Purine and Pyrimidine-Based Analogs and Suicide Gene Therapy

  • Zoran Gojkovic
  • Anna Karlsson
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Nucleobase and nucleoside analogs are widely used chemotherapeutic agents in the treatment of cancer and viral diseases. These compounds inhibit or disrupt DNA synthesis, and as tumor cells usually divide more rapidly than normal cells, there is a narrow therapeutic window to be exploited. Suicide gene therapy delivers genes to the cancer cells, enabling them to convert relatively nontoxic prodrugs into active chemotherapeutic agents. With this strategy, drug activation occurs primarily in the cancer cells, thereby maximizing damage to the cancer cells while keeping the systemic toxicity low. A number of suicide gene systems utilizing nucleobase and nucleoside analogs have been described. The best-known and most studied examples are the herpes simplex virus thymidine kinase gene in combination with ganciclovir and the Escherichia coli cytosine deaminase gene, which activates 5-fluorocytosine. Additional promising genes for use in suicide systems include the bacterial purine nucleoside phosphorylase gene; different deoxyribonucleoside kinases, such as the multisubstrate insect nucleoside kinase; and several other genes acting on a variety of different analogs. The efficiency of the currently used suicide systems depends on various biological parameters, such as the potential of activation, degree of activation, and bystander effect. In addition to these parameters, in-depth understanding of the biopharmaceutical properties of the prodrugs and suicide system kinetics should be known before selecting a specific system. Each suicide system offers not only specific advantages but also some limitations, and full understanding of the system can help overcome a number of problems associated with this type of gene therapy. Effective tumor destruction also depends on the delivery systems. Various vectors, including liposomes, retroviruses, and different adenoviruses, have been used to transfer suicide genes to tumor cells. Several of these approaches have been successful in many early clinical trials. Advances in new suicide systems, improved modulation of existing systems, and cell-specific delivery will definitely improve the clinical efficacy of suicide gene therapy and hopefully lead to better cancer treatments.

Key Words

Acyclovir cytosine deaminase deoxynucleoside kinase drug delivery system fluorocytosine ganciclovir gene therapy herpes thymidine kinase suicide genes thymidine kinase 


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  1. 1.
    Conte, P., Gennari, A., Landucci, E., et al. New combinations with epirubicin in advanced breast cancer. Oncology (Huntingt.), 15, 24–27, 2001.Google Scholar
  2. 2.
    Oettle, H. and Riess, H. Gemcitabine in combination with 5-fluorouracil with or without folinic acid in the treatment of pancreatic cancer. Cancer, 95, 912–922, 2002.PubMedCrossRefGoogle Scholar
  3. 3.
    Meropol, N. J., Niedzwiecki, D., Hollis, D., Schilsky, R. L., and Mayer, R. J. Phase II study of oral eniluracil, 5-fluorouracil, and leucovorin in patients with advanced colorectal carcinoma. Cancer, 91, 1256–1263, 2001.PubMedCrossRefGoogle Scholar
  4. 4.
    Takechi, T., Fujioka, A., Matsushima, E., and Fukushima, M. Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells. Eur. J. Cancer, 38, 1271–1277, 2002.Google Scholar
  5. 5.
    Henn, T. F., Garnett, M. C., Chhabra, S. R., Bycroft, B. W., and Baldwin, R. W. Synthesis of 2′-deoxyuridine and 5-fluoro-2?-deoxyuridine derivatives and evaluation in antibody targeting studies. J. Med. Chem., 36, 1570–1579, 1993.PubMedCrossRefGoogle Scholar
  6. 6.
    Crosasso, P., Brusa, P., Dosio, F., et al. Antitumoral activity of liposomes and immunoliposomes containing 5-fluorouridine prodrugs. J. Pharm. Sci., 86, 832–839, 1997.PubMedCrossRefGoogle Scholar
  7. 7.
    Mantripragada, S. A lipid based depot (DepoFoam technology) for sustained release drug delivery. Prog. Lipid Res., 41, 392–406, 2002.PubMedCrossRefGoogle Scholar
  8. 8.
    Murry, D. J. and Blaney, S. M. Clinical pharmacology of encapsulated sustained-release cytarabine. Ann. Pharmacother., 34, 1173–1178, 2000.PubMedCrossRefGoogle Scholar
  9. 9.
    Maxwell, I. H., Glode, L. M., and Maxwell, F. Expression of the diphtheria toxin A-chain coding sequence under the control of promoters and enhancers from immunoglobulin genes as a means of directing toxicity to B-lymphoid cells. Cancer Res., 51, 4299–4304, 1991.PubMedGoogle Scholar
  10. 10.
    Maxwell, I. H., Glode, L. M., and Maxwell, F. Expression of diphtheria toxin A-chain in mature B-cells: a potential approach to therapy of B-lymphoid malignancy. Leuk. Lymphoma, 7, 457–462, 1992.PubMedGoogle Scholar
  11. 11.
    Bundgaard H. Design of Prodrugs. Amsterdam: Elsevier; 1985.Google Scholar
  12. 12.
    Domin, B. A., Mahony, W. B., and Zimmerman, T. P. Transport of 5-fluorouracil and uracil into human erythrocytes. Biochem. Pharmacol., 46, 503–510, 1993.PubMedCrossRefGoogle Scholar
  13. 13.
    Baldwin, S. A., Mackey, J. R., Cass, C. E., and Young, J. D. Nucleoside transporters: molecular biology and implications for therapeutic development. Mol. Med. Today, 5, 216–224, 1999.PubMedCrossRefGoogle Scholar
  14. 14.
    Cass, C. E., Young, J. D., and Baldwin, S. A. Recent advances in the molecular biology of nucleoside transporters of mammalian cells. Biochem. Cell Biol., 76, 761–770, 1998.PubMedCrossRefGoogle Scholar
  15. 15.
    Arner, E. S. and Eriksson, S. Mammalian deoxyribonucleoside kinases. Pharmacol. Ther., 67, 155–186, 1995.Google Scholar
  16. 16.
    Culver, K. W., Ram, Z., Wallbridge, S., Ishii, H., Oldfield, E. H., and Blaese, R. M. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science, 256, 1550–1552, 1992.PubMedCrossRefGoogle Scholar
  17. 17.
    Huber, B. E., Richards, C. A., and Krenitsky, T. A. Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy. Proc. Natl. Acad. Sci. U. S. A, 88, 8039–8043, 1991.PubMedCrossRefGoogle Scholar
  18. 18.
    Moolten, F. L., Wells, J. M., Heyman, R. A., and Evans, R. M. Lymphoma regression induced by ganciclovir in mice bearing a herpes thymidine kinase transgene. Hum. Gene Ther., 1, 125–134, 1990.PubMedGoogle Scholar
  19. 19.
    Mullen, C. A., Kilstrup, M., and Blaese, R. M. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocy-tosine: a negative selection system. Proc. Natl. Acad. Sci. U. S. A., 89, 33–37, 1992.PubMedCrossRefGoogle Scholar
  20. 20.
    Parker, W. B., King, S. A., Allan, P. W., et al. In vivo gene therapy of cancer with E. coli purine nucleoside phosphorylase. Hum. Gene Ther., 8, 1637–1644, 1997.PubMedGoogle Scholar
  21. 21.
    Zheng, X., Johansson, M., and Karlsson, A. Retroviral transduction of cancer cell lines with the gene encoding Drosophila melanogaster multisubstrate deoxyribonucleoside kinase. J. Biol. Chem., 275, 39,125–39,129, 2000.PubMedCrossRefGoogle Scholar
  22. 22.
    Mulligan, R. C. and Berg, P. Selection for animal cells that express the Escherichia coli gene coding for xanthine-guanine phosphoribosyltransferase. Proc. Natl. Acad. Sci. U. S. A., 78, 2072–2076, 1981.PubMedCrossRefGoogle Scholar
  23. 23.
    Manome, Y., Wen, P. Y., Dong, Y., et al. Viral vector transduction of the human deoxycytidine kinase cDNA sensitizes glioma cells to the cytotoxic effects of cytosine arabinoside in vitro and in vivo. Nat. Med., 2, 567–573, 1996.PubMedCrossRefGoogle Scholar
  24. 24.
    Patterson, A. V., Zhang, H., Moghaddam, A., et al. Increased sensitivity to the prodrug 5′-deoxy-5-fluorouridine and modulation of 5-fluoro-2′-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. Br. J. Cancer, 72, 669–675, 1995.PubMedGoogle Scholar
  25. 25.
    Rainov, N. G., Kramm, C. M., Banning, U., et al. Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme. Gene Ther., 7, 1853–1858, 2000.PubMedCrossRefGoogle Scholar
  26. 26.
    Connors, T. A. The choice of prodrugs for gene directed enzyme prodrug therapy of cancer. Gene Ther., 2, 702–709, 1995.PubMedGoogle Scholar
  27. 27.
    Christians, F. C., Scapozza, L., Crameri, A., Folkers, G., and Stemmer, W. P. Directed evolution of thymidine kinase for AZT phosphorylation using DNA family shuffling. Nat. Biotechnol., 17, 259–264, 1999.PubMedCrossRefGoogle Scholar
  28. 28.
    Springer, C. J. and Niculescu-Duvaz, I. Prodrug-activating systems in suicide gene therapy. J. Clin. Invest., 105, 1161–1167, 2000.PubMedGoogle Scholar
  29. 29.
    Ishii-Morita, H., Agbaria, R., Mullen, C. A., et al. Mechanism of “bystander effect” killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment. Gene Ther., 4, 244–251, 1997.PubMedCrossRefGoogle Scholar
  30. 30.
    Rubsam, L. Z., Boucher, P. D., Murphy, P. J., KuKuruga, M., and Shewach, D. S. Cytotoxicity and accumulation of ganciclovir triphosphate in bystander cells cocultured with herpes simplex virus type 1 thymidine kinase-expressing human glioblastoma cells. Cancer Res., 59, 669–675, 1999.PubMedGoogle Scholar
  31. 31.
    Kilstrup, M., Meng, L. M., Neuhard, J., and Nygaard, P. Genetic evidence for a repressor of synthesis of cytosine deaminase and purine biosynthesis enzymes in Escherichia coli. J. Bacteriol., 171, 2124–2127, 1989.PubMedGoogle Scholar
  32. 32.
    Andersen, L., Kilstrup, M., and Neuhard, J. Pyrimidine, purine and nitrogen control of cytosine deaminase synthesis in Escherichia coli K 12. Involvement of the glnLG and purR genes in the regulation of cod A expression. Arch. Microbiol., 152, 115–118, 1989.PubMedCrossRefGoogle Scholar
  33. 33.
    Diasio, R. B. and Harris, B. E. Clinical pharmacology of 5-fluorouracil. Clin. Pharmacokinet., 16, 215–237, 1989.PubMedGoogle Scholar
  34. 34.
    Diasio, R. B., Lakings, D. E., and Bennett, J. E. Evidence for conversion of 5-fluorocytosine to 5-fluorouracil in humans: possible factor in 5-fluorocytosine clinical toxicity. Antimicrob. Agents Chemother., 14, 903–908, 1978.Google Scholar
  35. 35.
    Hayden, M. S., Linsley, P. S., Wallace, A. R., Marquardt, H., and Kerr, D. E. Cloning, overexpression, and purification of cytosine deaminase from Saccharomyces cere-visiae. Protein Expr. Purif., 12, 173–184, 1998.PubMedCrossRefGoogle Scholar
  36. 36.
    Porter, D. J. Escherichia coli cytosine deaminase: the kinetics and thermodynamics for binding of cytosine to the apoenzyme and the Zn(2+) holoenzyme are similar. Biochim. Biophys. Acta, 1476, 239–252, 2000.PubMedGoogle Scholar
  37. 37.
    Ireton, G. C., McDermott, G., Black, M. E., and Stoddard, B. L. The structure of Escherichia coli cytosine deaminase. J. Mol. Biol., 315, 687–697, 2002.PubMedCrossRefGoogle Scholar
  38. 38.
    Ireton, G. C., Black, M. E., and Stoddard, B. L. The 1.14 A crystal structure of yeast cytosine deaminase: evolution of nucleotide salvage enzymes and implications for genetic chemotherapy. Structure. (Camb.), 11, 961–972, 2003.CrossRefGoogle Scholar
  39. 39.
    Kievit, E., Bershad, E., Ng, E., et al. Superiority of yeast over bacterial cytosine deaminase for enzyme/prodrug gene therapy in colon cancer xenografts. Cancer Res., 59, 1417–1421, 1999.PubMedGoogle Scholar
  40. 40.
    Huber, B. E., Austin, E. A., Good, S. S., Knick, V. C., Tibbels, S., and Richards, C. A. In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. Cancer Res., 53, 4619–4626, 1993.PubMedGoogle Scholar
  41. 41.
    Peng, X. Y., Won, J. H., Rutherford, T., et al. The use of the L-plastin promoter for adenoviral-mediated, tumor-specific gene expression in ovarian and bladder cancer cell lines. Cancer Res., 61, 4405-4413, 2001.Google Scholar
  42. 42.
    Miller, C. R., Williams, C. R., Buchsbaum, D. J., and Gillespie, G. Y. Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas. Cancer Res., 62, 773–780, 2002.PubMedGoogle Scholar
  43. 43.
    Mullen, C. A., Coale, M. M., Lowe, R., and Blaese, R. M. 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, 1994.PubMedGoogle Scholar
  44. 44.
    Huber, B. E., Austin, E. A., Richards, C. A., Davis, S. T., 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. U. S. A., 91, 8302–8306, 1994.PubMedCrossRefGoogle Scholar
  45. 45.
    Trinh, Q. T., Austin, E. A., Murray, D. M., Knick, V. C., and Huber, B. E. Enzyme/prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine vs thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line. Cancer Res., 55, 4808–4812, 1995.PubMedGoogle Scholar
  46. 46.
    Hoganson, D. K., Batra, R. K., Olsen, J. C., and Boucher, R. C. Comparison of the effects of three different toxin genes and their levels of expression on cell growth and bystander effect in lung adenocarcinoma. Cancer Res., 56, 1315–1323, 1996.PubMedGoogle Scholar
  47. 47.
    Hirschowitz, E. A., Ohwada, A., Pascal, W. R., Russi, T. J., and Crystal, R. G. 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, 1995.PubMedGoogle Scholar
  48. 48.
    Greco, O. and Dachs, G. U. Gene directed enzyme/prodrug therapy of cancer: historical appraisal and future prospectives. J. Cell Physiol., 187, 22–36, 2001.PubMedCrossRefGoogle Scholar
  49. 49.
    Cunningham, C., and Nemunaitis, J. A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Version: April 9, 2001. Hum. Gene Ther., 12, 1594–1596, 2001.PubMedGoogle Scholar
  50. 50.
    Freytag, S. O., Khil, M., Stricker, H., et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res., 62, 4968–4976, 2002.PubMedGoogle Scholar
  51. 51.
    Pandha, H. S., Martin, L. A., Rigg, A., et al. Genetic prodrug activation therapy for breast cancer: a phase I clinical trial of erbB-2-directed suicide gene expression. J. Clin. Oncol., 17, 2180–2189, 1999.PubMedGoogle Scholar
  52. 52.
    Freytag, S. O., Stricker, H., Pegg, J., et al. Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate-to high-risk prostate cancer. Cancer Res., 63, 7497–7506, 2003.PubMedGoogle Scholar
  53. 53.
    Adachi, Y., Tamiya, T., Ichikawa, T., et al. Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine. Hum. Gene Ther., 11, 77–89, 2000.PubMedCrossRefGoogle Scholar
  54. 54.
    Milano, G. and Etienne, M. C. Potential importance of dihydropyrimidine de-hydrogenase (DPD) in cancer chemotherapy. Pharmacogenetics, 4, 301–306, 1994.PubMedCrossRefGoogle Scholar
  55. 55.
    Eriksson, S., Munch-Petersen, B., Johansson, K., and Eklund, H. Structure and function of cellular deoxyribonucleoside kinases. Cell Mol. Life Sci., 59, 1327–1346, 2002.PubMedCrossRefGoogle Scholar
  56. 56.
    Van Rompay, A. R., Johansson, M., and Karlsson, A. Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases. Pharmacol. Ther., 100, 119–139, 2003.PubMedCrossRefGoogle Scholar
  57. 57.
    Brockman, R. W., Cheng, Y. C., Schabel, F. M., Jr., and Montgomery, J. A. Metabolism and chemotherapeutic activity of 9-β-D-arabinofuranosyl-2-fluo-roadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. Cancer Res., 40, 3610–3615, 1980.PubMedGoogle Scholar
  58. 58.
    Carson, D. A., Wasson, D. B., Taetle, R., and Yu, A. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood, 62, 737–743, 1983.PubMedGoogle Scholar
  59. 59.
    Bouffard, D. Y., Laliberte, J., and Momparler, R. L. Kinetic studies on 2′,2′-di-fluorodeoxycytidine (gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem. Pharmacol., 45, 1857–1861, 1993.Google Scholar
  60. 60.
    Ullman, B., Coons, T., Rockwell, S., and McCartan, K. Genetic analysis of 2′,3′-dideoxycytidine incorporation into cultured human T lymphoblasts. J. Biol. Chem., 263, 12,391–12,396, 1988.PubMedGoogle Scholar
  61. 61.
    Bergman, A. M., Giaccone, G., van Moorsel, C. J., et al. Cross-resistance in the 2′,2′-difluorodeoxycytidine (gemcitabine)-resistant human ovarian cancer cell line AG6000 to standard and investigational drugs. Eur. J. Cancer, 36, 1974–1983, 2000.PubMedCrossRefGoogle Scholar
  62. 62.
    Dumontet, C., Fabianowska-Majewska, K., Mantincic, D., et al. Common resistance mechanisms to deoxynucleoside analogues in variants of the human ery-throleukaemic line K562. Br. J. Haematol., 106, 78–85, 1999.PubMedCrossRefGoogle Scholar
  63. 63.
    Blackstock, A. W., Lightfoot, H., Case, L. D., et al. Tumor uptake and elimination of 2′,2′-difluoro-2′-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response. Clin. Cancer Res., 7, 3263–3268, 2001.PubMedGoogle Scholar
  64. 64.
    Hapke, D. M., Stegmann, A. P., and Mitchell, B. S. Retroviral transfer of deoxycytidine kinase into tumor cell lines enhances nucleoside toxicity. Cancer Res., 56, 2343–2347, 1996.PubMedGoogle Scholar
  65. 65.
    Kojima, H., Iida, M., Miyazaki, H., Koga, T., Moriyama, H., and Manome, Y. Enhancement of cytarabine sensitivity in squamous cell carcinoma cell line trans-fected with deoxycytidine kinase. Arch. Otolaryngol. Head Neck Surg., 128, 708–713, 2002.Google Scholar
  66. 66.
    Sabini, E., Ort, S., Monnerjahn, C., Konrad, M., and Lavie, A. Structure of human dCK suggests strategies to improve anticancer and antiviral therapy. Nat. Struct. Biol., 10, 513-519, 2003.Google Scholar
  67. 67.
    Wang, L., Munch-Petersen, B., Herrstrom, S. A., et al. Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates. FEBS Lett., 443, 170–174, 1999.PubMedCrossRefGoogle Scholar
  68. 68.
    Sjoberg, A. H., Wang, L., and Eriksson, S. Substrate specificity of human recom-binant mitochondrial deoxyguanosine kinase with cytostatic and antiviral purine and pyrimidine analogs. Mol. Pharmacol., 53, 270–273, 1998.PubMedGoogle Scholar
  69. 69.
    Zhu, C., Johansson, M., Permert, J., and Karlsson, A. Enhanced cytotoxicity of nucleoside analogs by overexpression of mitochondrial deoxyguanosine kinase in cancer cell lines. J. Biol. Chem., 273, 14,707–14,711, 1998.PubMedCrossRefGoogle Scholar
  70. 70.
    Malspeis, L., Grever, M. R., Staubus, A. E., and Young, D. Pharmacokinetics of 2-F-ara-A (9-β-D-arabinofuranosyl-2-fluoroadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate. Semin. Oncol., 17, 18–32, 1990.PubMedGoogle Scholar
  71. 71.
    Xu, Y. Z. and Plunkett, W. Modulation of deoxycytidylate deaminase in intact human leukemia cells. Action of 2′,2′-difluorodeoxycytidine. Biochem. Pharmacol., 44, 1819–1827, 1992.PubMedCrossRefGoogle Scholar
  72. 72.
    Frewin, R. J., and Johnson, S. A. The role of purine analogue combinations in the management of acute leukemias. Hematol. Oncol., 19, 151–157, 2001.PubMedCrossRefGoogle Scholar
  73. 73.
    Robak, T. Purine nucleoside analogues in the treatment of myleoid leukemias. Leuk. Lymphoma, 44, 391–409, 2003.CrossRefGoogle Scholar
  74. 74.
    Larsson, R., Fridborg, H., Liliemark, J., et al. In vitro activity of 2-chlorodeoxyadenosine (CdA) in primary cultures of human haematological and solid tumours. Eur. J. Cancer, 30A:1022–1026, 1994.PubMedCrossRefGoogle Scholar
  75. 75.
    Nabhan, C., Krett, N., Gandhi, V., and Rosen, S. Gemcitabine in hematologic malignancies. Curr. Opin. Oncol., 13, 514–521, 2001.PubMedCrossRefGoogle Scholar
  76. 76.
    Csoka, K., Liliemark, J., Larsson, R., and Nygren, P. Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin. Oncol., 22, 47–53, 1995.PubMedGoogle Scholar
  77. 77.
    Huang, P. and Plunkett, W. Fludarabine-and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Cancer Chemother. Pharmacol., 36, 181–188, 1995.Google Scholar
  78. 78.
    Huang, P. and Plunkett, W. Induction of apoptosis by gemcitabine. Semin. Oncol., 22, 19–25, 1995.PubMedGoogle Scholar
  79. 79.
    Robertson, L. E., Chubb, S., Meyn, R. E., et al. Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-β-D-ara-binosyl-2-fluoroadenine. Blood, 81, 143–150, 1993.PubMedGoogle Scholar
  80. 80.
    Dionne, C. A., Camoratto, A. M., Jani, J. P., et al. Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587). Clin. Cancer Res., 4, 1887–1898, 1998.PubMedGoogle Scholar
  81. 81.
    Sadi, M. V. and Barrack, E. R. Determination of growth fraction in advanced prostate cancer by Ki-67 immunostaining and its relationship to the time to tumor progression after hormonal therapy. Cancer, 67, 3065–3071, 1991.PubMedCrossRefGoogle Scholar
  82. 82.
    Munch-Petersen, B., Piskur, J., and Sondergaard, L. Four deoxynucleoside kinase activities from Drosophila melanogaster are contained within a single monomeric enzyme, a new multifunctional deoxynucleoside kinase. J. Biol. Chem., 273, 3926–3931, 1998.PubMedCrossRefGoogle Scholar
  83. 83.
    Johansson, M., Van Rompay, A. R., Degreve, B., Balzarini, J., and Karlsson, A. Cloning and characterization of the multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster. J. Biol. Chem., 274, 23,814–23,819, 1999.PubMedCrossRefGoogle Scholar
  84. 84.
    Degreve, B., De Clercq, E., and Balzarini, J. Bystander effect of purine nucleoside analogues in HSV-1 tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues. Gene Ther., 6, 162–170, 1999.PubMedCrossRefGoogle Scholar
  85. 85.
    Zheng, X., Johansson, M., and Karlsson, A. Bystander effects of cancer cell lines transduced with the multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster and synergistic enhancement by hydroxyurea. Mol. Pharmacol., 60, 262–266, 2001.PubMedGoogle Scholar
  86. 86.
    Piskur, J., Sandrini, M. P., Knecht, W., and Munch-Petersen, B. Animal deoxyribonucleoside kinases: “forward” and “retrograde” evolution of their substrate specificity. FEBS Lett., 560, 3–6, 2004.PubMedCrossRefGoogle Scholar
  87. 87.
    Johansson, K., Ramaswamy, S., Ljungcrantz, C., et al. Structural basis for substrate specificities of cellular deoxyribonucleoside kinases. Nat. Struct. Biol., 8, 616–620, 2001.PubMedCrossRefGoogle Scholar
  88. 88.
    Knecht, W., Sandrini, M. P., Johansson, K., Eklund, H., Munch-Petersen, B., and Piskur, J. A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines. EMBO J., 21, 1873–1880, 2002.PubMedCrossRefGoogle Scholar
  89. 89.
    Solaroli, N., Bjerke, M., Amiri, M. H., Johansson, M., and Karlsson, A. Active site mutants of Drosophila melanogaster multisubstrate deoxyribonucleoside kinase. Eur. J. Biochem., 270, 2879–2884, 2003.PubMedCrossRefGoogle Scholar
  90. 90.
    Knecht, W., Petersen, G. E., Munch-Petersen, B., and Piskur, J. Deoxyribonucleoside kinases belonging to the thymidine kinase 2 (TK2)-like group vary significantly in substrate specificity, kinetics and feed-back regulation. J. Mol. Biol., 315, 529–540, 2002.PubMedCrossRefGoogle Scholar
  91. 91.
    Knecht, W., Petersen, G. E., Sandrini, M. P., Sondergaard, L., Munch-Petersen, B., and Piskur, J. Mosquito has a single multisubstrate deoxyribonucleoside kinase characterized by unique substrate specificity. Nucleic Acids Res., 31, 1665–1672, 2003.PubMedCrossRefGoogle Scholar
  92. 92.
    Jensen, K. F. Two purine nucleoside phosphorylases in Bacillus subtilis. Purification and some properties of the adenosine-specific phosphorylase. Biochim. Biophys. Acta, 525,346–356, 1978.Google Scholar
  93. 93.
    Stoeckler, J. D., Cambor, C., and Parks, R. E., Jr. Human erythrocytic purine nucleoside phosphorylase: reaction with sugar-modified nucleoside substrates. Biochemistry, 19, 102–107, 1980.PubMedCrossRefGoogle Scholar
  94. 94.
    Curlee, K. V., Parker, W. B., and Sorscher, E. J. Tumor sensitization to purine analogs by E. coli PNP. Methods Mol. Med., 90, 223–245, 2004.PubMedGoogle Scholar
  95. 95.
    Gadi, V. K., Alexander, S. D., Waud, W. R., Allan, P. W., Parker, W. B., and Sorscher, E. J. A long-acting suicide gene toxin, 6-methylpurine, inhibits slow growing tumors after a single administration. J. Pharmacol. Exp. Ther., 304, 1280–1284, 2003.PubMedCrossRefGoogle Scholar
  96. 96.
    Martiniello-Wilks, R., Garcia-Aragon, J., Daja, M. M., et al. In vivo gene therapy for prostate cancer: preclinical evaluation of two different enzyme-directed pro-drug therapy systems delivered by identical adenovirus vectors. Hum. Gene Ther., 9, 1617–1626, 1998.PubMedGoogle Scholar
  97. 97.
    Krohne, T. U., Shankara, S., Geissler, M., et al. Mechanisms of cell death induced by suicide genes encoding purine nucleoside phosphorylase and thymidine kinase in human hepatocellular carcinoma cells in vitro. Hepatology, 34, 511–518, 2001.PubMedCrossRefGoogle Scholar
  98. 98.
    Mohr, L., Shankara, S., Yoon, S. K., et al. Gene therapy of hepatocellular carcinoma in vitro and in vivo in nude mice by adenoviral transfer of the Escherichia coli purine nucleoside phosphorylase gene. Hepatology, 31, 606–614, 2000.PubMedCrossRefGoogle Scholar
  99. 99.
    Moolten, F. L. and Wells, J. M. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J. Natl. Cancer Inst., 82, 297–300, 1990.PubMedCrossRefGoogle Scholar
  100. 100.
    Beltinger, C., Fulda, S., Kammertoens, T., Meyer, E., Uckert, W., and Debatin, K. M. Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc. Natl. Acad. Sci. U. S. A., 96, 8699–8704, 1999.PubMedCrossRefGoogle Scholar
  101. 101.
    Wei, S. J., Chao, Y., Hung, Y. M., et al. S-and G2-phase cell cycle arrests and apoptosis induced by ganciclovir in murine melanoma cells transduced with herpes simplex virus thymidine kinase. Exp. Cell Res., 241, 66–75, 1998.PubMedCrossRefGoogle Scholar
  102. 102.
    Oldfield, E. H., Ram, Z., Culver, K. W., Blaese, R. M., DeVroom, H. L., and Anderson, W. F. Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum. Gene Ther., 4, 39–69, 1993.PubMedGoogle Scholar
  103. 103.
    Smythe, W. R. Prodrug/drug sensitivity gene therapy: current status. Curr. Oncol. Rep., 2, 17–22, 2000.PubMedCrossRefGoogle Scholar
  104. 104.
    Degreve, B., Andrei, G., Izquierdo, M., et al. Varicella-zoster virus thymidine kinase gene and antiherpetic pyrimidine nucleoside analogues in a combined gene/chemotherapy treatment for cancer. Gene Ther., 4, 1107–1114, 1997.PubMedCrossRefGoogle Scholar
  105. 105.
    Bonini, C., Ferrari, G., Verzeletti, S., et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-vs-leukemia. Science, 276, 1719–1724, 1997.PubMedCrossRefGoogle Scholar
  106. 106.
    Ackland, S. P. and Peters, G. J. Thymidine phosphorylase: its role in sensitivity and resistance to anticancer drugs. Drug Resist. Updat., 2, 205–214, 1999.PubMedCrossRefGoogle Scholar
  107. 107.
    Kanyama, H., Tomita, N., Yamano, T., et al. Enhancement of the anti-tumor effect of 5′-deoxy-5-fluorouridine by transfection of thymidine phosphorylase gene into human colon cancer cells. Jpn. J. Cancer Res., 90, 454–459, 1999.PubMedGoogle Scholar
  108. 108.
    Evrard, A., Cuq, P., Ciccolini, J., Vian, L., and Cano, J. P. Increased cytotoxicity and bystander effect of 5-fluorouracil and 5-deoxy-5-fluorouridine in human col-orectal cancer cells transfected with thymidine phosphorylase. Br. J. Cancer, 80, 1726–1733, 1999.PubMedCrossRefGoogle Scholar
  109. 109.
    Ciccolini, J., Cuq, P., Evrard, A., et al. Combination of thymidine phosphorylase gene transfer and deoxyinosine treatment greatly enhances 5-fluorouracil antitu-mor activity in vitro and in vivo. Mol. Cancer Ther., 1, 133–139, 2001.PubMedGoogle Scholar
  110. 110.
    Manome, Y., Watanabe, M., Abe, T., et al. Transduction of thymidine phosphorylase cDNA facilitates efficacy of cytosine deaminase/5-FC gene therapy for malignant brain tumor. Anticancer Res., 21, 2265–2272, 2001.PubMedGoogle Scholar
  111. 111.
    Rogulski, K. R., Wing, M. S., Paielli, D. L., Gilbert, J. D., Kim, J. H., and Freytag, S. O. 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, 2000.PubMedCrossRefGoogle Scholar
  112. 112.
    Uckert, W., Kammertons, T., Haack, K., et al. 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, 1998.PubMedCrossRefGoogle Scholar
  113. 113.
    Moriuchi, S., Wolfe, D., Tamura, M., et al. Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model. Gene Ther., 9, 584–591, 2002.PubMedCrossRefGoogle Scholar
  114. 114.
    Norman, R. A., Barry, S. T., Bate, M., et al. Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor. Structure. (Camb.), 12, 75–84, 2004.CrossRefGoogle Scholar
  115. 115.
    Krenitsky, T. A., Neil, S. M., and Miller, R. L. Guanine and xanthine phosphori-bosyltransfer activities of Lactobacillus casei and Escherichia coli. Their relationship to hypoxanthine and adenine phosphoribosyltransfer activities. J. Biol. Chem., 245, 2605–2611, 1970.PubMedGoogle Scholar
  116. 116.
    Vos, S., de Jersey, J., and Martin, J. L. Crystal structure of Escherichia coli xanthine phosphoribosyltransferase. Biochemistry, 36, 4125-4134, 1997.Google Scholar
  117. 117.
    Tamiya, T., Ono, Y., Wei, M. X., Mroz, P. J., Moolten, F. L., and Chiocca, E. A. Escherichia coli gpt gene sensitizes rat glioma cells to killing by 6-thioxanthine or 6-thioguanine. Cancer Gene Ther., 3, 155–162, 1996.PubMedGoogle Scholar
  118. 118.
    Ono, Y., Ikeda, K., Wei, M. X., Harsh, G. R., Tamiya, T., and Chiocca, E. A. Regression of experimental brain tumors with 6-thioxanthine and Escherichia coli gpt gene therapy. Hum. Gene Ther., 8, 2043–2055, 1997.PubMedGoogle Scholar
  119. 119.
    Freeman, S. M., Abboud, C. N., Whartenby, K. A., et al. The “bystander effect” tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res., 53, 5274–5283, 1993.PubMedGoogle Scholar
  120. 120.
    Holder, J. W., Elmore, E., and Barrett, J. C. Gap junction function and cancer. Cancer Res., 53, 3475–3485, 1993.PubMedGoogle Scholar
  121. 121.
    Asklund, T., Appelskog, I. B., Ammerpohl, O., et al. Gap junction-mediated bystander effect in primary cultures of human malignant gliomas with recombi-nant expression of the HSVtk gene. Exp. Cell Res., 284, 185–195, 2003.PubMedCrossRefGoogle Scholar
  122. 122.
    Colombo, B. M., Benedetti, S., Ottolenghi, S., et al. 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, 1995.PubMedGoogle Scholar
  123. 123.
    Frank, D. K., Frederick, M. J., Liu, T. J., and Clayman, G. L. Bystander effect in the adenovirus-mediated wild-type p53 gene therapy model of human squamous cell carcinoma of the head and neck. Clin. Cancer Res., 4, 2521–2528, 1998.PubMedGoogle Scholar
  124. 124.
    Burrows, F. J., Gore, M., Smiley, W. R., et al. Purified herpes simplex virus thymidine kinase retroviral particles: III. Characterization of bystander killing mechanisms in transfected tumor cells. Cancer Gene Ther., 9, 87–95, 2002.PubMedCrossRefGoogle Scholar
  125. 125.
    Kwong, Y. L., Chen, S. H., Kosai, K., Finegold, M. J., and Woo, S. L. Adenoviral-mediated suicide gene therapy for hepatic metastases of breast cancer. Cancer Gene Ther., 3, 339–344, 1996.PubMedGoogle Scholar
  126. 126.
    Rosenfeld, M. E., Feng, M., Michael, S. I., Siegal, G. P., Alvarez, R. D., and Curiel, D. T. Adenoviral-mediated delivery of the herpes simplex virus thymidine kinase gene selectively sensitizes human ovarian carcinoma cells to ganciclovir. Clin. Cancer Res., 1, 1571–1580, 1995.PubMedGoogle Scholar
  127. 127.
    Estin, D., Li, M., Spray, D., and Wu, J. K. Connexins are expressed in primary brain tumors and enhance the bystander effect in gene therapy. Neurosurgery, 44, 361–368, 1999.PubMedCrossRefGoogle Scholar
  128. 128.
    Dilber, M. S., Abedi, M. R., Christensson, B., et al. Gap junctions promote the bystander effect of herpes simplex virus thymidine kinase in vivo. Cancer Res., 57, 1523–1528, 1997.PubMedGoogle Scholar
  129. 129.
    Kunishige, I., Samejima, Y., Moriyama, A., Saji, F., and Murata, Y. cAMP stimulates the bystander effect in suicide gene therapy of human choriocarcinoma. Anticancer Res., 18, 3411–3419, 1998.PubMedGoogle Scholar
  130. 130.
    Yamamoto, S., Yamano, T., Tanaka, M., et al. A novel combination of suicide gene therapy and histone deacetylase inhibitor for treatment of malignant melanoma. Cancer Gene Ther., 10, 179–186, 2003.PubMedCrossRefGoogle Scholar
  131. 131.
    Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature, 389, 349–352, 1997.PubMedCrossRefGoogle Scholar
  132. 132.
    Yoshida, M., Horinouchi, S., and Beppu, T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays, 17, 423–430, 1995.PubMedCrossRefGoogle Scholar
  133. 133.
    Freeman, S. M., Ramesh, R., and Marrogi, A. J. Immune system in suicide-gene therapy. Lancet, 349, 2, 3, 1997.Google Scholar
  134. 134.
    Yamamoto, S., Suzuki, S., Hoshino, A., Akimoto, M., and Shimada, T. 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, 1997.PubMedGoogle Scholar
  135. 135.
    Dilber, M. S. and Smith, C. I. Suicide genes and bystander killing: local and distant effects. Gene Ther., 4, 273, 274, 1997.Google Scholar
  136. 136.
    Anderson, W. F. Human gene therapy. Science, 256,808–813, 1992.PubMedCrossRefGoogle Scholar
  137. 137.
    Naldini, L., Blomer, U., Gage, F. H., Trono, D., and Verma, I. M. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc. Natl. Acad. Sci. U. S. A., 93, 11,382–11,388, 1996.PubMedCrossRefGoogle Scholar
  138. 138.
    Schneider, M. D. and French, B. A. The advent of adenovirus. Gene therapy for cardiovascular disease. Circulation, 88, 1937–1942, 1993.PubMedGoogle Scholar
  139. 139.
    Leon, R. P., Hedlund, T., Meech, S. J., et al. Adenoviral-mediated gene transfer in lymphocytes. Proc. Natl. Acad. Sci. U. S. A., 95, 13,159–13,164, 1998.PubMedCrossRefGoogle Scholar
  140. 140.
    Okegawa, T., Li, Y., Pong, R. C., Bergelson, J. M., Zhou, J., and Hsieh, J. T. The dual impact of coxsackie and adenovirus receptor expression on human prostate cancer gene therapy. Cancer Res., 60, 5031–5036, 2000.PubMedGoogle Scholar
  141. 141.
    Grill, J., Van Beusechem, V. W., Van, D. V., et al. Combined targeting of aden-oviruses to integrins and epidermal growth factor receptors increases gene transfer into primary glioma cells and spheroids. Clin. Cancer Res., 7, 641–650, 2001.Google Scholar
  142. 142.
    Heise, C. C., Williams, A. M., Xue, S., Propst, M., and Kirn, D. H. Intravenous administration of ONYX-015, a selectively replicating adenovirus, induces anti-tumoral efficacy. Cancer Res., 59, 2623–2628, 1999.PubMedGoogle Scholar
  143. 143.
    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.PubMedCrossRefGoogle Scholar
  144. 144.
    Lou, E. Oncolytic herpes viruses as a potential mechanism for cancer therapy. Acta Oncol., 42, 660–671, 2003.PubMedCrossRefGoogle Scholar
  145. 145.
    Wildner, O. Comparison of replication-selective, oncolytic viruses for the treatment of human cancers. Curr. Opin. Mol. Ther., 5, 351–361, 2003.PubMedGoogle Scholar
  146. 146.
    Karara, A. L., Bumaschny, V. F., Fiszman, G. L., Casais, C. C., Glikin, G. C., and Finocchiaro, L. M. Lipofection of early passages of cell cultures derived from murine adenocarcinomas: in vitro and ex vivo testing of the thymidine kinase/gan-ciclovir system. Cancer Gene Ther., 9, 96–99, 2002.PubMedCrossRefGoogle Scholar
  147. 147.
    Zheng, X., Lundberg, M., Karlsson, A., and Johansson, M. Lipid-mediated protein delivery of suicide nucleoside kinases. Cancer Res., 63, 6909–6913, 2003.PubMedGoogle Scholar
  148. 148.
    Hasegawa, H., Shimada, M., Yonemitsu, Y., et al. Preclinical and therapeutic utility of HVJ liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex virus thymidine kinase. Cancer Gene Ther., 8, 252–258, 2001.PubMedCrossRefGoogle Scholar
  149. 149.
    Harsh, G. R., Deisboeck, T. S., Louis, D. N., et al. Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropatho-logical study. J. Neurosurg., 92, 804–811, 2000.PubMedCrossRefGoogle Scholar
  150. 150.
    Hassenbusch, S. J., Nardone, E. M., Levin, V. A., Leeds, N., and Pietronigro, D. Stereotactic injection of DTI-015 into recurrent malignant gliomas: phase I/II trial. Neoplasia, 5, 9–16, 2003.PubMedGoogle Scholar
  151. 151.
    Richards, C. A., Austin, E. A., and Huber, B. E. Transcriptional regulatory sequences of carcinoembryonic antigen: identification and use with cytosine deaminase for tumor-specific gene therapy. Hum. Gene Ther., 6, 881–893, 1995.PubMedCrossRefGoogle Scholar
  152. 152.
    Black, M. E., Kokoris, M. S., and Sabo, P. Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Cancer Res., 61, 3022–3026, 2001.PubMedGoogle Scholar
  153. 153.
    Knecht, W., Munch-Petersen, B., and Piskur, J. Identification of residues involved in the specificity and regulation of the highly efficient multisubstrate deoxyribonucleoside kinase from Drosophila melanogaster. J. Mol. Biol., 301, 827–837, 2000.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Zoran Gojkovic
    • 1
  • Anna Karlsson
    • 2
  1. 1.ZGene A/SHørsholmDenmark
  2. 2.Department of Laboratory Medicine, Division of Metabolic DisordersKarolinska InstitutetStockholmSweden

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