Abstract
Many types of cancer become resistant to current chemotherapeutic and radiotherapeutic interventions. To overcome this situation, applications of gene therapy may be promising. Whereas many types of transgene, such as tumor suppressor genes and cytokine genes, have potential tumoricidal effects (1), genes encoding for prodrug-activating enzymes, the so-called suicide genes, are very promising and have been intensively investigated (2,3). The basic principle underlying suicide gene systems is intracellular conversion of a relatively nontoxic prodrug to a highly toxic drug by an enzyme that is not normally present in the cell. Viruses, bacteria, and fungi often use unique metabolic pathways not used by mammalian cells and contain genes for enzymes that perform metabolic conversions that mammalian cells do not perform. Such distinctive enzymes have often been the targets of drugs developed for the treatment of infections. Such agents are lethal for the infecting microbes but do not harm the host cell because it lacks the enzyme system necessary to activate the drug (4,5). After genetically modifying tumor cells to express such enzymes, systemic prodrug treatment leads to the selective killing of tumor cells. The effectiveness of suicide gene-prodrug strategies against cancer has been shown in animal models carrying various types of cancer, and the transfer of a suicide gene into tumor cells followed by administration of the appropriate prodrug is currently being used in various clinical gene therapy trials for the treatment of cancer (6–10).
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References
Roth, J. A. and Cristiano, R. J. (1997) Gene therapy for cancer: what have we done and where are we going? J. Natl. Cancer Inst. 89, 21–39.
Connors, T. A. (1995) The choice of prodrugs for gene directed enzyme prodrug therapy on cancer. Gene Ther. 2, 702–709.
Aghi, M., Hochberg, F., and Breakefield, X. O. (2000) Prodrug activation enzymes in cancer gene therapy. J. Gene Med. 2, 148–164.
Mullen, C. A. (1994) Metabolic suicide genes in gene therapy. Pharmacol. Ther. 63, 199–207.
Moolten, F. L. (1994) Drug sensitivity (“suicide”) genes for selective cancer chemotherapy. Cancer Gene Ther. 1, 279–287.
Crystal, R. G. (1995) Transfer of genes to humans: early lessons and obstacles to success. Science 270, 404–410.
Ross, G. (1996) Gene therapy in the United States: a five-year status report. Hum. Gene Ther. 7, 1781–1790.
Marcel, T. and Grausz, J.D. (1996) The TMC worldwide gene therapy enrollment report (June 1996). Hum. Gene Ther. 7, 2025–2046.
Smythe, W. R. (2000) Prodrug/drug sensitivity gene therapy: current status. Curr. Oncol. Rep. 2, 17–22.
Human gene marker/therapy clinical protocols. (2000) Hum. Gene Ther. 11, 2543–2617.
Elion, G. B., Furman, P. A., Fyfe, J. A., de Miranda, P., Beauchamp, L., and Schaeffer, H. J. (1977) Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc. Natl. Acad. Sci. USA 74, 5716–5720.
Field, A. K., Davies, M. E., DeWitt, C., et al. (1983) 9-[2-Hydroxyl-1-(hydroxymethyl) ethoxy] methyl guanine: a selective inhibitor of herpes group virus replication. Proc. Natl. Acad. Sci. USA 80, 4139–4143.
Matthews, T. and Boehme, R. (1988) Antiviral activity and mechanism of action of ganciclovir. Rev. Infect. Dis. 10(Suppl. 3), 490–494.
Balzarini, J., Bohman, C., and De Clercq, E. (1993) Differential mechanism of cytostatic effect of (E)-5-(2-bromovinyl)-2′-deoxyuridine, 9-(1,3-dihydroxy-2-propoxymethyl) guanine, and other antiherpetic drugs on tumor cells transfected by the thymidine kinase gene of herpes simplex virus type 1 or type 2. J. Biol. Chem. 268, 6332–6337.
Kuriyama, S., Nakatani, T., Masui, K., et al. (1996) Evaluation of prodrugs ability to induce effective ablation of cells transduced with viral thymidine kinase gene. Anticancer Res. 16, 2623–2628.
Danielsen, S., Kilstrup, M., Barilla, K., Jochimsen, B., and Neuhard, J (1992) Characterization of the Escherichia coli codBA operon encoding cytosine permease and cytosine deaminase. Mol. Microbiol. 6, 1335–1344.
Mullen, C. A., Kilstrup, M., and Blaese, R. M. (1992) Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a new negative selection system. Proc. Natl. Acad. Sci. USA 89, 33–37.
Bi, W. L., Parysek, L. M., Warnick, R., and Stambrook, P. J. (1993) In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSVtk retroviral gene therapy. Hum. Gene Ther. 4, 725–731.
Mesnil, M., Piccoli, C., Tiraby, G., Willecke, K., and Yamasaki, H. (1996) Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc. Natl. Acad. Sci. USA 93, 1831–1835.
Elshami, A. A., Saavedra, A., Zhang, H., et al. (1996) Gap junctions play a role in the “bystander effect” of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther. 3, 85–92.
Ishii-Morita, H., Agbaria, R., Mullen, C. A., et al. (1997) Mechanism of “bystander effect” killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment. Gene Ther. 4, 244–251.
Freeman, S. M., Abboud, C. N., Whartenby, K. A., et al. (1993) The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 53, 5274–5283.
Samejima, Y. and Meruelo, D. (1995) “Bystander killing” induces apoptosis and is inhibited by forskolin. Gene Ther. 2, 50–58.
Hamel, W., Magnelli, L., Chiarogi, V. P., and Israel, M. A. (1996) Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res. 56, 2696–2702.
Hirschowitz, E. A., Ohwada, A., Pascal, W. R., Russi, T. J., and Crystal, R. G. (1995) In vivo adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine. Hum. Gene Ther. 6, 1055–1063.
Dong, Y., Wen, P., Manome, Y., et al. (1996) In vivo replication-deficient adenovirus vector-mediated transduction of the cytosine deaminase gene sensitizes glioma cells to 5-fluorocytosine. Hum. Gene Ther. 7, 713–720.
Kuriyama, S., Mitoro, A., Yamazaki, M., et al. (1999) Comparison of gene therapy with the herpes simplex virus thymidine kinase gene and the bacterial cytosine deaminase gene for the treatment of hepatocellular carcinoma. Scand. J. Gastroenterol. 34, 1033–1041.
Kuriyama, S., Masui, K., Sakamoto, T., et al. (1995) Bacterial cytosine deaminase suicide gene transduction renders hepatocellular carcinoma sensitive to the prodrug 5-fluorocytosine. Int. Hepatol. Commun. 4, 72–79.
Kuriyama, S., Masui, K., Sakamoto, T., et al. (1998) Bystander effect caused by cytosine deaminase gene and 5-fluorocytosine in vitro is substantially mediated by generated 5-fluorouracil. Anticancer Res. 18, 3399–3406.
Ram, Z., Walbridge, S., Heiss, J. D., Culver, K. W., Blaese, R. M., and Oldfield, E. H. (1994) In vivo transfer of the human interleukin-2 gene: negative tumoricidal results in experimental brain tumors. J. Neurosurg. 80, 535–540.
Dilber, M. S., Abedi, M. R., Christensson, B., et al. (1997) Gap junctions promote the bystander effect of herpes simplex virus thymidine kinase in vivo. Cancer Res. 57, 1523–1528.
Kuriyama, S., Sakamoto, T., Masui, K., et al. (1997) Tissue-specific expression of HSV-TK gene can induce efficient antitumor effect and protective immunity to wild-type hepatocellular carcinoma. Int. J. Cancer 71, 470–475.
Kuriyama, S., Kikukawa, M., Masui, K., et al. (1999) Cancer gene therapy with HSV-TK/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo. Int. J. Cancer 83, 374–380.
Kuriyama, S., Tsujinoue, H., Nakatani, T., et al. (2000) Gene therapy for hepatocellular carcinoma, in Molecular Target for Hematological Malignancies and Cancer (Niho, Y., ed.), Kyushu University Press, Fukuoka, Japan, pp. 29–37.
Kuriyama, S., Yoshikawa, M., Tominaga, K., et al. (1993) Gene therapy for the treatment of hepatoma by retroviral-mediated gene transfer of the herpes simplex virus thymidine kinase. Int. Hepatol. Commun. 1, 253–259.
Kuriyama, S., Nakatani, T., Masui, K., et al. (1995) Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma. Hepatology 22, 1838–1846.
Holder, J. W., Elmore, E., and Barrett, J. C. (1993) Gap junction function and cancer. Cancer Res. 53, 3475–3485.
Caruso, M., Panis, Y., Gagandeep, S., Houssin, D., Salzmann, J. L., and Klatzmann, D. (1993) Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc. Natl. Acad. Sci. USA 90, 7024–7028.
Vile, R. G., Nelson, J. A., Castleden, S., Chong, H., and Hart, I. R. (1994) Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. Cancer Res. 54, 6228–6234.
Barba, D., Hardin, J., Sadelain, M., and Gage, F. H. (1994) Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors. Proc. Natl. Acad. Sci. USA 91, 4348–4352
Gagandeep, S., Brew, R., Green, B., et al. (1996) Prodrug-activated gene therapy: involvement of an immunological component in the “bystander effect.” Cancer Gene Ther. 3, 83–88.
Kianmanesh, A. R., Perrin, H., Panis, Y., et al. (1997) A “distant” bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Hum. Gene Ther. 8, 1807–1814.
Freeman, S. M., Ramesh, R., and Marrogi, A. J. (1997) Immune system in suicide-gene therapy. Lancet 349, 2–3.
Yamamoto, S., Suzuki, S., Hoshino, A., Akimoto, M., and Shimada, T. (1997) Herpes simplex virus thymidine kinase/ganciclovir-mediated killing of tumor cell induces tumor-specific cytotoxic T cells in mice. Cancer Gene Ther. 4, 91–96.
Ramesh, R., Munshi, A., Abboud, C. N., Marrogi, A. J., and Freeman, S. M. (1996) Expression of costimulatory molecules: B7 and ICAM up-regulation after treatment with a suicide gene. Cancer Gene Ther. 3, 373–384.
Ramesh, R., Marrogi, A. J., Munshi, A., Abbound, C. N., and Freeman, S. M. (1996) In vivo analysis of the “bystander effect”: a cytokine cascade. Exp. Hematol. 24, 829–838.
Colombo, B. M., Benedetti, S., Ottolenghi, S., et al. (1995) The “bystander effect”: association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice. Hum. Gene Ther. 6, 763–772.
Mullen, C. A., Anderson, L., Woods, K., Nishino, M., and Petropoulos, D. (1998) Ganciclovir chemoablation of herpes thymidine kinase suicide gene-modified tumors produces tumor necrosis and induces systemic immune responses. Hum. Gene Ther. 9, 2019–2030.
Vile, R. G., Castleden, S., Marshall, J., Camplejohn, R., Upton, C., and Chong, H. (1997) Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoral cytokine expression. Int. J. Cancer 71, 267–274.
Seder, R. A. and Paul, W. E. (1994) Acquisition of lymphokine-producing phenotype by CD4+ T cells. Ann. Rev. Immunol. 12, 635–673.
Thompson, C. B. (1995) Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation. Cell 81, 979–982.
Felzmann, T., Ramsey, W. J., and Blaese, R. M. (1997) Characterization of the antitumor immune response generated by treatment of murine tumors with recombinant adenoviruses expressing HSVtk, IL-2, IL-6 or B7-1. Gene Ther. 4, 1322–1329.
Rogers, R. P., Ge, J.-Q., Holley-Guthrie, E., et al. (1996) Killing Epstein-Barr virus-positive B lymphocytes by gene therapy: comparing the efficacy of cytosine deaminase and herpes simplex virus thymidine kinase. Hum. Gene Ther. 7, 2235–2245.
Hall, S. J., Sanford, M. A., Atkinson, G., and Chen, S.-H. (1998) Induction of potent antitumor natural killer cell activity by herpes simplex virus-thymidine kinase and ganciclovir therapy in an orthotopic mouse model of prostate cancer. Cancer Res. 58, 3221–3225.
Tapscott, S. J., Miller, A. D., Olson, J. M., Berger, M. S., Groudine, M., and Spence, A. M. (1994) Gene therapy of rat 9L gliosarcoma tumors by transduction with selectable genes does not require drug selection. Proc. Natl. Acad. Sci. USA 91, 8185–8189.
Freeman, S. M., Ramesh, R., Shastri, M., Munshi, A., Jensen, A. K., and Marrogi, A. J. (1995) The role of cytokines in mediating the bystander effect using HSVtk xenogeneic cells. Cancer Lett. 92, 167–174.
Bi, W., Kim, Y. G., Feliciano, E. S., et al. (1997) 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.
Dziarski, R. (1984) Opposing effects of xid and nu mutations on proliferative and polyclonal antibody and autoantibody responses to peptidoglycan, LPS, protein A and PWM. Immunology 53, 563–574.
Fidler, I. J., Murray, J. L., and Kleinerman, E. S. (1991) Systemic activation of macrophages by liposomes containing immunomodulators, in Biologic Therapy of Cancer: Principles and Practice (Hellman, S., DeVita, V. T. and Jr., Rosenberg, S. A., eds.), Lippincott, Philadelphia, pp. 730–742.
Nishiyama, T., Kawamura, Y., Kawamoto, K., et al. (1985) Antineoplastic effects in rats of 5-fluorocytosine in combination with cytosine deaminase capsules. Cancer Res. 45, 1753–1761.
Cao, G., Kuriyama, S., Gao, J., et al. (1999) Effective and safe gene therapy for colorectal carcinoma using the cytosine deaminase gene directed by the carcinoembryonic antigen promoter. Gene Ther. 6, 83–90.
Cao, G., Kuriyama, S., Cui, L., et al. (1999) Analysis of the human carcinoembryonic antigen promoter core region in colorectal carcinoma-selective cytosine deaminase gene therapy. Cancer Gene Ther. 6, 572–580.
Cao, G., Kuriyama, S., Gao, J., et al. (1999) In vivo gene transfer of a suicide gene under the transcriptional control of the carcinoembryonic antigen promoter results in bone marrow transduction but can avoid bone marrow suppression. Int. J. Oncol. 15, 107–112.
Mullen, C. A., Coale, M. M., Lowe, R., and Blaese, R. M. (1994) Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor. Cancer Res. 54, 1503–1506.
Huber, B. E., Austin, E. A., Richards, C. A., Davis, S. T., and Good, S. S. (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.
Rowley, S., Lindauer, M., Gebert, J. F., et al. (1996) Cytosine deaminase gene as a potential tool for the genetic therapy of colorectal cancer. J. Surg. Oncol. 61, 42–48.
Kuriyama, S., Kikukawa, M., Masui, K., et al. (1999) Cytosine deaminase/5-fluorocytosine gene therapy can induce efficient anti-tumor effects and protective immunity in immuno-competent mice but not in athymic nude mice. Int. J. Cancer 81, 592–597.
Kuriyama, S., Sakamoto, T., Kikukawa, M., et al. (1998) Expression of a retrovirally transduced gene under control of an internal housekeeping gene promoter does not persist due to methylation and is restored partially by 5-azacytidine treatment. Gene Ther. 5, 1299–1305.
Kuriyama, S., Masui, K., Kikukawa, M., et al. (1999) Complete cure of established murine hepatocellular carcinoma is achievable by repeated injections of retroviruses carrying the herpes simplex virus thymidine kinase gene. Gene Ther. 6, 525–533.
Uckert, W., Kammertöns, T., Haack, K., et al. (1998) Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo. Hum. Gene Ther. 9, 855–865.
Consalvo, M., Mullen, C. A., Modesti, A., et al. (1995) 5-Fluorocytosine-induced eradication of murine adenocarcinomas engineered to express the cytosine deaminase suicide gene requires host immune competence and leaves an efficient memory. J. Immunol. 154, 5302–5312.
Pierrefite-Carle, V., Baqué, P., Gavelli, A., et al. (1999) Cytosine deaminase/5-fluorocytosine-based vaccination against liver tumors: evidence of distant bystander effect. J. Natl. Cancer Inst. 91, 2014–2019.
Haack, K., Linnebacher, M., Eisold, S., Zöller, M., von mnKnebel Doeberitz, M., and Gebert, J. (2000) Induction of protective immunity against syngeneic rat cancer cells by expression of the cytosine deaminase suicide gene. Cancer Gene Ther. 7, 1357–1364.
Roszman, T., Elliott, L., and Brooks, W. (1991) Modulation of T-cell function by gliomas. Immunol. Today 12, 370–374.
Chen, S.-H., Kosai, K., Xu, B. et al. (1996) Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival. Cancer Res. 56, 3758–3762.
Mullen, C. A., Petropoulos, D., and Lowe, R. M. (1996) Treatment of microscopic pulmonary metastases with recombinant autologous tumor vaccine expressing interleukin 6 and Escherichia coli cytosine deaminase suicide genes. Cancer Res. 56, 1361–1366.
O’Malley, B. W., Cope, K. A., Chen, S. H., Li, D., Schwarta, M. R., and Woo, S. L. (1996) Combination gene therapy for oral cancer in a murine model. Cancer Res. 56, 1737–1741.
O’Malley, B. W., Jr., Sewell, D. A., Li, D., et al. (1997) The role of interleukin-2 in combination adenovirus gene therapy for head and neck cancer. Mol. Endocrinol. 11, 667–673.
Coll, J.-L., Mesnil, M., Lefebvre, M.-F., Lancon, A., and Favrot, M. C. (1997) Long-term survival of immunocompetent rats with intraperitoneal colon carcinoma tumors using herpes simplex thymidine kinase/ganciclovir and IL-2 treatments. Gene Ther. 4, 1160–1166.
Santodonato, L., Ferrantini, M., Gabriele, L., et al. (1996) Cure of mice established metastatic friend leukemia cell tumors by a combined therapy with tumor cells expressing both interferon-α1 and herpes simplex thymidine kinase followed by ganciclovir. Hum. Gene Ther. 7, 1–10.
Santodonato, L., D’Agostino, G., Santini, S. M., et al. (1997) Local and systemic antitumor response after combined therapy of mouse metastatic tumors with tumor cells expressing IFN-α and HSVtk: perspectives for the generation of cancer vaccines. Gene Ther. 4, 1246–1255.
Benedetti, S., Dimeco, F., Pollo, B., et al. (1997) Limited efficacy of the HSV-TK/GCV system for gene therapy of malignant gliomas and perspectives for the combined transduction of the interleukin-4 gene. Hum. Gene Ther. 8, 1345–1353.
Nanni, P., De Giovanni, C., Nicoletti, G., et al. (1998) The immune response elicited by mammary adenocarcinoma cells transduced with interferon-γ and cytosine deaminase genes cures lung metastases by parental cells. Hum. Gene Ther. 9, 217–224.
Cao, X., Ju, D. W., Tao, Q., et al. (1998) Adenovirus-mediated GM-CSF gene and cytosine deaminase gene transfer followed by 5-fluorocytosine administration elicit more potent antitumor response in tumor-bearing mice. Gene Ther. 5, 1130–1136.
Okada, H., Giezeman-Smits, K. M., Tahara, H., et al. (1999) Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine. Gene Ther. 6, 219–226.
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.
Miller, P. W., Sharma, S., Stolina, M., et al. (1998) Dendritic cells augment granulocyte-macrophage colony-stimulating factor (GM-CSF)/herpes simplex virus thymidine kinase-mediated gene therapy of lung cancer. Cancer Gene Ther. 5, 380–389.
Ju, D. W., Tao, Q., Cheng, D. S., et al. (2000) Adenovirus-mediated lymphotactin gene transfer improves therapeutic efficacy of cytosine deaminase suicide gene therapy in established murine colon carcinoma. Gene Ther. 7, 329–338.
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Kuriyama, S., Tsujinoue, H., Yoshiji, H. (2004). Immune Response to Suicide Gene Therapy. In: Springer, C.J. (eds) Suicide Gene Therapy. Methods in Molecular Medicine™, vol 90. Humana Press. https://doi.org/10.1385/1-59259-429-8:353
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