Skip to main content
Log in

Introduction to the background, principles, and state of the art in suicide gene therapy

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Gene therapy is defined as a technology that aims to modify the genetic component of cells to gain therapeutic benefits. Suicide gene therapy (or gene-directed enzyme prodrug therapy [GDEPT]) is a two-step treatment for cancer (especially, solid tumors). In the first step, a gene for a foreign enzyme is delivered to the tumor by a vector. Following the expression of the foreign enzyme, a prodrug is administered during the second step, which is selectively activated in the tumor. This article discusses the principles and the theoretical background of GDEPT. A special emphasis is put on enzyme/prodrug systems developed for GDEPT, the design of prodrugs and the kinetic of their activation, the types and the mechanisms of bystander effect and its immunological implications. The possible strategies to improve GDEPT are also discussed.

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

Access this article

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. Marais, R., Spooner, R. A., Light, Y., Martin, J., and Springer, C. J. (1996) Gene-directed enzyme prodrug therapy with a mustard prodrug/carboxypeptidase G2 combination. Cancer Res. 56, 4735–4742.

    PubMed  CAS  Google Scholar 

  2. Bridgewater, G., Springer, C. J., Knox, R., Minton, N., Michael, P., and Collins, M. (1995) Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB1954. Eur. J. Cancer 31A, 2362–2370.

    Article  PubMed  CAS  Google Scholar 

  3. Huber, B. E., Richards, C. A., and Austin, E. A. (1995) VDEPT; an enzyme/prodrug gene therapy approach for the treatment of metastatic colorectal cancer. Adv. Drug Delivery Rev. 17, 279–292.

    Article  CAS  Google Scholar 

  4. Eaton, J. L., Perry, M. J. A., Todryk, S. M., et al. (2001) Genetic prodrug activation therapy (GPAT) in two rat prostate models generates an immune bystander effect and can be monitored by magnetic resonance techniques. Gene Ther. 8, 557–567.

    Article  PubMed  CAS  Google Scholar 

  5. Hermiston, T. (2000) Gene-delivery from replication-selective viruses: arming guided missiles in the war against cancer. J. Clin. Invest. 105, 1169–1172.

    PubMed  CAS  Google Scholar 

  6. Roth, J. A. and Cristiano, R. G. (1997) Gene therapy for cancer: what have we done and where are we going? J. Natl. Cancer Inst. 89, 21–30.

    Article  PubMed  CAS  Google Scholar 

  7. Niculescu-Duvaz, I., Spooner, R., Marais, R., and Springer, C. J. (1998) Gene-directed enzyme prodrug therapy. Bioconj. Chem. 9, 4–22.

    Article  CAS  Google Scholar 

  8. Springer, C. J. and Niculescu-Duvaz, I. (1999) Patent property of prodrug involving gene therapy (1996–1999). Exp. Opin. Ther. Patents 9, 1381–1388.

    Article  CAS  Google Scholar 

  9. Bilbao, G., Contreras, J. L., Gómez-Navarro, J., and Curiel, D. T. (1998) Improving adenoviral vectors for cancer gene therapy. Tumor Target. 3, 59–79.

    CAS  Google Scholar 

  10. Nguyen, J. T., Wu, P., Clouse, M. E., Hlatky, L., and Terwilliger, E. F. (1998) Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor stratergy. Cancer Res. 58, 5673–5677.

    PubMed  CAS  Google Scholar 

  11. Robbins, P. D. and Ghivizzani, S. C. (1998) Viral vectors for gene therapy. Pharm. Ther. 80, 35–47.

    Article  CAS  Google Scholar 

  12. Zhang, W. W. (1999) Development and application of adenoviral vectors for gene therapy of cancer. Cancer Gene Ther. 7, 113–138.

    Article  CAS  Google Scholar 

  13. Curiel, D. T., Gerritsen, W. R. and Krul, M. R. (2000) Progress in cancer gene therapy. Cancer Gene Ther. 7, 1197–1199.

    Article  PubMed  CAS  Google Scholar 

  14. Roth, M. G. and Curiel, D. T. (2000) Toward the optimal vector for prostate cancer gene therapy; a CaPCURE meeting report. Cancer Gene Ther. 7, 1507–1510.

    Article  CAS  Google Scholar 

  15. Kirn, D. (2001) Clinical research results with dI 1520 (ONYX-015), a replication selective adenovirus for the treatment of cancer: what have we learned? Gene Ther. 8, 89–98.

    Article  PubMed  CAS  Google Scholar 

  16. Miller, A. D. (1998) Cationic liposomes for gene therapy. Angew. Chem. Int. Ed. 37, 1768–1785.

    Article  Google Scholar 

  17. Schatzlein, A. G. (2001) Non-viral vectors in cancer gene therapy: principles and progress. Anti-Cancer Drug Des. 12, 275–304.

    Article  CAS  Google Scholar 

  18. Springer, C. J. and Niculescu-Duvaz, I. (2000) Prodrug-activating systems in suicide gene therapy. J. Clin. Investig. 105, 1161–1167.

    PubMed  CAS  Google Scholar 

  19. Encell, L. P., Landis, D. M. and Loeb, L. A. (1999) Improving enzymes for gene therapy. Nature Biotechnol. 17, 143–147.

    Article  CAS  Google Scholar 

  20. Mesnil, M. and Yamasachi, H. (2000) Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communications. Cancer Res. 60, 3989–3999.

    PubMed  CAS  Google Scholar 

  21. Denny, W. A. and Wilson, W. R. (1998) The design of selectively-activated anti-cancer prodrugs for use in antibody-directed and gene-directed enzyme prodrugs therapies. J. Pharm. Pharmacol. 50, 387–394.

    PubMed  CAS  Google Scholar 

  22. Niculescu-Duvaz, J., Friedlos, F., Niculescu-Duvaz, D., Davies, L., and Springer, C. J. (1999) Prodrugs for antibody- and gene-directed enzyme prodrug therapies (ADEPT and GDEPT). Anticancer Drug Des. 14, 517–538.

    PubMed  CAS  Google Scholar 

  23. Springer, C. J. and Niculescu-Duvaz, I. (2002) Genedirected enzyme prodrug therapy. In: Anticancer Drug Development (Baguley, B., ed.). Academic, New York, pp. 137–135.

    Google Scholar 

  24. Marais, R., Spooner, R. A., Stribbling, S. M., Light, Y., Martin, J., and Springer, C. J. (1997) A cell surface tethered enzyme improves efficiency in gene-directed enzyme prodrug therapy. Nature Biotechnol. 15, 1373–1377.

    Article  CAS  Google Scholar 

  25. Loimas, S., Toppinen, M.-R., Visakorpi, T., Janne, J., and Wahlfors, D. (2001) Human prostate carcinoma cells as target for herpes simplex virus thymidine kinase-mediated suicide gene therapy. Cancer Gene Ther. 8, 137–144.

    Article  PubMed  CAS  Google Scholar 

  26. Jones, R. K., Pope, I. M., Kinsella, A. R., Watson, A. J. M., and Christmas, S. E. (2000) Combined suicide and granulocyte-macrophage colony-stimulating factor gene therapy induces complete tumor regression and generates antitumor immunity. Cancer Gene Ther. 7, 1519–1528.

    Article  PubMed  CAS  Google Scholar 

  27. Walling, H. W., Swarthout, G. T., and Culver, K. W. (2000) 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.

    Article  PubMed  CAS  Google Scholar 

  28. Howard, B. D., Boenicke, L., Schniewind, B., Henne-Bruns, D., and Kalthoff, H. (2000) Transduction of human pancreatic tumor cells with vesicular stomatitis virus G-pseudotyped retroviral vectors containing a herpes simplex virus thymidine kinase mutant gene enhances bystander effects and sensitivity to ganciclovir. Cancer Gene Ther. 7, 927–938.

    Article  PubMed  CAS  Google Scholar 

  29. Sandmair, A.-M., Turunen, M., Tyynela, K., et al. (2000) Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C glioma model: effect of the percentage of thymidine kinase-positive glioma cells on treatment effect, survival time, and tissues reactions. Cancer Gene Ther. 7, 413–421.

    Article  PubMed  CAS  Google Scholar 

  30. Kruse, C. A., Lamb, C., Hogan, S., Russell Smiley, W., Kleinschmidt-DeMasters, B., and Burrows, F. G. (2000) Purified herpes simplex thymidine kinase retroviral particles. II. Influence of clinical parameters and bystander killing mechanisms. Cancer Gene Ther. 7, 118–127.

    Article  PubMed  CAS  Google Scholar 

  31. Hamel, W., Zirkel, D., Mehdorn, H. M., Westphal, M., and Israel, M. A. (2001) E-5-(2-bromovinyl)-2′-deoxyuridine potentiates ganciclovir-mediated cytotoxicity on herpes simplex virus-thymidine kinase-expressing cells. Cancer Gene Ther. 8, 388–396.

    Article  PubMed  CAS  Google Scholar 

  32. Grignet-Debrus, C., Cool, V., Baudson, N., et al. (2000) Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-β-d-arabinofuranosyluracil (BVaraU), against tumor cells expressing either the Varicella zoster or the Herpes simplex virus thymidine kinase. Cancer Gene Ther. 7, 215–223.

    Article  PubMed  CAS  Google Scholar 

  33. Erbs, P., Regulier, E., Kintz, J., et al. (2000) In vivo cancer gene therapy by adenovirus-mediated transfer of a bifunctional yeast cytosine deaminase/uracil phosphoribosyltransferase fusion gene. Cancer Res. 60, 3813–3822.

    PubMed  CAS  Google Scholar 

  34. Bentires-Alj, M., Helin, A.-C., Lechanteur, C., et al. (2000) Cytosine deaminase suicide gene therapy for peritoneal carcinomatosis. Cancer Gene Ther. 7, 20–26.

    Article  PubMed  CAS  Google Scholar 

  35. Spooner, R. A., Maycroft, K. A., Paterson, H., Friedlos, F., Springer, C. J., and Marais, R. (2001) Appropriate subcellular location of prodrug-activating enzymes has important consequences for suicide gene therapy. Int. J. Cancer 93, 123–130.

    Article  PubMed  CAS  Google Scholar 

  36. Westphal, E.-M., Ge, J., Catchpole, J. R., Ford, M., and Kennedy, S. C. (2000) The nitroreductase/CB1954 combination in Epstein-Barr virus-positive B cell lines: induction of bystander killing in vitro and in vivo. Cancer Gene Ther. 7, 97–106.

    Article  PubMed  CAS  Google Scholar 

  37. Tatcher, N. J., Edwards, R. J., Lemoine, N. R., Doehmer, J., and Davies, D. S. (2000) The potential of acetaminophen as a prodrug in gene-directed enzyme therapy. Cancer Gene Ther. 7, 521–525.

    Article  CAS  Google Scholar 

  38. Heine, D., Muller, R., and Brusselbach, S. (2001) Cell surface display of a lysosomal enzyme for extra-cellular gene-directed enzyme prodrug therapy. Gene Ther. 8, 1005–1010.

    Article  PubMed  CAS  Google Scholar 

  39. Hamstra, D. A., Page, M., Maybaum, J., and Rehemtulla, A. (2000) Expression of endogenously activated secreted or cell surface carboxypeptidase A sensitizes tumor cells to methotrexate-_-peptide prodrugs. Cancer Res. 60, 657–665.

    PubMed  CAS  Google Scholar 

  40. Stribbling, S. M., Friedlos, F., Martin, J., et al. (2000) Regressions of established breast cancer xenografts by carboxypeptidase G2 suicide gene therapy and the prodrug CMDA are due to a bystander effect. Hum. Gene Ther. 11, 285–292.

    Article  PubMed  CAS  Google Scholar 

  41. Greco, O., Folkes, L. K., Wardman, P., Tozer, G. M., and Dachs, G. U. (2000) Development of a novel enzyme/prodrug combination for gene therapy of cancer: horseradish per-oxidase/indole-3-acetic acid. Cancer Gene Ther. 7, 1414–1420.

    Article  PubMed  CAS  Google Scholar 

  42. Simonova, M., Wall, A., Weissleder, R., and Bogdanov, A. (2000). Tyrosinase mutants are capable of prodrug activation in transfected non-melanotic cells. Cancer Res. 60, 6656–6662.

    PubMed  CAS  Google Scholar 

  43. Kawamura, K., Tasaki, K., Hamada, H., Takenaga, K., Sakiyama, S., and Tagawa, M. (2000) Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity. Cancer Gene Ther. 7, 637–643.

    Article  PubMed  CAS  Google Scholar 

  44. Cuq, P., Rouquet, C., Evrard, A., Ciccolini, J., Vian, L., and Cano, J.-P. (2001) Fluoropyrimidine sensitivity of human MCF-7 breast cancer cells stably transfected with human uridine phosphorylase. Br. J. Cancer 84, 1677–1680.

    Article  PubMed  CAS  Google Scholar 

  45. Weyel, D., Sedlacek, H. H., Muller, R., and Brusselbach, S. (2000) Secreted human_-glucuronidase: a novel tool for gene-directed enzyme prodrug therapy. Gene Ther. 7, 224–231.

    Article  PubMed  CAS  Google Scholar 

  46. Black, M. E., Newcomb, T. G., Wilson, H. M., and Loeb, L. A. (1996) Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc. Natl. Acad. Sci. USA 93, 3525–3529.

    Article  PubMed  CAS  Google Scholar 

  47. Black, M., Kokoris, M. S., and Sabo, P. (2001) Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Cancer Res. 61, 3022–3026.

    PubMed  CAS  Google Scholar 

  48. Blanche, F., Cameron, B., Couder, M., and Crouzet, J. (1997). Enzymes Combinations for Destroying Proliferative Cells, US Patent W09735024, Rhone-Poulenc Roerer, p. 1–61.

  49. Chen, L., Yu, L. J., and Waxman, D. J. (1997) Potentiation of cytochrome P450/cyclo-phosphamide-based cancer gene therapy by coexpression of the P450 reductase gene. Cancer Res. 57, 4830–4837.

    PubMed  CAS  Google Scholar 

  50. Kim, Y. G., Bi, W., Feliciano, E. S., Drake, R. R., and Stambrook, P. J. (2000) Ganciclovir-mediated cell killing and bystander effect is enhanced in cells with two copies of the herpes simplex virus thymidine kinase. Cancer Gene Ther. 7, 240–246.

    Article  PubMed  CAS  Google Scholar 

  51. Kammertoens, T., Gelbmann, W., Karle, P., et al. (2000) Combined chemotherapy of murine mammary tumors by local activation of the prodrug ifosfamide and 5-fluorocytosine. Cancer Gene Ther. 7, 629–636.

    Article  PubMed  CAS  Google Scholar 

  52. Rogulski, K. R., Wing, M. S., Paielli, D. L., Gilbert, J. D., Kim J. H., and Freytag, S. O. (2000) Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization. Hum. Gene Ther. 11, 67–76.

    Article  PubMed  CAS  Google Scholar 

  53. Toda, M., Martuza, R. L., and Rabkin, S. D. (2001) Combination suicide/cytokine gene therapy as adjuvants to a defective herpes simplex virus-based cancer vaccine. Gene Ther. 8, 332–339.

    Article  PubMed  CAS  Google Scholar 

  54. Candotti, F., Agbaria, R., Mullen, C. A., et al. (2000) Use of a herpes thymidine kinase/neomycin phosphotransferase chimeric gene for metabolic suicide gene therapy. Cancer Gene Ther. 7, 574–580.

    Article  PubMed  CAS  Google Scholar 

  55. Thust, R., Tomicic, M., Klocking, R., Voutilainen, N., Wutzler, P., and Kaina, B. (2000) Comparison of the genotoxic and apoptosis-inducing properties of ganciclovir and penciclovir in Chinese hamster ovary cells transfected with the thymidine kinase gene of herpes simplex virus-1: implication for gene therapeutic approaches. Cancer Gene Ther. 7, 107–117.

    Article  PubMed  CAS  Google Scholar 

  56. Hasegawa, Y., Nishiyama, Y., Imaizumi, K., et al. (2000) Avoidance of bone marrow suppression using A-5021 as a nucleoside analog for retrovirus-mediated herpes simplex virus type I thymidine kinase gene therapy. Cancer Gene Ther. 7, 557–562.

    Article  PubMed  CAS  Google Scholar 

  57. Hayashi, K., Hayashi, T., Sun, H.-D., and Takeda, I. (2000) Potentiation of ganciclovir toxicity in the herpes simplex virus thymidine kinase/ganciclovir administration system by ponicidin. Cancer Gene Ther. 7, 45–42.

    Article  PubMed  CAS  Google Scholar 

  58. McMasters, R. A., Wilbert, T. N., Jones, K. E., et al. (2000) Two-drug combinations that increase apoptosis and modulate Bak and Bcl-XL expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase. Cancer Gene Ther. 7, 563–573.

    Article  PubMed  CAS  Google Scholar 

  59. Rubsam, L. Z., Davidson, L., and Shewach, D. S. (1998) Superior cytotoxicity with gancyclovir compared with acyclovir and 1-β-d-arabinofuranosylthymine in herpes simplex virus-thymidine kinase-expressing-cells: a novel paradigm for cell killing. Cancer Res. 58, 3873–3882.

    PubMed  CAS  Google Scholar 

  60. Boucher, P. D., Ostruszka, L. J., and Shewach, D. S. (2000) Synergistic enhancement of herpes simplex virus thymidine kinase/ganciclovir mediated cytotoxicity by hydroxyurea. Cancer Res. 60, 1631–1636.

    PubMed  CAS  Google Scholar 

  61. Huang, Z., Raychowdhury, K., and Waxman, D. J. (2000) Impact of liver P450 reductase suppression on cyclophosphamide activation, pharmacokinetics and antitumoral activity in a cytochrom P450-based cancer gene therapy model. Cancer Gene Ther. 7, 1034–1042.

    Article  PubMed  CAS  Google Scholar 

  62. Jounaidi, Y. and Waxman, D. J. (2000) Combination of the bioreductive drug tirapazamine with the chemotherapeutic prodrug cyclophosphamide for P450/P450-reductase-based cancer gene therapy. Cancer Res. 60, 3761–3769.

    PubMed  CAS  Google Scholar 

  63. Kanyama, H., Tomita, N., Yamano, T., et al. (2001) Usefulness of repeated intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy. Cancer Res. 61, 14–18.

    PubMed  CAS  Google Scholar 

  64. Jounaidi, Y. and Waxman, D. J. (2001) Frequent, moderate dose cyclophosphamide administration improves the efficacy of cytochrome P-450/cytochrome P-450 reductase based cancer gene therapy. Cancer Res. 61, 4437–4444.

    PubMed  CAS  Google Scholar 

  65. Brust, D., Feden, J., Farnsworth, J., Amir, C., Broaddus, W. C., and Valerie, K. (2000) Radiosensitization of rat glioma with bromodeoxycytidine and adenovirus expressing herpes simplex virus-thymidine kinase delivered by slow, rate-controlled positive pressure infusion. Cancer Gene Ther. 7, 778–788.

    Article  PubMed  CAS  Google Scholar 

  66. Valerie, K., Brust, D., Farnsworth, J., et al. (2000) Improved radiosensitization of rat glioma cells with adenovirus-expressed mutant herpes simplex virusthymidine kinase in combination with acyclovir. Cancer Gene Ther. 7, 879–884.

    Article  PubMed  CAS  Google Scholar 

  67. Valerie, K., Hawkins, W., Farnsworth, J., et al. (2001) Substantially improved in vivo radiosensitization of rat glioma with mutant HSV-TK and acyclovir. Cancer Gene Ther. 8, 3–8.

    Article  PubMed  CAS  Google Scholar 

  68. Kawashita, Y., Ohtsuru, A., Kaneda, Y., et al. (1999) Regression of hepatocellular carcinoma in vitro and in vivo by radiosensitising suicide gene therapy under the inducible and spatial control of radiation. Hum. Gene Ther. 10, 1509–1519.

    Article  PubMed  CAS  Google Scholar 

  69. Nuyts, S., Theys, J., Landuyt, W., Van Mellaert, L., Lambin, P., and Anne, J. (2001) Increasing specificity of anti-tumour therapy: cytotoxic proteins delivery by non-pathogenic Clostridia under regulation of radio-induced promoter. Anticancer Res. 21, 857–862.

    PubMed  CAS  Google Scholar 

  70. Nuyts, S., Van Mellaert, L., Theys, J., Landuyt, W., Lambin, P., and Anne, J. (2001) The use of radiation-induced bacterial promoters in anaerobic-conditions: a means to control gene expression in Clostridium-mediated gene therapy. Radiat. Res. 155, 716–723.

    Article  PubMed  CAS  Google Scholar 

  71. Steffens, S., Frank, S., Fisher, U., et al. (2000) Enhanced green fluorescent proteinfusion proteins of herpes simplex virus type 1 thymidine kinase and cytochrome P450 4B1: applications for prodrug-activating gene therapy. Cancer Gene Ther. 7, 806–812.

    Article  PubMed  CAS  Google Scholar 

  72. Tjuvajev, J.G., Finn, R., Watanabe, K., et al. (1996) Noninvasive imaging of herpes simplex virus thymidine kinase gene transfer and expression: a potential method for monitoring clinical gene therapy. Cancer Res. 56, 4087–4095.

    PubMed  CAS  Google Scholar 

  73. Tjuvajev, J.G., Avril, N., Oku, T., et al. (1998) Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res. 58, 4333–4341.

    PubMed  CAS  Google Scholar 

  74. Yagoubi, S. S., Wu, L., Liang, Q., et al. (2001) Direct correlation between positron emission tomographic images of two reporter genes delivered by two distinct adenoviral vectors. Gene Ther. 8, 1072–1080.

    Article  CAS  Google Scholar 

  75. Brust, P., Haubner, R., Friedrich, A., et al. (2001) Comparison of [18F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene expression. Eur. J. Nucl. Med 28, 721–729.

    Article  PubMed  CAS  Google Scholar 

  76. Huber, B. E., Austin, E. A., Richards, C. A., Davis, S. T., and Good, S. S. (1994) Metabolism of 5-fluorocytidine 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.

    Article  PubMed  CAS  Google Scholar 

  77. Imaizumi, K., Hasegawa, Y., Kawabe, T., Emi, N., Saito, H., Naruse, K., and Shimokata, K. (1998) Bystander tumoricidal effect and gap junctional communication in lung cancercells. Am. J. Respir. Cell Mol. Biol. 18, 205–212.

    PubMed  CAS  Google Scholar 

  78. Wygoda, M. R., Wilson, M. R., Davis, M. A., Trosko, J. E., Rehemtulla, A., and Lawrence, T. S. (1997) Protection of herpes simplex virus thymidine kinase-transduced cells fromganciclovir-mediated cytotoxicityby bystander cells: the good Samaritan effect. Cancer Res. 57, 1699–1703.

    PubMed  CAS  Google Scholar 

  79. Andrade-Rosental, A. F., Rosental, R., Hopperstad, M. D., Wu, J. K., Vrionis, F. D., and Spray, D. C. (2000) Gap junctions: the “kiss of death” and the “kiss of life.” Brain Res. Rev. 32, 308–315.

    Article  Google Scholar 

  80. Touraine, R. L., Vahanian, N., Ramsey, W. J., and Blaese, R. M. (1998) Enhancement of the herpes simplex virus thymidine kinase/ganciclovir bystander effect and its antitumor efficacy in vivo by pharmacologic manipulation of gap junctions. Hum. Gene Ther. 9, 2385–2391.

    Article  PubMed  CAS  Google Scholar 

  81. Touraine, R. L., Ishii-Morita, H., Ramsey, W. J., and Blaese, R. M. (1998) The bystander effect in the HSVtk/ganciclovir system and its relation to gap junctional communication. Gene Ther. 5, 1705–1711.

    Article  PubMed  CAS  Google Scholar 

  82. Grignet-Debrus, C., Cool, V., Baudson, N., Velu, T., and Calberg-Bacq, C.-M. (2000) The role of cellular-and prodrug-associated factors in the bystander effect induced by the Varicella zoster and Herpes simplex viral thymidine kinases in suicide gene therapy. Cancer Gene Ther. 7, 1456–1468.

    Article  PubMed  CAS  Google Scholar 

  83. Kaneko, Y. and Tsukamoto, A. (1995) Gene therapy of hepatoma: bystander effects and non-apoptotic cell death induced by thymidine kinase and ganciclovir. Cancer Lett. 96, 105–110.

    Article  PubMed  CAS  Google Scholar 

  84. Ramesh, R., Marrogi, A. J., Munshi, A., Abboud, C. N., and Freeman, S. M. (1996) In vivo analysis of the “bystander effect”: a cytokine cascade. Exp. Hematol. 24, 829–838.

    PubMed  CAS  Google Scholar 

  85. Agard, C., Ligeza, C., Dupas, B., et al. (2001) Immune-dependent distant bystander effect after adenovirus-mediated suicide gene transfer in a rat model of liver colorectal metastasis. Cancer Gene Ther. 8, 128–136.

    Article  PubMed  CAS  Google Scholar 

  86. Majumdar, A., Zolotorev, A., Samuel, S., et al. (2000) Efficacy of herpes simplex virus thymidine kinase in combination with cytokine gene therapy in an experimental metastatic breast cancer model. Cancer Gene Ther. 7, 1086–1099.

    Article  PubMed  CAS  Google Scholar 

  87. Cao, X., Huang, X., Ju, D.W., Zhang, W.P., Hamada, H., and Wang, J. (2000) Enhanced antitumoral effect of adenovirus-mediated cytosine deaminase gene therapy by induction of antigen-presenting cells through stem cell factor/granulocyte macrophage colony-stimu-lating factor gene transfer. Cancer Gene Ther. 7, 177–186.

    Article  PubMed  CAS  Google Scholar 

  88. Rivas, C., Chandler, P., Melo, J. V., Simpson, E., and Apperley, J. F. (2000) Absence of in vitro or in vivo bystander effects in a thymidine kinase-transduced murine T-lymphoma. Cancer Gene Ther. 7, 954–962.

    Article  PubMed  CAS  Google Scholar 

  89. Karle, P., Renner, M., Salmons, B., and Gunzburg, W. H. (2001) Necrotic, rather than apoptotic death caused by cytochrome P450-activated ifosfamide. Cancer Gene Ther. 8, 220–230.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Caroline J. Springer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niculescu-Duvaz, I., Springer, C.J. Introduction to the background, principles, and state of the art in suicide gene therapy. Mol Biotechnol 30, 71–88 (2005). https://doi.org/10.1385/MB:30:1:071

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/MB:30:1:071

Index Entries

Navigation