Role of Gene Therapy in Radiation Oncology

  • Dennis E. Hallahan
  • Ralph Weichselbaum
Part of the Cancer Treatment and Research book series (CTAR, volume 93)


Optimization of the treatment of neoplasms with radiation therapy can be achieved by reduction of the radiation sensitivity of surrounding normal tissues, or by enhancement of the tumoricidal effects of radiation. Both strategies are best illustrated by the therapeutic ratio, which is the ratio of the probability of tumor control to the probability of normal tissue injury (Figure 7-1). The therapeutic ratio can be improved by localizing a radiation-sensitizing agent to the tumor and not to normal tissue. An alternative approach is to localize a radioprotective agent to the normal tissues while avoiding administration of this protector to the tumor cells. The physical characteristics of ionizing radiation allow for spatial definition and limitation of the irradiated volume. X-rays allow for penetration into deep tissues and precise localized ionization of tissues. Because radiation therapy is a localized treatment modality, localizing a radiation-sensitizing agent to the neoplasm and/or localizing a radioprotecting agent to the surrounding normal tissues are both means of optimizing the therapeutic ratio in radiation oncology.


Gene Therapy Malignant Glioma Cationic Liposome Therapeutic Gene Cancer Gene Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weichselbaum RR, Hallahan DE, Chen GTY. 1997. Physical and biological basis to radiation oncology. In Holland J, Frei E, Bast RC, Kufe D, Morton DL, Weichselbaum RR, eds. Cancer Medicine 4th ed. Baltimore: Williams & Wilkins, pp. 697–726.Google Scholar
  2. 2.
    Huber BE, Austin EA, Richards CA, Davis ST, Good SS. 1994. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: Significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA 91:8302–8306.PubMedCrossRefGoogle Scholar
  3. 3.
    Mullen CA, Kilstrup M, Blaese RM. 1992. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: A negative selection system. Proc Natl Acad Sci USA 89:33–37.PubMedCrossRefGoogle Scholar
  4. 4.
    Kaplitt MG, Tjuvajev JG, Leib DA, Berk J, Pettigrew KD, Posner JB, Pfaff DW, Rabkin SD, Blasberg RG. 1994. Mutant herpes simplex virus induced regression of tumors growing in immunocompetent rats. J Neuro Oncol 19:137–147.CrossRefGoogle Scholar
  5. 5.
    Jia WW, McDermott M, Goldie J, Cynader M, Tan J, Tufaro F. 1994. Selective destruction of gliomas in immunocompetent rats by thymidine kinase-defective herpes simplex virus type 1. J Natè Cancer Inst 86:1209–1215.CrossRefGoogle Scholar
  6. 6.
    Markert JM, Malick A, Coen DM, Martuza RL. 1993. Reduction and elimination of encephalitis in an experimental glioma therapy model with attenuated herpes simplex mutants that retain susceptibility to acyclovir. Neurosurgery 32: 5597–5603.Google Scholar
  7. 7.
    Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM. 1991. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252:854–856.PubMedCrossRefGoogle Scholar
  8. 8.
    Mineta T, Rabkin SD, Martuza RL. 1994. Treatment of malignant gliomas using ganciclovir-hypersensitive, ribonucleotide reductase-deficient herpes simplex viral mutant. Cancer Res 54:3963–3966.PubMedGoogle Scholar
  9. 9.
    Chambers R, Gillespie GY, Soroceanu L, Andreansky S, Chatterjee S, Chou J, Roizman B, Whitley RJ. 1995. Comparison of genetically engineered herpes simplex viruses for the treatment of brain tumors in a scid mouse model of human malignant glioma. Proc Natl Acad Sci USA 92:1411–1415.PubMedCrossRefGoogle Scholar
  10. 10.
    Boviatsis EJ, Chase M, Wei MX, Tamiya T, Hurford R Jr, Kowall NW, Tepper RI, Breakefield XO, Chiocca EA. 1994. Gene transfer into experimental brain tumors mediated by adenovirus, herpes simplex virus, and retrovirus vectors. Hum Gene Ther 5:183–191.PubMedCrossRefGoogle Scholar
  11. 11.
    Boviatsis EJ, Park JS, Sena-Esteves M, Kramm CM, Chase M, Efird JT, Wei MX, Breakefield XO, Chiocca EA. 1994. Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Cancer Res 54:5745–5751.PubMedGoogle Scholar
  12. 12.
    Song P, Sibley GS, Advani S, Hallahan D, Hyland J, Kufe DW, Chou J, Roizman B, Weichselbaum RR. 1996. Enhanced tumor control of human glioblastoma multiforme xenograft with the concomitant use of radiotherapy and an attentuated herpes simplex-1 virus (abstrt). Proceedings of the 38th Annual ASTRO Meeting 36(Suppl. 1):227.Google Scholar
  13. 13.
    Sibley GS, Hallahan DE, Hyland J, Seung LP, Maucer HJ, Chou J, Roizman B, Weichselbaum RR. 1995. Evaluation of a gene therapy system using a replication competent, non-neurovirulent HSV-1 viral vector used in combination with radiotherapy. Proceedings of the 37th Annual ASTRO Meeting 32(Suppl. 1): 173.Google Scholar
  14. 14.
    Chou J, Kern ER, Whitley RJ, Roizman B. 1994. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nones-sential for growth in culture. Science 250:1262–1266.CrossRefGoogle Scholar
  15. 15.
    Glorioso JC, Goins WF, Meaney CA, Fink DJ, DeLuca NA. 1994. Gene transfer to brain using herpes simplex virus vectors. Ann Neurol 35: S28–S34.PubMedCrossRefGoogle Scholar
  16. 16.
    Gilboa E, Kolbe M, Noonan K, Kucherlapati R. 1982. Construction of a mammalian transducing vector from the genome of Moloney murine leukemia virus. J Virol 44:845–851.PubMedGoogle Scholar
  17. 17.
    Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK. 1994. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 54:3352–3356.PubMedGoogle Scholar
  18. 18.
    O’Malley B Jr, Chen SH, Schwartz MR, Woo SL. 1995. Adenovirus-mediated gene therapy for human head and neck squamous cell cancer in a nude mouse model. Cancer Res 55:1080–1085.PubMedGoogle Scholar
  19. 19.
    Hallahan DE, Mauceri HJ, Seung LP, Dunphy EJ, Toledano A, Hellman S, Kufe DW, Weichselbaum RR. 1995. Spatial and temporal control of gene therapy by ionizing radiation. Nature Med 1:786–791.PubMedCrossRefGoogle Scholar
  20. 20.
    Wickham TJ, Carrion ME, Kovesdi I. 1995. Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs. Gene Therapy 2:750–756.PubMedGoogle Scholar
  21. 21.
    Feigner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JP, Ringold GM, Danielsen M. 1987. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA 84:7413–7417.CrossRefGoogle Scholar
  22. 22.
    Gao X, Huang L. 1995. Cationic liposome-mediated gene transfer. Gene Therapy 2:710–722.PubMedGoogle Scholar
  23. 23.
    Caplen NJ, Kinrade E, Sorgi F, Gao X, Gruenert D, Geddes D, Coutelle C, Huang L, Alton EW, Williamson R. 1995. In vitro liposome-mediated DNA transfection of epithelial cell lines using the cationic liposome DC-Choi/ DOPE. Gene Therapy 2:603–613.PubMedGoogle Scholar
  24. 24.
    Nabel GJ, Nabel EG, Yang ZY, Fox BA, Plautz GE, Gao X, Huang L, Shu S, Gordon D, Chang AE. 1993. Direct gene transfer with DNA-liposome complexes in melanoma: Expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci USA 90:11307–11311.PubMedCrossRefGoogle Scholar
  25. 25.
    Seung LP, Mauceri HJ, Hallahan DE, Beckett MA, Hellman S, Weichselbaum RR. 1995. Genetic radiotherapy overcomes resistance to cytotoxic agents. Cancer Res 55:5561–5565.PubMedGoogle Scholar
  26. 26.
    Bottega R, Epand RM. 1991. Inhibition of protein kinase C by cationic amphiphiles. Biochemistry 31:9025–9030.CrossRefGoogle Scholar
  27. 27.
    Brown K, Gertsberger S, Carlson L, Franzoso G, Siebenlist U. 1995. Control of IkB-alpha proteolysis by site-specific, signal induced phosphorylation. Science 267:600–611.CrossRefGoogle Scholar
  28. 28.
    Hallahan DE, Sukhatme VP, Sherman ML, Virudachalam S, Kufe D, Weichselbaum RR. 1991. Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and JUN. Proc Natl Acad Sci USA 88:2156–2160.PubMedCrossRefGoogle Scholar
  29. 29.
    Mack KD, Rosemary W, Zeldis JB. 1994. Cationic lipid enhances in vitro recrptor-mediated transfection. Am J Med Sci 307:138–143.PubMedCrossRefGoogle Scholar
  30. 30.
    Curiel DT, Agarwal S, Wagner E, Cotten M. 1991. Adenovirus enhancement of transferrin-polylysine-mediated gene delivery. Proc Natl Acad Sci USA 88:8850–8854.PubMedCrossRefGoogle Scholar
  31. 31.
    Jain RK. 1994. Barriers to drug delivery in solid tumors. Sci Am 271:58–65.PubMedCrossRefGoogle Scholar
  32. 32.
    Yang NS, Sun WH. 1995. Gene gun and other non-viral approaches for cancer gene therapy. Nature Med 1:481–483.PubMedCrossRefGoogle Scholar
  33. 33.
    Nicolet CM, Burkholder JK, Gan J, Culp J, Kashmiri SV, Schlom J, Yang NS, Sondel PM. 1995. Expression of a tumor-reactive antibody-interleukin 2 fusion protein after in vivo particle-mediated gene delivery. Cancer Gene Ther 2:161–170.PubMedGoogle Scholar
  34. 34.
    Sun WH, Burkholder JK, Sun J, Culp J, Turner J, Lu XG, Pugh TD, Ershler WB, Yang NS. 1995. In vivo cytokine gene transfer by gene gun reduces tumor growth in mice. Proc Natl Acad Sci USA 92:2889–2893.PubMedCrossRefGoogle Scholar
  35. 35.
    Chan HY, Harris AL. 1995. Gene Therapy targeting to tumor endothelium. Gene Therapy.Google Scholar
  36. 36.
    Folkman J. 1992. The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71.PubMedGoogle Scholar
  37. 37.
    Mauceri H, Lee H, Beckett M, Sukhatme V, Kufe D, Hallahan D, Weichselbaum RR. 1996. Tumor size does not limit radiation-inducible gene therapy in a human xenograft model. Radiat Oncol Invest, in press.Google Scholar
  38. 38.
    Gossen M, Bujard H. 1992. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551.PubMedCrossRefGoogle Scholar
  39. 39.
    Furth PA, St. Onge L, Boger H, Gruss P, Gossen M, Kistner A, Bujard H, Hennighausen L. 1994. Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci USA 91:9302–9306.PubMedCrossRefGoogle Scholar
  40. 40.
    Datta R, Rubin E, Sukhatme V, Qureshi S, Hallahan D, Weichselbaum RR, Kufe DW. 1992. Ionizing radiation activates transcription of the EGR1 gene via CArG elements. Proc Natl Acad Sci USA 89:10149–10153.PubMedCrossRefGoogle Scholar
  41. 41.
    Behrends U, Peter RU, Hintermeier-Knabe R, Eissner G, Holler E, Bornkamm GW, Caughman SW, Degitz K. 1994. Ionizing radiation induces human intercellular adhesion molecule-1 in vitro. J Invest Dermatol 103:726–730.PubMedCrossRefGoogle Scholar
  42. 42.
    Hallahan DE, Clark ET, Kuchibhotla J, Gewertz B, Collins T. 1995. E-selectin gene induction by ionizing radiation is independent of cytokine induction. Biochem Biophys Res Commun 217:784–795.PubMedCrossRefGoogle Scholar
  43. 43.
    Weichselbaum RR, Hallahan DE, Beckett MA, Mauceri HJ, Lee H, Sukhatme VP, Kufe DW. 1994. Radiation targeting of gene therapy preferentially radiosensitizes tumor cells. Cancer Res 54:4266–4269.PubMedGoogle Scholar
  44. 44.
    Abe M, Kufe D. 1993. Characterization of cisacting elements regulating transcription of the human DF3 breast carcinoma-associated antigen (MUC1) gene. Proc Natl Acad Sci USA 90:282–286.PubMedCrossRefGoogle Scholar
  45. 45.
    Manome Y, Abe M, Hagen MF, Fine HA, Kufe DW. 1994. Enhancer sequences of the DF3 gene regulate expression of the herpes simplex virus thymidine kinase gene and confer sensitivity of human breast cancer cells to ganciclovir. Cancer Res 54:5408–5413.PubMedGoogle Scholar
  46. 46.
    Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA. 1995. Definition of two angiogenic pathways by distinct alpha v integrins. Science 270:1500–1502.PubMedCrossRefGoogle Scholar
  47. 47.
    Folkman J. 1995. Clinical applications of research on angiogenesis. N Engl J Med 333: 1757–1763.PubMedCrossRefGoogle Scholar
  48. 48.
    Guzman RJ, Hirschowitz EA, Brody SL, Crystal RG, Epstein SE, Finkel T. 1994. In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. Proc Natl Acad Sci USA 91:10732–10736.PubMedCrossRefGoogle Scholar
  49. 49.
    Bickneu R. 1994. Vascular targeting and the inhibition of angiogenesis. Ann Oncol 5(Suppl. 4):45–50.Google Scholar
  50. 50.
    Holmgren L, O’Reilley MS, Folkman J. 1995. Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med 1:149–153.PubMedCrossRefGoogle Scholar
  51. 51.
    Nabel EG, Plautz G, Nabel GJ. 1990. Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science 249:1285–1288.PubMedCrossRefGoogle Scholar
  52. 52.
    Nabel EG, Plautz G, Boyce FM, Stanley JC, Nabel GJ. 1989. Recombinant gene expression in vivo within endothelial cells of the arterial wall. Science 244:1342–1344.PubMedCrossRefGoogle Scholar
  53. 53.
    Hallahan DE, Kuchibholta J, Wyble C. 1996. Cell adhesion molecules (CAMs) mediate radiation-inudced leukocyte adhesion to the vascular endothelium. Cancer Res, in press.Google Scholar
  54. 54.
    Hong JH, Chiang CS, Campbell IL, Sun JR, Withers HR, McBride WH. 1995. Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys 33:619–626.PubMedCrossRefGoogle Scholar
  55. 55.
    Culver KW, Blaese RM. 1994. Gene therapy for cancer. Trends Genet 10:174–178.PubMedCrossRefGoogle Scholar
  56. 56.
    Anderson WF. 1994. Gene therapy for cancer [editorial]. Hum Gene Ther 5:1–2.PubMedCrossRefGoogle Scholar
  57. 57.
    Losordo DW, Pickering JG, Takeshita S, Leclerc G, Gal D, Weir L, Kearney M, Jekanowski J, Isner JM. 1994. Use of the rabbit ear artery to serially assess foreign protein secretion after site-specific arterial gene transfer in vivo. Evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression. Circulation 89: 785–792.PubMedCrossRefGoogle Scholar
  58. 58.
    Connors TA. 1995. The choice of prodrugs for gene directed enzyme prodrug therapy of cancer. Gene Ther 2:702–709.PubMedGoogle Scholar
  59. 59.
    Khil MS, Kim JH, Mullen CA, Kim SH, Freytag SO. 1996. Radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells in culture transduced with cytosine deaminase gene. Clin Cancer Res 2:53–57.PubMedGoogle Scholar
  60. 60.
    Hanna N, Hallahan DE, Wayne JD, Weichselbaum RR. 1996. Modification of the radiation response by the administration of exogenous genes. Semin Rad Oncol 6:1–9.CrossRefGoogle Scholar
  61. 61.
    Kim JH, Kim SH, Brown SL, Freytag SO. 1994. Selective enhancement by an antiviral agent of the radiation-induced cell killing of human glioma cells transduced with HSV-tk gene. Cancer Res 54:6053–6056.PubMedGoogle Scholar
  62. 62.
    Epperly MW, Jahroudi N, Rosenstein M, Shields D, Engelhardt J, Huang L, Greenberger JS. 1995. Protection of the lung ionizing irradiation damage by inhalation gene therapy. Proceedings of the 37th Annual ASTRO Meeting 32(Suppl. 1):173.Google Scholar
  63. 63.
    Wong GHW, Elwell JH, Oberley LW, Goeddel DV. 1989. Manganeous Superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell 58:923–931.PubMedCrossRefGoogle Scholar
  64. 64.
    Fuks Z, Persaud RS, Alfieri A, McLoughlin M, Ehleiter D, Schwartz JL, Seddon AP, Cordon-Cardo C, Haimovitz-Friedman A. 1994. Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res 54:2582–2590.PubMedGoogle Scholar
  65. 65.
    Vokes EE. 1994. The promise of biochemical modulation in combined modality therapy. Semin Oncol 21:29–33.PubMedGoogle Scholar
  66. 66.
    Angioli R, Sevin BU, Perras JP, Untch M, Koechli OR, Nguyen HN, Steren A, Schwade JG, Villani C, Averette HE. 1993. In vitro potentiation of radiation cytotoxicity by recombinant interferons in cervical cancer cell lines. Cancer 71:3717–3725.PubMedCrossRefGoogle Scholar
  67. 67.
    Angioli R, Sevin BU, Perras JP, Untch M, Hightower RD, Nguyen HN, Steren A, Villani C, Averette HE. 1992. Rationale of combining radiation and interferon for the treatment of cervical cancer. Oncology 49:445–449.PubMedCrossRefGoogle Scholar
  68. 68.
    Hallahan DE, Dunphy E, Virudachalam S, Sukhatme VP, Kufe DW, Weichselbaum RR. 1995. c-jun and Egr-1 participate in DNA synthesis and cell survival in response to ionizing radiation exposure. J Biol Chem 270:30303–30309.PubMedCrossRefGoogle Scholar
  69. 69.
    Lowe SW, Ruley HE, Jacks T, Housman DE. 1993. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967.PubMedCrossRefGoogle Scholar
  70. 70.
    Lee JM, Bernstein A. 1993. p53 mutations increase resistance to ionizing radiation. Proc Natl Acad Sci USA 90:5742–5746.PubMedCrossRefGoogle Scholar
  71. 71.
    Wong GH. 1995. Protective roles of cytokines against radiation: Induction of mitochondrial MnSOD. Biochim Biophys Acta 1271:205–209.PubMedCrossRefGoogle Scholar
  72. 72.
    McBride WH, Economou JS, Kuber N, Hong JH, Chiang CS, Syljuasen R, Dougherty ST, Dougherty GJ. 1995. Modification of tumor microenvironment by cytokine gene transfer. Acta Oncol 34:447–451.PubMedCrossRefGoogle Scholar
  73. 73.
    Neta R, Oppenheim P. 1996. Cytokine-induced radiation protection and sensitization. Semin Radiat Oncol 6:306–320PubMedCrossRefGoogle Scholar
  74. 74.
    Seki H, Iwai K, Kanegane H, Konno A, Ohta K, Ohta K, Yachie A, Taniguchi N, Miyawaki T. 1995. Differential protective action of cytokines on radiation-induced apoptosis of peripheral lymphocyte subpopulations. Cell Immunol 163: 30–36.PubMedCrossRefGoogle Scholar
  75. 75.
    Ross HJ, Antoniono RJ, Buckmeier JA, Redpath JL. 1994. Variable expression of IL-1 beta has minimal effect on the radiation sensitivity of three human glioma cell lines. Int J Radiat Biol 66:785–791.PubMedGoogle Scholar
  76. 76.
    Guigon M, Lemoine F, Najman A. 1994. Bone marrow protection. Bone Marrow Transplant 13:93–95.PubMedGoogle Scholar
  77. 77.
    Reed JC. 1550. Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol 7:541–546.CrossRefGoogle Scholar
  78. 78.
    Prehn JH, Bindokas VP, Marcuccilli CJ, Krajewski S, Reed JC, Miller RJ. 1994. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons. Proc Natl Acad Sci USA 91:12599–12603.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Dennis E. Hallahan
  • Ralph Weichselbaum

There are no affiliations available

Personalised recommendations