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Cancer Gene Therapy pp 411–422Cite as

Suicide Gene Therapy

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 465))

Conclusions

Since conventional cancer treatments are not able to cure approximately 50% of cancers in patients, novel therapies must be developed. A number of different cancer gene therapy protocols are currently underway, including those using suicide genes. Gene therapy provides one approach by which tumors that are resistant to conventional agents may be treated. Inserting a suicide gene into tumor cells will lead to tumor cell death upon exposure to a prodrug, even in chemotherapy resistant tumor cells. One major limitation to using gene therapy for cancer is that modification of an entire tumor is not possible and untreated cells can grow back into tumors. However, the HSV-TK/GCV system has a critical advantage, since the gene-modified cells are toxic to nearby unmodified cells when exposed to the prodrug. This has been termed the “bystander effect”. Although the mechanism of this “bystander effect” is complex, the in vitro mechanism relies on transfer of toxic metabolites from gene-modified to unmodified cells, while the in vivo mechanism appears to be more complex and related to chemosensitization, hemorrhagic tumor necrosis, and activation of immune response.

Clinical trials are underway using the HSV-TK gene in localized tumors including ovarian cancer and brain tumors. To date, it appears that the HSV-TK suicide gene therapy clinical approach is relatively non-toxic and preliminary results show that some patients have achieved partial and complete clinical remission. Future studies will involve better systems to more efficiently and specifically modify the tumor with the suicide gene and focus on methods to enhance the immune aspect of the “bystander effect”.

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References

  • Austin, E.A., and Huber, B.E., A first step in the development of gene therapy for colorectal carcinoma: cloning, sequencing, and expression of escherichia coli cytosine deaminase. Mol Pharmacol, 1992. 43: p. 380–387.

    Google Scholar 

  • Barba, D., Hardin, J., Sadelain, M., and Gage, F.H., Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors. Proc Natl Acad Sci, 1994. 91: p. 4348–4352.

    CAS  PubMed  Google Scholar 

  • Bi, W.L., Parysek, L.M., Warnick, R., and Stambrook, P.J., In vitro evidence that metabolic cooperation is reponsible for the Bystander Effect observed with HSV tk retroviral gene therapy. Human Gene Therapy, 1993. 4: p. 725–731.

    CAS  PubMed  Google Scholar 

  • Bi, W., Kim, Y.G., Feliciano, E.S., Pavelic, L., Wilson, K.M., Pavelic, Z.P., and Stambrook, P.J., An HSVtk-mediated local and distant antitumor bystander effect in tumors of head and neck origin in athymic mice. Cancer Gene Therapy, 1997. 4(4): p. 246–252.

    CAS  PubMed  Google Scholar 

  • Boring, C.C., Squires, T.S., and Tong, T., Cancer statistics 1992. Ca. A Cancer Journal for Clinicians, 1992.42: p

    CAS  PubMed  Google Scholar 

  • Chen, S.H., Li Chen, X.H., Wang, Y., Kosai, K.I., Finegold, M.J., Rich, S.S., and Woo, S.L.C., Combination gene therapy for liver metastasis of colon carcioma in vivo. Proc Natl Acad Sci USA, 1995. 92(March): p. 2577–2581.

    CAS  PubMed  Google Scholar 

  • Chen, S.H., Kosai, K., Xu, B., Pham-Nguyen, K., Contant, C., Finegold, M.J., and Woo, S.L., Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival. Cancer Research, 1996. 56(16): p. 3758–3762.

    CAS  PubMed  Google Scholar 

  • Colombo, B.M., Benedetti, S., Ottolenghi, S., Mora, M., Pollo, B., Poli, G., and Finocchiaro, G., The “bystander effect”: association of U87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice. Human Gene Therapy, 1995. 6: p. 763–772.

    CAS  PubMed  Google Scholar 

  • Consalvo, M., Mullen, C.A., Modesti, A., Piero, M., Allione, A., Cavallo, F., Giovarelli, M., and Forni, G., 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, 1995. 154: p. 5302–5312.

    CAS  PubMed  Google Scholar 

  • Davidson, R.L, Kaufman, E.R., Crumpacker, C.S., and Schnipper, L.E., Inhibition of herpes simplex virus transformed and nontransformed cells by acycloguanosine: mechanisms of uptake and toxicity. Virology, 1981. 113: p. 9–19.

    CAS  PubMed  Google Scholar 

  • Elion, G.B., Furman, P.A., Fyfe, J.A., de Miranda, P., Beauchamp, L., and Schaeffer, H.J., Selectivity of action of an antiherpetic agent. 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci USA, 1977. 74: p. 5716–5720.

    CAS  PubMed  Google Scholar 

  • Elion, G.B., The chemotherapeutic exploitation of virus-specified enzymes. Adv Enzyme Regul, 1980. 18: p. 53–60.

    CAS  PubMed  Google Scholar 

  • Feldman, A.R., Kessler, L., Myers, M.H., and Naughton, M.D., The prevalence of cancer. Estimates based on the Connecticut Tumor Registry. N Engl J Med, 1986. 315: p. 1394–1397.

    CAS  PubMed  Google Scholar 

  • Field, A.K., Davies, M.E., DeWitt, C., Perry, H.D., Liou, R., Germershausen, J., Karkas, J.D., Ashton, W.T., Johnston, D.B.R., and Tolman, R.L., Selectivity of action of an antiherpetic agent. 9-[2-hydroxy-1-(hydroxy-methyl) ethoxy] methyl guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci USA, 1983. 80: p. 4139–4143.

    CAS  PubMed  Google Scholar 

  • Freeman, S.M., Whartenby, K.A., Keoplin, D.S., Moolten, F.L., Abboud, C.N., and Abraham, C.N., Tumor regression when a fraction of the tumor mass contains the HSV-TV gene. J Cell Biochem, 1992. 16F: p. 47.

    Google Scholar 

  • Freeman, S.M., McCune, C., Angel, C., Abraham, G.N., and Abboud, C.N., Treatment of ovarian cancer using HSV-TK gene-modified vaccine-regulatory issues. Human Gene Therapy, 1992. 3: p. 342–349.

    Google Scholar 

  • Freeman, S.M., Abboud, C.N., Whartenby, K.A., and Abraham, G.N., The bystander effect: Tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res, 1993. 53: p. 5274–5284.

    CAS  PubMed  Google Scholar 

  • Freeman, S.M., Ramesh, R., Marrogi, A.J., Jensen, A., and Aboud, C.N., In vivo studies on the mechanism of the “Bystander Effect”. Cancer Gene Therapy, 1994. 4: p. 326.

    Google Scholar 

  • Freeman, S.M.. Ramesh. R., Shastri, M., Munshi, A., Jensen, A.K., and Marrogi, A.J., The role of cytokines in mediating the bystander effect using HSV-TK xenogeneic cells. Cancer Letters, 1995. 92(2): p. 167–174.

    CAS  PubMed  Google Scholar 

  • Freeman, S.M., McCune, C., Robinson, W., Abboud, C.N., Angel, C., Abraham, G.N., and Marrogi. A.J., Treatment of ovarian cancer using a gene-modified vaccine. Human Gene Therapy, 1995. 6: p. 927–939.

    CAS  PubMed  Google Scholar 

  • Freeman, S.M., Whartenby, K.A., Freeman, J.L, Abboud, C.N., and Marrogi, A.J., In situ use of suicide genes for cancer therapy. Seminars in Oncology, 1996. 23(1): p. 31–45.

    CAS  PubMed  Google Scholar 

  • Freeman, S.M., Ramesh, R., and Marrogi, A.J., Immune system in suicidegene therapy. Lancet, 1997. 349(9044): p. 2–3.

    CAS  PubMed  Google Scholar 

  • Freeman, S.M., Ramesh, R., Munshi, A., and Marrogi, A.J., Tumor killing using the HSV-TK suicide gene. Cancer Gene Therapy, 1997. 4: p. 542.

    Google Scholar 

  • Goldstein, L.J., Pastan, I., and Gottesman, M.M., Multidrug resistance in human cancer. Drit Rev Oncol Hematol, 1992. 12: p. 243–253.

    CAS  Google Scholar 

  • Goldstein, L.J., Gottesman, M.M., and Pastan, I., Expression of the MDR1 gene in human cancers. Cancer Treat Res, 1991. 57: p. 101–119.

    CAS  PubMed  Google Scholar 

  • Huber B.E., Austin, E.A., Richards, C.A., Davis, ST., and Good, S.S., 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, 1994. 91: p. 8302–8306.

    CAS  PubMed  Google Scholar 

  • Ioannides, C.G., Fisk, B., Jerome, K.R., Irimura, T. Wharton, J.T., and Finn, O.J., Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelia mucin core peptides. Journal of Immunology, 1993. 151: p. 3693–3703.

    CAS  Google Scholar 

  • Katsuragi, T, Sakai, T, and Tonomura, K., Implantable enzyme capsules for cancer chemotherapy from bakers yeast cytosine deaminase immobilized on epoxy-acrylic resin and urethane prepolymer. Appl Biochem Biotechnol, 1987. 16: p. 61–69.

    CAS  PubMed  Google Scholar 

  • Kolberg, R., The bystander effect in gene therapy: Great, but how does it work. J N1H Res, 1994. 6: p. 62–64.

    Google Scholar 

  • Kruse, C.A., Roper, M.D., Kleinschmidt-DeMasters, B.K., Banuelos, S.J., Smiley, W.R., Robbins, J.M., and Burrows, F.J., Purified herpes simplex thymidine kinase Retrovector particles. I. In vitro characterization, in situ transduction efficiency, and histopathological analyses of gene therapy-treated brain tumors. Cancer Gene Therapy, 1997. 4(2): p. 118–128.

    CAS  PubMed  Google Scholar 

  • Kuiper, M., Peakman, M., and Farzaneh, F., Ovarian tumour antigens as potential targets for immune gene therapy. Gene Therapy, 1995. 2: p. 7–15.

    CAS  PubMed  Google Scholar 

  • Kuriyama, S., Nakatani, T, Masui, K., Sakamoto, T, Tominaga, K., Yoshikawa, M., Fukui, H., Ikenaka, K., and Tsujii, T, Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma. Hepatology, 1995. 22(6): p. 1838–1946.

    CAS  PubMed  Google Scholar 

  • Marcel, T., and Grausz, J.D., The TMC Worldwide Gene Therapy Enrollment Report (June 1996). Human Gene Therapy, 1996. 7(16): p. 2025–2046.

    CAS  PubMed  Google Scholar 

  • Moolten, F.L., Drug sensitivity (“suicide”) genes for selective cancer chemotherapy. Cancer Gene Therapy, 1994. 4: p. 279–287.

    Google Scholar 

  • Moolten, F.L., and Wells, J.M., Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. Journal of the National Cancer Institute, 1990. 82: p. 297–300.

    CAS  PubMed  Google Scholar 

  • Moolten, F.L., Wells, J.M., Heyman, R.A., and Evans, R.M., Lymphoma regression induced by ganciclovir in mice bearing a herpesthymidine kinase transgene. Human Gene Therapy, 1990. 1: p. 125–134.

    CAS  PubMed  Google Scholar 

  • Moolten, F.L., Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: Paradigm for a prospective cancer control strategy. Cancer Res, 1986. 46: p. 5276–5281.

    CAS  PubMed  Google Scholar 

  • Nishiyama, Y., and Rapp, F., Anticellular effects of 9-(2-hydroxy-ethoxymethyl) guanine against herpes simplex virus-transformed cells. J Gen Virol, 1979. 45: p. 227–230.

    CAS  PubMed  Google Scholar 

  • Nishiyama, T., Kawamura, Y., Kawamoto, K., Matsumura, H., Yamamoto, N., Ito, T., Ohyama, A., Katsuragi, T, and Sakai, T., Antineoplastic effects in rats of 5-fluorocytosine in combination with cytosine deaminase capsules. Cancer Research, 1985. 45: p. 1753–1761.

    CAS  PubMed  Google Scholar 

  • Oliver, S., Bubley, G., and C., C., Inhibition of HSV-transformed murine cells by nucleoside analogs, 2′-NDG and2′-nor-cGMP: mechanisms of inhibition and reversal by exogenous nucleosides. Virology, 1985. 145: p. 84–93.

    CAS  PubMed  Google Scholar 

  • Ram, Z., Walbridge, S., Shawker, T, Culver, K.W., Blaese, R.M., and Oldfield, E.H., The effect of thymidine kinase transduction and ganciclovir therapy on tumor vasculature and growth of 9L gliomas in rats. J Neurosurg, 1994. 81: p. 256–260.

    CAS  PubMed  Google Scholar 

  • Ramesh, R, Marrogi, A.J., Munshi, A., Abboud, C.N., and Freeman, S.M., In vivo analysis of the “bystander effect”: a cytokine cascade. Experimental Hematology, 1996. 24(7): p. 829–838.

    CAS  PubMed  Google Scholar 

  • Ramesh, R., Munshi, A., Abboud, C.N., Marrogi, A.J., and Freeman, S.M., Expression of costimulatory molecules: B7 and ICAM up-regulation after treatment with a suicide gene. Cancer Gene Therapy, 1996. 3(6): p. 373–384.

    CAS  PubMed  Google Scholar 

  • Roth, J.A., and Cristiano, R.J., Gene therapy for cancer: What have we done and where are we going? J Natl Cancer Inst, 1997. 89: p. 21–29.

    CAS  PubMed  Google Scholar 

  • Sakai, T., Katsuragi, T., Tonomura, K., Nishiyama, T, and Kawamura, Y, Implantable encapsulated cytosine deaminase havine 5-fluorocytosine deaminating activity. Journal of Biotechnology, 1985. 2: p. 13–21.

    CAS  Google Scholar 

  • Santodonato, L., Ferrantini, M., Gabriele, L., Proietti, E., Venditti, M., Musiani, A., Modesti, A., Modica, A., Lupton, S.K., and Belardelli, F., Cure of mice with established metastatic friend leukemia cell tumors by a combined therapy with tumor cells expressing both intereron-alpha 1 and herpes simplex thymidine kinase followed by ganciclovir. Hum Gen Ther, 1996. 7: p. 1–10.

    Google Scholar 

  • Seachrist, L., Successful gene therapy has researchers looking for the bystander effect. J Natl Cancer Inst, 1994. 86: p. 82–83.

    CAS  PubMed  Google Scholar 

  • Shepp, D.H., Dandiliker, P., DeMiranda, P., Burnette, T.C., Cederberg, D.M., Kirk, L.E., and Meyers, J.D., Activity of 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine in the treatment of cytomegalovirus pneumonia. Ann Intern Med, 1985. 103: p. 368–373.

    CAS  PubMed  Google Scholar 

  • Tracey, K.J., Beutler, B., Lowry, S.F., and et al., Shock and tissue injury induced by recombinant human cachectin. Science, 1986. 234: p. 470–474.

    CAS  PubMed  Google Scholar 

  • Vrionis, F.D., Wu, J.K., Qi, P., Cano, W., and Cherington, V, A more potent bystander cytocidal effect elicited by tumor cells expressing the herpes simples virus-thymidine kinase gene than by fibroblast virus-producer cells in vitro. Journal of Neurosurgery, 1995. 83(4): p. 698–704.

    CAS  PubMed  Google Scholar 

  • Vile, R.G., Nelson, J.A., Castleden, S., Chong, H., and Hart, I.R., Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. Cancer Research, 1994. 54(23): p. 6228–6234.

    CAS  PubMed  Google Scholar 

  • Vile, R.G., Castleden, S., Marshall, J., Camplejohn, R., Upton, C., and Chong, H., Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a monocuclear cell infiltrate and a th1-like profile of intratumoural cytokine expression. Intl J Cancer, 1997. 71: p. 267–274.

    CAS  Google Scholar 

  • Vile, R.G., Diaz R.M., Castleden, S., and Chong, H., Targeted gene therapy for cancer: herpes simplex virus thymidine kinase gene-mediated cell killing leads to anti-tumour immunity that can be augmented by co-expression of cytokines in the tumour cells. Biochemical Society Transactions, 1997. 25(2): p. 717–722.

    CAS  PubMed  Google Scholar 

  • Wu, J.K., Cano, W.G., Meylaerts, S.A., Qi, P., Vrionis, F., and Cherington, V, Bystander tumoricidal effect in the treatment of experimental brain tumors. Neurosurgery, 1994. 35(6): p. 1094–1102; discussion 1103-1103.

    CAS  PubMed  Google Scholar 

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  1. Schering-Plough Research Institute, Clinical Research Oncology, Kenilworth, New Jersey, USA

    Scott M. Freeman

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  1. Imperial College School of Medicine, Hammersmith Hospital, London, UK

    Nagy A. Habib

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© 2002 Kluwer Academic Publishers

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Freeman, S.M. (2002). Suicide Gene Therapy. In: Habib, N.A. (eds) Cancer Gene Therapy. Advances in Experimental Medicine and Biology, vol 465. Springer, New York, NY. https://doi.org/10.1007/0-306-46817-4_36

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  • DOI: https://doi.org/10.1007/0-306-46817-4_36

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