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Cancer gene therapy: Combination with radiation therapy and the role of bystander cell killing in the anti-tumor effect

  • Seminar
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Pathology & Oncology Research

Abstract

Current anti-cancer modalities such as surgery, chemo- and radiation therapies have only limited success in cancer treatment. Gene therapy is a promising new tool to improve outcomes. In this review, first we summarize the various strategies to kill tumor cells, and then focus on the bystander effect of gene therapy. A variety of strategies, such as gene-directed enzyme pro-drug therapy, activation of an anti-tumor immune attack, application of replication-competent and oncolytic viral vectors, tumor-specific as well as radiation and hypoxiainduced gene expression, might be applied to target tumor cells. We put special emphasis on the combination of these approaches with local tumor irradiation. Using the available vector systems, only a small portion of cancer cells contains the therapeutic genes under clinical situations. However, cells directly targeted by gene therapy will transfer death signals to neighboring cancer cells. This bystander cell killing improves the efficiency of cancer gene therapy. Death signals are delivered by cell-to-cell communication through gap junction intercellular contacts, release of toxic metabolites into the neighborhood or to larger distances, phagocytosis of apoptotic bodies, and the activation of the immune system. Bystander cell killing can be enhanced by the introduction of gap junction proteins into cells, by further activating the immune system with immune-stimulatory molecules, or by introducing genes that help the transfer of cytotoxic genes and/or metabolites into bystander cells. In conclusion, although bystander cell killing can improve therapeutic effects, there should be additional developments in cancer gene therapy for a more efficient clinical application.(Pathology Oncology Research Vol 12, No 2, 118–124)

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References

  1. Vile RG, Russell SJ, Lemoine NR: Cancer gene therapy: hard lessons and new courses. Gene Ther 7: 2–8, 2000

    Article  PubMed  CAS  Google Scholar 

  2. Inaba M, Sawaa H, Sadata A, Hamada H: Circumvention of 5fluorouracil resistance in human stomach cancer cells by uracil phosphoribosyl transferase gene transduction. Jpn J Cancer Res 90: 349–354, 1999

    PubMed  CAS  Google Scholar 

  3. Aghi M, Hochberg F, Breakfield XO: Prodrug activation enzymes in cancer gene therapy. J Gene Med 2: 148–164, 2000

    Article  PubMed  CAS  Google Scholar 

  4. Aghi M, Kramm CM, Chou T, et al: Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/ cytosine deaminase gene therapies. J Natl Cancer Inst 90: 370–380, 1998

    Article  PubMed  CAS  Google Scholar 

  5. Takamiya Y, Short MP, Ezzeddine ZD, et al: Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells. J Neurosci Res 33: 493–503, 1992

    Article  PubMed  CAS  Google Scholar 

  6. Kanai F, Kawakami T, Hamada H, et al: Adenovirus-mediated transduction of Escherichia coli uracil phosphoribosyltransferase gene sensitizes cancer cells to low concentrations of 5fluorouracil. Cancer Res 58: 1946–1951, 1998

    PubMed  CAS  Google Scholar 

  7. Maron A, Gustin T, Le Roux A, et al: Gene therapy of rat C6 glioma using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene: long-term follow-up by magnetic resonance imaging. Gene Ther 3: 315–322, 1996

    PubMed  CAS  Google Scholar 

  8. Desaknai S, Lumniczky K, Esik O, et al: Local tumor irradiation enhances the anti-tumor effect of a double-suicide gene therapy system in a murine glioma model. J Gene Med 5: 377–385, 2003

    Article  PubMed  CAS  Google Scholar 

  9. Showier DL, Fakhrai H, Van Beveren C, et al: Gene therapy approaches to enhance antitumor immunity. Adv Pharmacol 40: 309–337, 1997

    Article  Google Scholar 

  10. Dranoff G, Jaffee E, Lazenby A, et al: Vaccination with irradiated tumor cells engineered to secrete murine granulocytemacrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90: 3539–3543, 1993

    Article  PubMed  CAS  Google Scholar 

  11. Allione A, Consalvo M, Nanni P, et al: Immunizing and curative potential of replicating and non-replicating murine mammary adenocarcinoma cells engineered with interleukin IL-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and gamma-interferon gene or admixed with conventional adjuvants. Cancer Res 54: 6022–6026, 1994

    PubMed  CAS  Google Scholar 

  12. Li J, Andres ML, Fodor I, et al: Evaluation of pGL1-TNF-alpha therapy in combination with radiation. Oncol Res 10: 379–387, 1998

    PubMed  CAS  Google Scholar 

  13. Staba MJ, Mauceri HJ, Kufe DW, et al: Adenoviral TNF-alpha gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft. Gene Ther 5: 293–300, 1998

    Article  PubMed  CAS  Google Scholar 

  14. Lumniczky K, Désaknai S, Mangel L, et al: Local tumor irradiation augments the anti-tumor effect of cytokine producing autologous cancer cell vaccines in a murine glioma model. Cancer Gene Ther 9: 44–52, 2002

    Article  PubMed  CAS  Google Scholar 

  15. Hann B, Balmain A: Replication of an E1B 55-kilodalton proteindeficient adenovirus ONYX-015 is restored by gain-of-function rather than loss-function p53 mutants. J Virol 77: 11588–11595, 2003

    Article  PubMed  CAS  Google Scholar 

  16. Nemunaitis J, Khuri F, Ganly I, et al: Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol 19: 289–298, 2001

    PubMed  CAS  Google Scholar 

  17. Nemunaitis J, Cunningham C, Buchanan A, et al: Intravenous infusion of a replication-selective adenovirus ONYX-015 in cancer patients: safety, feasibility and biological activity. Gene Ther 8: 746–759, 2001

    Article  PubMed  CAS  Google Scholar 

  18. Rogulski KR, Freytag SO, Zhang K, et al: In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy. Cancer Res 60: 1193–1196, 2000

    PubMed  CAS  Google Scholar 

  19. Geoerger B, Grill J, Opolon P, et al: Potentiation of radiation therapy by the oncolytic adenovirus dl 1520 ONYX-015 in human malignant glioma xenografts. Br J Cancer 89: 577–584, 2003

    Article  PubMed  CAS  Google Scholar 

  20. Lin E, Nemunaitis J: Oncolytic viral therapies. Cancer Gene Ther 11:643–664, 2004

    Article  PubMed  CAS  Google Scholar 

  21. Stanziale SF, Petrowsky H, et al: Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase. Surgery 132: 353–359, 2002

    Article  PubMed  Google Scholar 

  22. Timiryasova TM, Gridley DS, Chen B, et al: Radiation enhances the anti-tumor effects of vaccinia-p53 gene therapy in glioma. Technol Cancer Res Treat 2: 223–235, 2003

    PubMed  CAS  Google Scholar 

  23. Robson T, Hirst DG: Transcriptional targeting in cancer gene therapy. J Biomed Biotechnol 110–137, 2003

  24. Hallahan DE, Mauceri HJ, Seung LP, et al: Spatial and temporal control of gene therapy using ionizing radiation. Nat Med 1: 786–791, 1995

    Article  PubMed  CAS  Google Scholar 

  25. Weichselbaum RR, Hallahan DE, Beckett MA, et al: Gene therapy targeted by radiation preferentially radiosensitizes tumor cells. Cancer Res 54: 4266–4269, 1994

    PubMed  CAS  Google Scholar 

  26. Horsman MR, Bohm L, Margison GP, et al: Tumor radiosensitizers-current status of development of various approaches: report of an International Atomic Energy Agency meeting. Int J Radiat Oncol Biol Phys 64: 551–561, 2006

    PubMed  Google Scholar 

  27. Chastel C, Jiricny J, Jaussi R: Activation of stress-responsive promoters by ionizing radiation for deployment in targeted gene therapy. DNA Repair 3: 201–215, 2004

    Article  PubMed  CAS  Google Scholar 

  28. Manome Y, Kunieda T, Wen PY, et al: Transgene expression in malignant glioma using a replication-defective adenoviral vector containing the Egr-1 promoter: activation by ionizing radiation or uptake of radioactive iodo-deoxyuridine. Hum Gene Ther 9: 1409–1417, 1998

    Article  PubMed  CAS  Google Scholar 

  29. Weichselbaum RR, Kufe DW Hellman S, et al: Radiation-induced tumor necrosis factor-a expression: clinical application of transcriptional and physical targeting of gene therapy. Lancet Oncol 3: 665–671, 2002

    Article  PubMed  CAS  Google Scholar 

  30. Joki T, Nakamura M, Ohno T: Activation of the radiosensitive EGR-1 promoter induces expression of the herpes simplex virus thymidine kinase gene and sensitivity of human glioma cells to ganciclovir. Hum Gene Ther 6: 1507–1513, 1995

    Article  PubMed  CAS  Google Scholar 

  31. Worthington J, Robson T, O’Keeffe M, Hirst DG: Tumor cell radiosensitization using constitutive CMV and radiation inducible WAF1 promoters to drive the iNOS gene: a novel suicide gene therapy. Gene Ther 9: 263–269, 2002

    Article  PubMed  CAS  Google Scholar 

  32. Worthington J, McCarthy HO, Barrett E, et al: Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment. J Gene Med 6: 673–680, 2004

    Article  PubMed  CAS  Google Scholar 

  33. Marples B, Greco O, Joiner MC, Scott SD: Radiogenetic therapy: strategies to overcome tumor resistance. Curr Pharm Des 9: 2105–2112, 2003

    Article  PubMed  CAS  Google Scholar 

  34. Shibata T, Giaccia AJ, Brown JM: Development of a hypoxiaresponsive vector for tumor-specific gene therapy. Gene Ther 7: 493–498, 2000

    Article  PubMed  CAS  Google Scholar 

  35. J Gene Med Clinical Trial Site.

  36. Rainov NG: A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 20: 2389–2401, 2000

    Article  Google Scholar 

  37. Immonen A, Vapalahti M, Tyynela K, et al: AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 10: 967–972, 2004

    Article  PubMed  CAS  Google Scholar 

  38. Palmer DH, Young LS, Mautner V: Cancer gene-therapy: clinical trials. Trends Biotechnol 24: 76–82, 2006

    Article  PubMed  CAS  Google Scholar 

  39. Laheru D, Joffe EM: Immunotherapy for pancreatic cancer science driving clinical progress. Nat Rev Cancer 5: 459–467, 2005

    Article  PubMed  CAS  Google Scholar 

  40. Pulkkanen KJ, Yla-Herttuala S: Gene therapy for malignant glioma: current clinical status. Mol Ther 12: 585–598, 2005

    Article  PubMed  CAS  Google Scholar 

  41. Lawler SE, Peruzzi PP, Chiocca EA: Genetic strategies for brain tumor therapy. Cancer Gene Ther 13: 225–233, 2006

    Article  PubMed  CAS  Google Scholar 

  42. Makower D, Rozenblit A, Kaufman H, et al: Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin Cancer Res 9: 693–702, 2003

    PubMed  Google Scholar 

  43. Chiocca EA, Abbed KM, Tatter S, et al: A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1Battenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther 10: 958–966, 2004

    Article  PubMed  CAS  Google Scholar 

  44. Khuri FR, Nemunaitis J, Gantly I, et al: A controlled trial of intratumoral ONYX-015, a selectively replicating adenovirus in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 16: 879–885, 2000

    Article  CAS  Google Scholar 

  45. Dilber MS, Gahrton G: Suicide gene therapy: possible applications in haematopoietic disorders. J Intern Med 249: 359–367, 2001

    Article  PubMed  CAS  Google Scholar 

  46. van Dillen IJ, Mulder NH, Vaalburg W, et al: Influence of the bystander effect on HSV-TK/GCV gene therapy. A review. Curr Gene Ther 2: 307–322, 2002

    Article  Google Scholar 

  47. Namba H, Iwadate Y, Kawamura K, et al: Efficacy of the bystander effect in the herpes simplex virus thymidine kinasemediated gene therapy is influenced by the expression of connexin43 in the target cells. Cancer Gene Ther 8: 414–420, 2001

    Article  PubMed  CAS  Google Scholar 

  48. Kim YG, Bi W, Feliciano ES, et al: Ganciclovir-mediated cell killing and bystander effect is enhanced in cells with two copies of the herpes simplex virus thymidine kinase gene. Cancer Gene Ther 7: 240–246, 2000

    Article  PubMed  CAS  Google Scholar 

  49. Princen F, Robe P, Lechanteur C, et al: A cell type-specific and gap junction-independent mechanism for the herpes simplex virus-1 thymidine kinase gene/ganciclovir-mediated bystander effect. Clin Cancer Res 5: 3639–3644, 1999

    PubMed  CAS  Google Scholar 

  50. Drake RR, Pitlyk K, McMasters RA, et al: Connexin-independent ganciclovir-mediated killing conferred on bystander effect-resistant cell lines by a herpes simplex virus-thymidine kinaseexpressing colon cell line. Mol Ther 2: 515–523, 2000

    Article  PubMed  CAS  Google Scholar 

  51. Freeman SM, Abboud CN, Whartenby KA, et al: The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 53: 5274–5283, 1993

    PubMed  CAS  Google Scholar 

  52. Hamel W, Magnelli L, Chiarugi VP, Israel MA: Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res 56: 2697–2702, 1996

    PubMed  CAS  Google Scholar 

  53. Barba D, Hardin J, Sadelain M, Gage FH: Development of antitumor immunity following thymidine kinase-mediated killing of experimental brain tumors. Proc Natl Acad Sci USA 91: 4348–4352, 1994

    Article  PubMed  CAS  Google Scholar 

  54. Bi W, Kim YG, Feliciano ES, et al: An HSVtk-mediated local and distant antitumor bystander effect in tumors of head and neck origin in athymic mice. Cancer Gene Ther 4: 246–252, 1997

    PubMed  CAS  Google Scholar 

  55. Park JY, Elshami AA, Amin K, et al: Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy. Gene Ther 4: 909–917, 1997

    Article  PubMed  CAS  Google Scholar 

  56. Robe PA, Princen F, Martin D, et al: Pharmacological modulation of the bystander effect in the herpes simplex virus thymidine kinase/ganciclovir gene therapy system: effects of dibutyryl adenosine 3’,5’-cyclic monophosphate, alpha-glycyrrhetinic acid, and cytosine arabinoside. Biochem Pharmacol 60: 241–249, 2000

    Article  PubMed  CAS  Google Scholar 

  57. Kunishige I, Samejima Y, Moriyama A, et al: cAMP stimulates the bystander effect in suicide gene therapy of human choriocarcinoma. Anticancer Res 18: 3411–3419, 1998

    PubMed  CAS  Google Scholar 

  58. Mesnil M, Piccoli C, Tiraby G, et al: Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc Natl Acad Sci USA 93: 1831–1835, 1996

    Article  PubMed  CAS  Google Scholar 

  59. Duflot-Dancer A, Piccoli C, Rolland A, et al: Long-term connexin-mediated bystander effect in highly tumorigenic human cells in vivo in herpes simplex virus thymidine kinase/ganciclovir gene therapy. Gene Ther 5: 1372–1378, 1998

    Article  PubMed  CAS  Google Scholar 

  60. Sanson M, Marcaud V, Robin E, et al: Connexin 43-mediated bystander effect in two rat glioma cell models. Cancer Gene Ther 9: 149–155, 2002

    Article  PubMed  CAS  Google Scholar 

  61. Walling HW, Swarthout JT, Culver KW: Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes. Cancer Gene Ther 7: 187–196, 2000

    Article  PubMed  CAS  Google Scholar 

  62. Liu CS, Kong B, Xia HH, et al: VP22 enhanced intercellular trafficking of HSV thymidine kinase reduced the level of ganciclovir needed to cause suicide cell death. J Gene Med 3: 145–152, 2001

    Article  PubMed  CAS  Google Scholar 

  63. Hyer ML, Sudarshan S, Schwartz DA, et al: Quantification and characterization of the bystander effect in prostate cancer cells following adenovirus-mediated FasL expression. Cancer Gene Ther 10: 330–339, 2003

    Article  PubMed  CAS  Google Scholar 

  64. Seol JY, Park KH, Hwang CI, et al: Adenovirus-TRAIL can overcome TRAIL resistance and induce a bystander effect. Cancer Gene Ther 10: 540–548, 2003

    Article  PubMed  CAS  Google Scholar 

  65. Park SY, Seol JW, Lee YJ, et al: IFN-gamma enhances TRAILinduced apoptosis through IRF-1. Eur J Biochem 271: 4222–4228, 2004

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Molecular and Tumor Radiobiology, National Research Institute for Radiobiology and Radiohygiene, Anna u. 5., H-1221, Budapest, Hungary

    Katalin Lumniczky & Géza Sáfrány

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  1. Katalin Lumniczky
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  2. Géza Sáfrány
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Correspondence to Géza Sáfrány.

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Lumniczky, K., Sáfrány, G. Cancer gene therapy: Combination with radiation therapy and the role of bystander cell killing in the anti-tumor effect. Pathol. Oncol. Res. 12, 118–124 (2006). https://doi.org/10.1007/BF02893457

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