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Chemoprotection of normal tissues by transfer of drug resistance genes

  • Gene Therapy of Cancer
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Abstract

The effectiveness of many types of antitumour agent is limited by (i) acute dose limiting cytotoxicity, principally myelosuppression but also lung, liver and gastrointestinal tract toxicity, (ii) the risk of therapy related secondary malignancy and (iii) the inherent or acquired drug-resistance of tumour cells. As the management of the acute toxic effects improve, the more insidious effects, and particularly haematological malignancies, are anticipated to increase. Furthermore, attempts to overcome tumour cell resistance to treatment can lead to increased collateral damage in normal tissues.

One approach to circumventing both the acute toxic and chronic carcinogenic effects of chemotherapy would be to use gene therapy to achieve high levels of expression of drug resistance proteins in otherwise drug-sensitive tissues. To date the products of the multi-drug resistance (MDR-1) and the human O 6-alkylguanine-DNA-alkyltransferase (ATase) gene have been used in reclinical experiments to demonstrate proof of principle, and the former of these is now being tested in a clinical situation.

Here we discuss the potential of drug-resistance gene therapy to provide chemoprotection to normal tissues and examine the prospects for a dual approach which combines this with pharmacological sensitisation of tumours to chemotherapeutic agents.

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References

  1. Van Hoef ME, Baumann I, Lange C, Luft T, De Wynter EA, Ranson M, Morgenstern GR, Yvers A, Dexter TM, Testa NG, Howell A: Dose-escalating induction chemotherapy supported by lenograstim preceding high-dose consolidation chemotherapy for advanced breast cancer. Selection of the most acceptable regimen to induce maximal tumour response and investigation of the optimal time to collect peripheral blood progenitor cells for haematological rescue after high-dose consolidation chemotherapy. Ann Oncol 5: 217–224, 1994

    Google Scholar 

  2. Testa NG, Dexter TM: Colony-stimulating factors in the clinic. Curr Opin Biotechnol 3: 687–692, 1992

    Google Scholar 

  3. Crowther D, Scarffe JH, Howell A, Thatcher N, Bronchud M, Steward WP, Testa N, Dexter M: Growth factor-assisted chemotherapy-the Manchester experience. Ciba Found Symp 148: 201–210; discussion 211–204, 1990

    Google Scholar 

  4. De Campos E, Radford J, Steward W, Milroy R, Dougal M, Swindell R, Testa N, Thatcher N: Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small-cell lung cancer. J Clin Oncol 13: 1623–1631, 1995

    Google Scholar 

  5. Case DCJr, Bukowski RM, Carey RW, Fishkin EH, Henry DH, Jacobson RJ, Jones SE, Keller AM, Kugler JW, Nochols CR, Salmon SE, Silver RT, Storniolo AM, Wampler GL, Dooley CM, Larholt KM, Nelson RA, Abels RI: Recombinant human erythropoietin therapy for anaemic cancer patients on combination chemotherapy. J Natl Cancer Inst 85: 801–806, 1993

    Google Scholar 

  6. Cascinu S, Del Ferro E, Fedeli A, Ligi M, Alessandroni P, Catalano G: Recombinant human erythropoietin treatment in elderly cancer patients with cisplatin-associated anaemia. Oncology 52: 422–426, 1993

    Google Scholar 

  7. Foster DC, Sprecher CA, Grant FJ, Kramer JM, Kuijper JL, Holly RD, Whitmore TE, Heipel MD, Bell LA, Ching AF, McGrane V, Hart C, Ohara PJ, Lok S: Human thrombopoietin: gene structure, cDNA sequence, expression and chromosomal localization. Proc Natl Acad Sci USA 91: 13023–10327, 1995

    Google Scholar 

  8. Sohma Y, Akahori H, Seki N, Hori T, Ogami K, Kato T, Shimada Y, Kawamura K, Miyazaki H: Molecular cloning and chromosomal localization of the human thrombopoietin gene. FEBS Lett 353: 57–61, 1995

    Google Scholar 

  9. Shpall EH, Jones RB, Bearman S: High-dose therapy with autologous bone marrow transplantation for the treatment of solid tumours. Curr Opin Oncol 6: 135–138, 1994

    Google Scholar 

  10. Heideman RL, Douglas EC, Krance RA, Fontanesi J, Langston JA, Sanford RA, Kovnar EH, Ochs J, Kuttesch J, Jenkins JJ, Fairclough DL, Kim LE: High-dose chemotherapy and autologous bone marrow rescue followed by interstitial and external-beam radiotherapy in newly diagnosed paediatric malignant gliomas [see comments]. J Clin Oncol 11: 1458–1465, 1993

    Google Scholar 

  11. Van Hoef ME, Ranson M, Morgenstern GR, Baumann I, Lange C, De Wynter EA, Testa NG, Howell A: Rapid haematological recovery after high-dose consolidation chemotherapy with peripheral blood progenitor cells (PBPC) as sole source of support collected at a single apheresis [letter]. Bone Marrow Transplant 13: 839–840, 1994

    Google Scholar 

  12. Pettengell R, Woll PJ, Thatchder N, Dexter TM, Testa NG: Multicyclic, dose-intensive chemotherapy supported by sequential reinfusion of haematopoietic progenitors in whole blood. J Clin Oncol 13: 148–156, 1995

    Google Scholar 

  13. Dunbar CE, Cottler Fox M, Ja OS, Doren S, Carter C, Berenson R, Brown S, Moen RC, Greenblatt J, Stewart FM, Leitman SF, Wilson WH, Cowan K, Young NS, Nienhuis AW: Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation. Blood 85: 3048–3057, 1995

    Google Scholar 

  14. Lord BI, Mori KJ, Wright EG, Lajtha LG: Inhibitor of stem cell proliferation in normal bone marrow. Br J Haematol 34: 441–445, 1976

    Google Scholar 

  15. Graham GJ, Wright EG, Hewick R, Wolpe SD, Wilkie NM, Donaldson D, Lorimore S, Pragnell IB: Identification and characterization of an inhibitor of haemopoietic stem cell proliferation. Nature 344: 442–444, 1990

    Google Scholar 

  16. Lord BI, Dexter TM, Clements JM, Hunter MA, Gearing AJ: Macrophage inflammatory protein protects multipotent haematopoietic cells from the cytotoxic effects of hydroxyurea in vivo. Blood 79: 2605–2609, 1992

    Google Scholar 

  17. Dunlop DJ, Wright EG, Lorimore S, Graham GJ, Holyoake T, Kerr DJ, Wolpe SD, Pragnell IB: Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1 alpha in vivo. Blood 79: 2221–2225, 1992

    Google Scholar 

  18. Ali M, Lemoine NR, Ring CJ: The use of DNA viruses as vectors for gene therapy. Gene Ther 1: 367–384, 1994

    Google Scholar 

  19. Miller AD: Retroviral vectors. Curr Top Microbiol Immunol 158: 1–24, 1992

    Google Scholar 

  20. Miller AD, Miller DG, Garcia JV, Lynch CM: Use of retroviral vectors for gene transfer and expression. Methods Enzymol 217: 581–599, 1993

    Google Scholar 

  21. Russell DW, Miller AD: Foamy virus vectors. J Virol 70: 217–222, 1996

    Google Scholar 

  22. Dexter TM, Spooncer E: Growth and differentiation in the hemopoietic system. Annu Rev Cell Biol 3: 423–441, 1987

    Google Scholar 

  23. Najean Y: The iatrogenic leukaemias induced by radio-and/or chemotherapy. Med Oncol Tumour Pharmacother 4: 245–257, 1987

    Google Scholar 

  24. Boffetta P, Kaldor JM: Secondary malignancies following cancer chemotherapy. Acta Oncol 33: 591–598, 1994

    Google Scholar 

  25. Williams GT, Smith CA, Spooncer E, Dexter TM, Taylor DR: Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature 343: 76–79, 1990

    Google Scholar 

  26. Berardi AC, Wang A, Levine JD, Lopez P, Scadden DT: Functional isolation and characterization of human haematopoietic stem cell. Science 267: 104–108, 1995

    Google Scholar 

  27. Luskey BD, Rosenblatt M, Zsebo K, Williams DA: Sten cell factor, interleukin-3, and interleukin-6 promote retroviral-mediated gene transfer into murine haematopoietic stem cells. Blood 80: 396–402, 1992

    Google Scholar 

  28. Dexter TM, Allen TD, Lajtha LG: Conditions controlling the proliferation of haemopoietic stem cell in vitro. J Cell Physiol 91: 335–344, 1977

    Google Scholar 

  29. Moore KA, Deisseroth AB, Reading CL, Williams DE, Belmont JW: Stromal support enhances cell-free retroviral vector transduction of human bone marrow long-term culture-initiating cells. Blood 79: 1393–1399, 1992

    Google Scholar 

  30. Gottesman MM, Hrycyna CA, Schoenlein PV, Germann UA, Pastan I: Genetic analysis of the multidrug transporter. Ann Rev Gen 29: 607–649, 1995

    Google Scholar 

  31. Moscow JA, Dixon KH: Glutathione-related enzymes, glutathione and multi-drug resistance. Cytotechnol 12: 155–170, 1993

    Google Scholar 

  32. Margison GP, O'Connor PJ: Biological consequences of reactions with DNA: role of specific lesions. In: Cooper CS, Grover PL (eds) Handbook of Experimental Pharmacology 94/1. Springer, Berlin/Heidelberg, 1990, pp 547–571

    Google Scholar 

  33. Juliano RL, Ling V: A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455: 152–162, 1976

    Google Scholar 

  34. Van der Bliek AM, Baas F, Van der Velde Koerts T, Biedler JL, Meyers MB, Ozols RF, Hamilton TC, Joenje H, Borst P: Genes amplified and overexpressed in human multidrug-resistant cell lines. Cancer Res 48: 5927–5932, 1988

    Google Scholar 

  35. Kessel D: Circumvention of resistance to anthracyclines by calcium antagonists and other membrane-perturbing agents. Cancer Surv 5: 109–127, 1986

    Google Scholar 

  36. Spiers AS: Multiple drug resistance, the MDR gene, and the law of maximum perversity as it applies to oncology: an hypothesis. Hematol Oncol 12: 155–161, 1994

    Google Scholar 

  37. Galski H, Sullivan M, Willingham MC, Chin KV, Gottesman MM, Pastan I, Merlino GT: Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leucopenia. Mol Cell Biol 9: 4357–4363, 1989

    Google Scholar 

  38. Gottesman MM, Mickisch GH, Pastan I: In vivo models of P-glycoprotein-mediated multidrug resistance. Cancer Res 73: 107–128, 1994

    Google Scholar 

  39. 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 88: 547–551, 1991

    Google Scholar 

  40. 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 human MDR1 gene results in longterm protection against the myelosuppressive effect of chemotherapy in mice. Blood 79: 1087–1093, 1992

    Google Scholar 

  41. Richardson C, Bank A. Preselection of transduced murine haematopoietic stem cell populations leads to increased long-term stability and expression of the human multiple drug resistance gene. Blood 86: 2579–2589, 1995

    Google Scholar 

  42. Licht T, Aksentijevich I, Gottesman MM, Pastan I: Efficient expression of functional human MDR1 gene in murine bone marrow after retroviral transduction of purified haematopoietic stem cells. Blood 86: 111–121, 1995

    Google Scholar 

  43. Metz MZ, Best DM, Kane SE: Harvey murine sarcoma virus/MDR1 retroviral vectors: efficient virus production and foreign gene transduction using MDR1 as a selectable marker. Virology 208: 634–643, 1995

    Google Scholar 

  44. Bodine DM, Seidel NE, Gale MS, Nienhuis AW, Orlic D: Efficient retrovirus transduction of mouse pluripotent haematopoietic stem cells mobilized into the peripheral blood by treatment with granulocyte colony-stimulating factor and stem cell factor. Blood 84: 1482–1491, 1994

    Google Scholar 

  45. Hanania EG, Deisseroth AB: Serial transplantation shows that early haematopoietic precursor cells are transduced by MDR-1 retroviral vector in a mouse gene therapy model. Cancer Gene Ther 1: 21–25, 1994

    Google Scholar 

  46. Ward M. Richardson C, Pioli P, Smith L, Podda S, Goff S, Hesdorffer C, Bank A: Transfer and expression of the human multiple drug resistance gene in human CD34+ cells. Blood 84: 1408–1414, 1994

    Google Scholar 

  47. Hegewisch Becker S, Hanania EG, Fu S, Korbling M, Deisseroth AB, Andreeff M: Transduction of MDR1 into human and mouse haemopoietic progenitor cells: use of rhodamine (Rh123) to determine transduction frequency and in vivo selection. Br J Haematol 90: 876–883, 1995

    Google Scholar 

  48. Hanania EG, Fu S, Zu Z, Hegewisch Becker S, Korbling M, Hester J, Durett A, Andreeff M, Mechetner E, Holzmayer T et al.: Chemotherapy resistance to taxol in clonogenic progenitor cells following transduction of CD34 selected marrow and peripheral blood cells with a retrovirus that contains the MDR-1 chemotherapy resistance gene [see comments]. Gene Ther 2: 285–294, 1995

    Google Scholar 

  49. Bertolini F, De Monte L, Corsini C, Lazzari L, Lauri E, Soligo D, Ward M, Bank A, Malavasi F: Retrovirus-mediated transfer of the multidrug resistance gene into human haemopoietic progenitor cells. Br J Haematol 88: 318–324, 1994

    Google Scholar 

  50. O'Shaughnessy JA, Cowan KH, Nienhuis AW, McDonagh KT, Sorrentino BP, Dunbar CE, Chiang Y, Wilson W, Goldspiel B, Kohler D et al.: Retroviral mediated transfer of the human multidrug resistance gene (MDR-1) into haematopoietic stem cells during autologous transplantation after intensive chemotherapy for metastatic breast cancer. Hum Gene Ther 5: 891–911, 1994

    Google Scholar 

  51. Hesdorffer C, Antman K, Bank A, Fetell M, Mears G, Begg M: Human MDR gene transfer in patients with advanced cancer. Hum Gene Ther 5: 1151–1160, 1994

    Google Scholar 

  52. Sugimoto Y, Aksentijevich I, Murray GJ, Brady RO, Pastan I, Gottesman MM: Retroviral coexpression of a multidrug resistance gene (MDR1) and human alpha-galactosidase A for gene therapy of Fabry disease. Hum Gene Ther 6: 905–915, 1995

    Google Scholar 

  53. Metz MZ, Matsumoto L, Winters KA, Doroshow JH, Kane SE: Bicistronic and 2-gene retroviral vectors for using MDR1 as a selectable marker and a therapeutic gene. Virology 217: 230–241, 1996

    Google Scholar 

  54. Tinwell H, Ashby J: Genetic toxicity and potential carcinogenicity of taxol. Carcinogenesis 15: 1499–1501, 1994

    Google Scholar 

  55. Pegg AE: Mammalian O 6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50: 6119–6129, 1990

    Google Scholar 

  56. Kohn KW, Gibson NW: DNA cross-linking by chloroethylating agents. IARC Sci Publ 70: 155–162, 1986

    Google Scholar 

  57. Voigt JM, Topal MD: O 6-methylguanine-induced replication blocks. Carcinogenesis 16: 1775–1782, 1995

    Google Scholar 

  58. Saffhill R, Margison GP, O'Connor PJ: Mechanisms of carcinogenesis induced by alkylating agents. Biochim Biophys Acta 823: 111–145, 1985

    Google Scholar 

  59. Gerson SL, Miller K, Berger NA: O 6 alkylguanine-DNA alkyltransferase activity in human myeloid cells. J Clin Invest 76: 2106–2114, 1985

    Google Scholar 

  60. Brent TP, Von Wronski MA, Edwards CC, Bromley M, Margison GP, Rafferty JA, Pegram CN, Bigner DD: Identification of nitrosourea-resistant human rhabdomyosarcomas by in situ immunostaining of O 6-methylguanine-DNA methyltransferase. Oncol Res 5: 83–86, 1993

    Google Scholar 

  61. Brennand J, Margison GP: Expression in mammalian cells of a truncated Escherichia coli gene coding for O 6-alkylguanine alkyltransferase reduces the toxic effects of alkylating agents. Carcinogenesis 7: 2081–2084, 1986

    Google Scholar 

  62. Brennand J, Margison GP: Reduction of the toxicity and mutagenicity of alkylating agents in mammalian cells harbouring the Escherichia coli alkyltransferase gene. Proc Natl Acad Sci USA 83: 6292–6296, 1986

    Google Scholar 

  63. White GR, Ockey CH, Brennand J, Margison GP: Chinese hamster cells harbouring the Escherichia coli O 6-alkylguanine alkyltransferase gene are less suceptible to sister chromatid exchange induction and chromosome damage by methylating agents. Carcinogenesis 7: 2077–2080, 1986

    Google Scholar 

  64. Jelinek J, Kleibl K, Dexter TM, Margison GP: Transfection of murine multi-potent haemopoietic stem cells with an E. coli DNA alkyltransferase gene confers resistance to the toxic effects of alkylating agents. Carcinogenesis 9: 81–87, 1988

    Google Scholar 

  65. Von Hofe E, Fairbairn L, Margison GP: Relationship between O 6-alkylguanine-DNA alkyltransferase activity and N-methyl-Ń-nitro-N-nitrosoguanidine-induced mutation, transformation, and cytotoxicity in C3H/10T1/2 cells expressing exogenous alkyltransferase genes. Proc Natl Acad Sci USA 89: 11199–11203, 1992

    Google Scholar 

  66. Nakatsuru Y, Matsukuma S, Nemoto N, Sugano H, Sekiguchi M, Ishikawa T: O 6-methylguanine-DNA methyltransferase protects against nitrosamine-induced hepatocarcinogenesis. Proc Natl Acad Sci USA 90: 6468–6472, 1993

    Google Scholar 

  67. Dumenco LL, Allay E, Norton K, Gerson SL: The prevention of thymic lymphomas in transgenic mice by human O 6-alkylguanine-DNA alkyltransferase. Science 259: 219–222, 1993

    Google Scholar 

  68. Dolan ME, Moschel RC, Pegg AE: Depletion of mammalian O 6-alkylguanine-DNA alkyltransferase activity by O 6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents. Proc Natl Acad Sci USA 87: 5368–5372, 1990

    Google Scholar 

  69. Dolan ME, Mitchell RB, Mummert C, Moschel RC, Pegg AE: Effect of O 6-benzylguanine analogues on sensitivity of human tumour cells to the cytotoxic effects of alkylating agents. Cancer Res 51: 3367–3372, 1991

    Google Scholar 

  70. Baer JC, Freeman AA, Newlands ES, Watson AJ, Rafferty JA, Margison GP: Depletion of O 6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells. Br J Cancer 67: 1299–1302, 1993

    Google Scholar 

  71. Mitchell RB, Moschel RC, Dolan ME: Effect of O 6-benzylguanine on the sensitivity of human tumour xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation. Cancer Res 52: 1171–1175, 1992

    Google Scholar 

  72. Dolan ME, Pegg AE, Moschel RC, Grindey GB: Effect of O 6-benzylguanine on the sensitivity of human colon tumour xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Biochem Pharmacol 46: 285–290, 1993

    Google Scholar 

  73. Fairbairn LJ, Watson AJ, Rafferty JA, Elder RH, Margison GP: O 6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide. Exp Hematol 23: 112–116, 1995

    Google Scholar 

  74. Elder RH, Margison GP, Rafferty JA: Differential inactivation of mammalian and Escherichia coli O 6-alkylguanine-DNA alkyltransferases by O 6-benzylguanine. Biochem J 298: 231–235, 1994

    Google Scholar 

  75. Crone TM, Pegg AE: A single amino acid change in human O 6-alkylguanine-DNA alkyltransferase decreasing sensitivity to inactivation by O 6-benzylguanine. Cancer Res 53: 4750–4753, 1993

    Google Scholar 

  76. Crone TM, Goodtzova K, Edara S, Pegg AE: Mutations in human O 6-alkylguanine-DNA alkyltransferase imparting resistance to O 6-benzylguanine. Cancer Res 54: 6221–6227, 1994

    Google Scholar 

  77. Hickson I, Fairburn LJ, Chinnasamy N, Margison GP, Dexter TM, Rafferty JA: Protection of mammalian cells against chloroethylating agent toxicity by an O 6-benzylguanine-resistant mutant of human O 6-alkylguanine-DNA-alkyl-transferase. Gene Therapy 3: 868–877, 1996

    Google Scholar 

  78. NgoGiang Huong N, Kayibanda M, Deprez B, Levy JP, Guillet JG, Tilkin AF: Mutations in residue 61 of H-Ras p21 protein influence MHC class II presentation. Int Immunol 7: 269–275, 1995

    Google Scholar 

  79. Jelinek J, Fairbairn LJ, Dexter TM, Rafferty JA, Stocking C, Ostertag W, Margison GP: Long-term protection of haematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O 6-alkylguanine DNA-alkyltransferase. Blood 87: 1957–1961, 1996

    Google Scholar 

  80. Allay JA, Dumenco LL, Koc ON, Liu L, Gerson SL: Retroviral transduction and expression of the human alkyltransferase cDNA provides nitrosourea resistance to haematopoietic cells. Blood 85: 3342–3351, 1995

    Google Scholar 

  81. Maze R, Carney JP, Moritz T, Kelly MR, Mackay W, Samson L, Williams DA: Nitrosourea (nu)-induced hematopoietic stem cell (hsc) damage and reduction of delayed myelosuppression in vivo using a O 6-methylguanine methyltransferase (MGMT) retroviral vector. Exp Hemat 22: 681–686, 1994

    Google Scholar 

  82. Moritz T, Mackay W, Glassner BJ, Williams DA, Samson L: Retrovirus-mediated expression of a DNA repair protein in bone marrow protects haematopoietic cells from nitrosourea-induced toxicity in vitro and in vivo. Cancer Res 55: 2608–2614, 1995

    Google Scholar 

  83. Maze R, Carney JP, Kelley MR, Glassner BJ, Williams DA, Samson L: Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1,3-bis(2)-chloroethyl-1-nitrosourea, a chemotherapeutic alkylating agent. Proc Natl Acad Sci USA 93: 206–210, 1996

    Google Scholar 

  84. Harris LC, Marathi UK, Edwards CC, Houghton PJ, Srivastava DK, Vanin EF, Sorrentino BP, Brent TP: Retroviral transfer of a bacterial alkyltransferase gene into murine bone marrow protects against chloroethylnitrosourea cytotoxicity. Clin Canc Res 1: 1359–1368, 1995

    Google Scholar 

  85. Challita PM, Kohn DB: Lack of expression from a retroviral vector after transduction of murine haematopoietic stem cells is associated with methylation in vivo. Proc Natl Acad Sci USA 91: 2567–2571, 1994

    Google Scholar 

  86. Grez M, Akgun E, Hilberg F, Ostertag W: Embryonic stem cell virus, a recombinant murine retrovirus with expression in embryonic stem cells. Proc Natl Acad Sci USA 87: 9202–9206, 1990

    Google Scholar 

  87. Baum C, Hegewisch Becker S, Eckert HG, Stocking C, Ostertag W: Novel retroviral vectors for efficient expression of the multidrug resistance (mdr-1) gene in early haematopoietic cells. J Virol 69: 7541–7547, 1995

    Google Scholar 

  88. Goldman MJ, Litzky LA, Engelhardt JF, Wilson JM: Transfer of the CFTR gene to the lung of nonhuman primates with E1-deleted, E2a-defective recombinant adenoviruses: a preclinical toxicology study. Hum Gene Ther 6: 839–851, 1995

    Google Scholar 

  89. Crystal RG, Jaffe A, Brody S, Mastrangeli A, McElvaney NG, Rosenfeld M, Chu CS, Danel C, Hay J, Eissa T: A phase 1 study, in cystic fibrosis patients, of the safety, toxicity, and biological efficacy of a single administration of a replication deficient, recombinant adenovirus carrying the cDNA of the normal cystic fibrosis transmembrane conductance regulator gene in the lung. Hum Gene Ther 6: 643–666, 1995

    Google Scholar 

  90. Westbrook CA, Chmura SJ, Arenas RB, Kim SY, Otto G: Human APC gene expression in rodent colonic epithelium in vivo using liposomal gene delivery. Hum Mol Genet 3: 2005–2010, 1994

    Google Scholar 

  91. Molineux G, Migdalska A, Haley J, Evans GS, Dexter TM: Total marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil. Blood 83: 3491–3499, 1994

    Google Scholar 

  92. Rasouli Nia A, Sibghat U, Mirzayans R, Paterson MC, Day RS: On the quantitative relationship between O 6-methylguanine residues in genomic DNA and production of sister-chromatid exchanges, mutations and lethal events in a Mer-human tumour cell line. Mutat Res 314:, 99–113, 1994

    Google Scholar 

  93. Rill DR, Santana VM, Roberts WM, Nilson T, Bowman LC, Krance RA, Heslop HE, Moen RC, Ihle JN, Brenner MK: Direct demonstration that autologous bone marrow transplantation for solid tumours can return a multiplicity of tumorigenic cells. Blood 84: 380–383, 1994

    Google Scholar 

  94. Rill DR, Moen RC, Buschle M, Bartholomew C, Foreman NK, Mirro JJr, Krance RA, Ihle JN, Brenner MK: An approach for the analysis of relapse and marrow reconstitution after autologous marrow transplantation using retrovirus-mediated gene transfer. Blood 79: 2694–2700, 1992

    Google Scholar 

  95. Brenner MK, Rill DR, Moen RC, Krance RA, Mirro JJr, Anderson WF, Ihle JN: Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet 341: 85–86, 1993

    Google Scholar 

  96. Verbeek W, Pies A, Humpe A, Grove D, Troff C, Kunze E, Hiddemann W, Wormann B: Mobilization of CD34-positive tumour cells in a patient with testicular mixed germ cell tumour. Br J Haematol 90: 947–950, 1995

    Google Scholar 

  97. Van de Rijn M, Lombard CM, Rouse RV: Expression of CD34 by solitary fibrous tumours of the pleura, mediastinum, and lung. Am J Surg Pathol 18: 814–820, 1994

    Google Scholar 

  98. Monihan JM, Carr NJ, Sobin LH: CD34 immunoexpression in stromal tumours of the gastrointestinal tract and in mesenteric fibromatoses. Histopathology 25: 469–473, 1994

    Google Scholar 

  99. Buschle M, Cotten M, Kirlappos H, Mechtler K, Schaffner G, Zauner W, Birnstiel ML, Wagner E: Receptor-mediated gene transfer into human T lymphocytes via binding of DNA/CD3 antibody particles to the CD3 T cell receptor complex. Hum Gene Ther 6: 753–761, 1995

    Google Scholar 

  100. Wagner E, Zatloukal K, Cotten M, Kirlappos H, Mechtler K, Curiel DT, Birnstiel ML: Coupling of adenovirus to transferrin-polylysine/DNA complexes greatly enhances receptor-mediated gene delivery and expression of transfected genes. Proc Natl Acad Sci USA 89: 6099–6103, 1992

    Google Scholar 

  101. Han X, Kasahara N, Kan YW: Ligand-directed retroviral targeting of human breast cancer cells. Proc Natl Acad Sci USA 92: 9747–9751, 1995

    Google Scholar 

  102. Somia NV, Zoppe M, Verma IM: Generation of targeted retroviral vectors by using single-chain variable fragment: an approach to in vivo gene delivery. Proc Natl Acad Sci USA 92: 7570–7574, 1995

    Google Scholar 

  103. Kashara N, Dozy AM, Kan YW: Tissue-specific targeting of retroviral vectors through ligand-receptor interactions [see comments]. Science 266: 1373–1376, 1994

    Google Scholar 

  104. Dighe AS, Campbell D, Hsieh CS, Clarke S, Greaves DR, Gordon S, Murphy KM, Schreiber RD: Tissue-specific targeting of cytokine unresponsiveness in transgenic mice. Immunity 3: 657–666, 1995

    Google Scholar 

  105. Burn TC, Satterthwaite AB, Tenen DG: The human CD34 haematopoietic stem cell antigen promoter and a 3′ enhancer direct haemotopoietic expression in tissue culture. Blood 80: 3051–3059, 1992

    Google Scholar 

  106. Yamaguchi Y, Zhang DE, Sun Z, Albee EA, Nagata S, Tenen DG, Ackerman SJ: Functional characterization of the promoter for the gene encoding human eosinophil peroxidase. J Biol Chem 269: 19410–19419, 1994

    Google Scholar 

  107. Dziennis S, Van Etten RA, Pahl HL, Morris DL, Rothstein TL, Blosch CM, Perlmutter RM, Tenen DG: The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice [published erratum appears in Blood 1995 Apr 1; 85 (7): 1983]. Blood 85: 319–329, 1995

    Google Scholar 

  108. Sun Z, Yergeau DA, Tuypens T, Tavernier J, Paul CC, Baumann MA, Tenen DG, Ackerman SJ: Identification and characterization of a functional promoter region in the human eosinophil IL-5 receptor alpha subunit gene. J Biol Chem 270: 1462–1471, 1995

    Google Scholar 

  109. Doroshow JH, Metz MZ, Matsumoto L, Winters KA, Sakai M, Muramatsu M, Kane SE: Transduction of NIH 3T3 cells with a retrovirus carrying both human MDR1 and glutathione S-transferase pi produces broad-range multidrug resistance. Cancer Res 55: 4073–4078, 1995

    Google Scholar 

  110. Harding M, Docherty V, Mackie R, Dorward A, Kaye S: Phase II studies of mitozolomide in melanoma, lung and ovarian cancer. Eur J Cancer Clin Oncol 25: 785–788, 1989

    Google Scholar 

  111. Gulick AM, Fahl WE: Forced evolution of glutathione S-transferase to create a more efficient drug detoxication enzyme. Proc Natl Acad Sci USA 92: 8140–8144, 1995

    Google Scholar 

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Authors and Affiliations

  1. CRC Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital (NHS)-Trust, M20 9BX, Manchester, UK

    J. A. Rafferty, I. Hickson, N. Chinnasamy & G. P. Margison

  2. CRC Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital (NHS)-Trust, M20 9BX, Manchester, UK

    I. Hickson, N. Chinnasamy, L. S. Lashford, T. M. Dexter & L. J. Fairbairn

Authors
  1. J. A. Rafferty
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  2. I. Hickson
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  3. N. Chinnasamy
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  4. L. S. Lashford
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  5. G. P. Margison
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  6. T. M. Dexter
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  7. L. J. Fairbairn
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Rafferty, J.A., Hickson, I., Chinnasamy, N. et al. Chemoprotection of normal tissues by transfer of drug resistance genes. Cancer Metast Rev 15, 365–383 (1996). https://doi.org/10.1007/BF00046348

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