline resistance in P388 murine leukemia and its circumvention by calcium antagonists. Cancer Res 1985; 45: 1687–91.PubMedGoogle Scholar
  40. 40.
    Krishan A, Sauerteig A, Gordon K, Swinkin C. Flow cytometric monitoring of cellular anthracycline accumulation in murine leukemic cells. Cancer Res 1986; 46: 1768–73.PubMedGoogle Scholar
  41. 41.
    Willingham MC, Cornwell MM, Cardarelli CO, Gottesman MM, Pastan I. Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effect of verapamil and other drugs. Cancer Res 1986; 46: 5941–6.PubMedGoogle Scholar
  42. 42.
    Yalowich JC, Ross WE. Verapamil-induced augmentation of etoposide accumulation in L1210 cellsin vitro. Cancer Res 1985; 45: 1651–6.PubMedGoogle Scholar
  43. 43.
    Akiyama S, Cornwell MM, Kuwano M, Pastan I, Gottesman MM. Most drugs that reverse multidrug resistance also inhibit photoaffinity labeling of P-glycoprotein by a vinblastine analog. Mol Pharmacol 1988; 33: 144–7.PubMedGoogle Scholar
  44. 44.
    Foxwell BMJ, Mackie A, Ling V, Ryffel B. Identification of the multidrug resistance-related P-glycoprotein as a cyclosporin binding protein. Mol Pharmacol 1989; 36: 543–6.PubMedGoogle Scholar
  45. 45.
    Sonneveld P, Durie BGM, Lokhorst HM, Marie J-P, Solbu G, Suciu S, Zittoun R, Löwenberg B, Nooter K. Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Lancet 1992; 340: 255–9.Google Scholar
  46. 46.
    Ueda K, Cardarelli C, Gottesman MM, Pastan I. Expression of a full-length cDNA for the humanmdr1 gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA 1987; 84: 3004–8.PubMedGoogle Scholar
  47. 47.
    Guild BC, Finer MH, Housman DE, Mulligan RC. Development of retrovirus vectors useful for expressing genes in cultured murine embryonal cells and hematopoietic cellsin vivo. J Virol 1988; 62: 3795–801.PubMedGoogle Scholar
  48. 48.
    Pastan I, Gottesman MM, Ueda K, Lovelace E, Rutherford AV, Willingham MC. A retrovirus carrying anmdr1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc Natl Acad Sci USA 1988; 85: 4486–90.PubMedGoogle Scholar
  49. 49.
    Mickisch GH, Merlino GT, Galski H, Gottesman MM, Pastan I. Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Proc Natl Acad Sci USA 1991; 88: 547–51.PubMedGoogle Scholar
  50. 50.
    Mickisch GH, Aksentijevich I, Schoenlein PV, Goldstein LJ, Galski H, Stahle C, Sachs DH, Pastan I, Gottesman MM. Transplantation of bone marrow cells from transgenic mice expressing the humanmdr1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice. Blood 1992; 79: 1087–93.PubMedGoogle Scholar
  51. 51.
    van Beusechem VW, Kukler A, Heidt PJ, Valerio D. Long-term expression of human adenosine deaminase in rhesus monkeys transplanted with retrovirus-infected bone-marrow cells. Proc Natl Acad Sci USA 1992; 89: 7640–4.PubMedGoogle Scholar
  52. 52.
    van Beusechem VW, Bakx TA, Kaptein LCM, BartBaumeister JAK, Kukler A, Braakman E, Valerio D. Retrovirus-mediated gene transfer into Rhesus monkey hematopoietic stem cells: the effect of viral titers on transduction efficiency. Human Gene Therapy 1993; 4: 239–47.PubMedGoogle Scholar
  53. 53.
    Mann R, Mulligan RC, Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free replication defective retrovirus. Cell 1983; 33: 153–9.PubMedGoogle Scholar
  54. 54.
    Yu SF, Von Ruden T, Kantoff PW, Garber C, Seiberg M, Rüther U, Anderson WF, Wagner EF, Gilboa E. Selfinactivating retroviral vectors designed for transfer of whole genes into mammalian cells. Proc Natl Acad Sci USA 1986; 83: 3194–8.PubMedGoogle Scholar
  55. 55.
    Valerio D, Einerhand MPW, Wamsley PM, Bakx TA, Li CL, Verma IM. Retrovirus-mediated gene transfer into embryonal carcinoma cells and hemopoietic stem cells: expression from a hybrid long terminal repeat. Gene 1989; 84: 419–27.PubMedGoogle Scholar
  56. 56.
    Markowitz D, Goff S, Bank A. Construction and use of a safe and efficient amphotropic packaging cell line. Virology 1988a; 167: 400–6.PubMedGoogle Scholar
  57. 57.
    Adams RM, Soriano HE, Wang M, Darlington G, Steffen D, Ledley FD. Transduction of primary human hepatocytes with amphotropic and xenotropic retroviral vectors. Proc Natl Acad Sci USA 1992; 89: 8981–5.PubMedGoogle Scholar
  58. 58.
    Battini J-L, Heard J-M, Danos O. Receptor choice determinants in the envelope glycoproteins of amphotropic, xenotropic, and polytropic murine leukemia viruses. J Virology 1992; 66: 1468–75.PubMedGoogle Scholar
  59. 59.
    Cone RD, Mulligan RC. High-efficiency gene transfer into mammalian cells: generation of helper-free recombinant retrovirus with broad mammalian host range. Proc Natl Acad Sci USA 1984; 81: 6349–53.PubMedGoogle Scholar
  60. 60.
    Miller AD, Law M-F, Verma IM. Generation of helperfree amphotropic retrovirus that transduce a dominantacting, methotrexate-resistant dihydrofolate reductase gene. Mol Cell Biol 1985; 5: 431–7.PubMedGoogle Scholar
  61. 61.
    Miller AD, Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol 1986; 6: 2895–902.PubMedGoogle Scholar
  62. 62.
    Danos O, Mulligan RD. Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci USA 1988; 85: 6460–4.PubMedGoogle Scholar
  63. 63.
    Markowitz D, Goff S, Bank A. A safe packaging line for gene transfer: separating viral genes on two different plasmids. J Virology 1988b; 62: 1120–4.PubMedGoogle Scholar
  64. 64.
    Takahara Y, Hamada K, Housman D. A new retrovirus packaging cell for gene transfer constructed from amplified long terminal repeat-free chimeric proviral genes. J Virology 1992; 66: 3725–32.PubMedGoogle Scholar
  65. 65.
    Anderson W, McGarrity GJ, Moen RC. Report to the NIH recombinant DNA advisory committee on murine replication-competent retrovirus (RCR) assays. 1992: 1–28.Google Scholar
  66. 66.
    Cornetta K, Moen RC, Culver K, Morgan RA, McLachlin JR, Sturm S, Selegue J, London W, Blaese RM, Anderson WF. Amphotropic murine leukemia retrovirus is not an acute pathogen for primates. Human Gene Therapy 1990; 1: 15–30.PubMedGoogle Scholar
  67. 67.
    Donahue RE, Kessler SW, Bodine D, McDonagh K, Dunbar C, Goodman S, Agricola B, Byrne E, Raffeld M, Moen R, Bacher J, Zsebo KM, Nienhuis AW. Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J Exp Medicine 1992; 176: 1125–35.Google Scholar
  68. 68.
    McLachlin JR, Eglitis MA, Ueda K, Kantoff PW, Pastan IH, Anderson F, Gottesman MM. Expression of a human complementary DNA for the multidrug resistance gene in murine hematopoietic precursor cells with the use of retroviral gene transfer. J Natl Cancer Inst 1990; 82: 1260–3.PubMedGoogle Scholar
  69. 69.
    Sorrentino BP, Brandt SJ, Bodine D, Gottesman MM, Pastan I, Cline A, Nienhuis AW. Selection of drugresistant bone marrow cellsin vivo after retroviral transfer of humanmdr1. Science 1992; 257: 99–103.PubMedGoogle Scholar
  70. 70.
    Podda S, Ward M, Himelstein A, Richardson C, De la Flor-Weiss E, Smith L, Gottesman M, Pastan I, Bank A. Transfer and expression of the human multiple drug resistance gene into live mice. Proc Natl Acad USA 1992; 89: 9676–80.Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Jan J. B. Boesen
    • 1
  • Kees Nooter
    • 2
  • Dinko Valerio
    • 3
  1. 1.TNO-Medical Biological LaboratoryHV Rijswijk
  2. 2.Rotterdam Cancer InstituteAE, Rotterdam
  3. 3.IntroGeneGG RijswijkThe Netherlands

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