The AAPS Journal

, Volume 17, Issue 1, pp 102–110 | Cite as

Gene-Directed Enzyme Prodrug Therapy

  • Jin Zhang
  • Vijay Kale
  • Mingnan Chen
Review Article Theme: Chemical, Pharmacologic, and Clinical Perspectives of Prodrugs
Part of the following topical collections:
  1. Theme: Chemical, Pharmacologic, and Clinical Perspectives of Prodrugs


As one targeting strategy of prodrug delivery, gene-directed enzyme prodrug therapy (GDEPT) promises to realize the targeting through its three key features in cancer therapy—cell-specific gene delivery and expression, controlled conversion of prodrugs to drugs in target cells, and expanded toxicity to the target cells’ neighbors through bystander effects. After over 20 years of development, multiple GDEPT systems have advanced into clinical trials. However, no GDEPT product is currently marketed as a drug, suggesting that there are still barriers to overcome before GDEPT becomes a standard therapy. In this review, we first provide a general introduction of this prodrug targeting strategy. Then, we utilize the four most thoroughly studied systems to illustrate components, mechanisms, preclinical and clinical results, and further development directions of GDEPT. These four systems are herpes simplex virus thymidine kinase/ganciclovir, cytosine deaminase/5-fluorocytosine, cytochrome P450/oxazaphosphorines, and nitroreductase/CB1954 system. Later, we focus our discussion on bystander effects including local and distant bystander effects. Lastly, we discuss carriers that are used to deliver genes for GDEPT including virus carriers and non-virus carriers. Among these carriers, the stem cell-based gene delivery system represents one of the newest carriers under development, and may brought about a breakthrough to the gene delivery issue of GDEPT.


bystander effects gene delivery gene-directed enzyme prodrug stem cell-based targeting 



This paper is a result of the Dr. Jin Zhang’s independent research and does not reflect the views of U.S. Food and Drug Administration.


  1. 1.
    Saukkonen K, Hemminki A. Tissue-specific promoters for cancer gene therapy. Expert Opin Biol Ther. 2004;4(5):683–96.PubMedGoogle Scholar
  2. 2.
    Maitland NJ, Stanbridge LJ, Dussupt V. Targeting gene therapy for prostate cancer. Curr Pharm Des. 2004;10(5):531–55.PubMedGoogle Scholar
  3. 3.
    Lo HW, Day CP, Hung MC. Cancer-specific gene therapy. Adv Genet. 2005;54:235–55.PubMedGoogle Scholar
  4. 4.
    Both GW. Recent progress in gene-directed enzyme prodrug therapy: an emerging cancer treatment. Curr Opin Mol Ther. 2009;11(4):421–32.PubMedGoogle Scholar
  5. 5.
    Hamstra DA et al. The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies. Mol Ther. 2004;10(5):916–28.PubMedGoogle Scholar
  6. 6.
    Aghi M, Hochberg F, Breakefield XO. Prodrug activation enzymes in cancer gene therapy. J Gene Med. 2000;2(3):148–64.PubMedGoogle Scholar
  7. 7.
    Balzarini J, Bohman C, De Clercq E. 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. 1993;268(9):6332–7.PubMedGoogle Scholar
  8. 8.
    Beltinger C et al. 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. 1999;96(15):8699–704.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Wei SJ 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. 1998;241(1):66–75.PubMedGoogle Scholar
  10. 10.
    Tomicic MT, Thust R, Kaina B. Ganciclovir-induced apoptosis in HSV-1 thymidine kinase expressing cells: critical role of DNA breaks, Bcl-2 decline and caspase-9 activation. Oncogene. 2002;21(14):2141–53.PubMedGoogle Scholar
  11. 11.
    Fischer U et al. Mechanisms of thymidine kinase/ganciclovir and cytosine deaminase/ 5-fluorocytosine suicide gene therapy-induced cell death in glioma cells. Oncogene. 2005;24(7):1231–43.PubMedGoogle Scholar
  12. 12.
    Ribot EJ et al. In vivo MR tracking of therapeutic microglia to a human glioma model. NMR Biomed. 2011;24(10):1361–8.PubMedGoogle Scholar
  13. 13.
    Staquicini FI et al. Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma. J Clin Invest. 2011;121(1):161–73.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Bondanza A et al. IL-7 receptor expression identifies suicide gene-modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors. Blood. 2011;117(24):6469–78.PubMedGoogle Scholar
  15. 15.
    Tang W et al. A novel Bifidobacterium infantis-mediated TK/GCV suicide gene therapy system exhibits antitumor activity in a rat model of bladder cancer. J Exp Clin Cancer Res. 2009;28:155.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Kakinoki K et al. Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyte chemoattractant protein-1 delivery in mice. J Gene Med. 2010;12(12):1002–13.PubMedGoogle Scholar
  17. 17.
    Chen LS et al. Efficient gene transfer using the human JC virus-like particle that inhibits human colon adenocarcinoma growth in a nude mouse model. Gene Ther. 2010;17(8):1033–41.PubMedGoogle Scholar
  18. 18.
    Ambade AV, Joshi GV, Mulherkar R. Effect of suicide gene therapy in combination with immunotherapy on antitumour immune response & tumour regression in a xenograft mouse model for head & neck squamous cell carcinoma. Indian J Med Res. 2010;132:415–22.PubMedGoogle Scholar
  19. 19.
    Greish K et al. Silk-elastinlike protein polymers improve the efficacy of adenovirus thymidine kinase enzyme prodrug therapy of head and neck tumors. J Gene Med. 2010;12(7):572–9.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther. 2000;11(17):2389–401.PubMedGoogle Scholar
  21. 21.
    Voges J et al. Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma. Ann Neurol. 2003;54(4):479–87.PubMedGoogle Scholar
  22. 22.
    Nasu Y et al. Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy. Mol Ther. 2007;15(4):834–40.PubMedGoogle Scholar
  23. 23.
    Xu F et al. Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors. Cancer Gene Ther. 2009;16(9):723–30.PubMedGoogle Scholar
  24. 24.
    Li N et al. Adjuvant adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of liver transplantation in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2007;13(19):5847–54.PubMedGoogle Scholar
  25. 25.
    Freytag SO et al. Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. Mol Ther. 2007;15(5):1016–23.PubMedGoogle Scholar
  26. 26.
    Hasegawa Y et al. 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. 2000;7(4):557–62.PubMedGoogle Scholar
  27. 27.
    Hu W, Liu W. Side populations of glioblastoma cells are less sensitive to HSV-TK/GCV suicide gene therapy system than the non-side population. In Vitro Cell Dev Biol Anim. 2010;46(6):497–501.PubMedGoogle Scholar
  28. 28.
    Kuriyama N et al. Protease pretreatment increases the efficacy of adenovirus-mediated gene therapy for the treatment of an experimental glioblastoma model. Cancer Res. 2001;61(5):1805–9.PubMedGoogle Scholar
  29. 29.
    Marples B et al. Molecular approaches to chemo-radiotherapy. Eur J Cancer. 2002;38(2):231–9.PubMedGoogle Scholar
  30. 30.
    Nishihara E et al. Retrovirus-mediated herpes simplex virus thymidine kinase gene transduction renders human thyroid carcinoma cell lines sensitive to ganciclovir and radiation in vitro and in vivo. Endocrinology. 1997;138(11):4577–83.PubMedGoogle Scholar
  31. 31.
    Black ME, Kokoris MS, Sabo P. Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Cancer Res. 2001;61(7):3022–6.PubMedGoogle Scholar
  32. 32.
    Tong XW et al. Improvement of gene therapy for ovarian cancer by using acyclovir instead of ganciclovir in adenovirus mediated thymidine kinase gene therapy. Anticancer Res. 1998;18(2A):713–8.PubMedGoogle Scholar
  33. 33.
    Hasenburg A et al. Thymidine kinase (TK) gene therapy of solid tumors: valacyclovir facilitates outpatient treatment. Anticancer Res. 1999;19(3B):2163–5.PubMedGoogle Scholar
  34. 34.
    Chiocca EA et al. Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma. J Clin Oncol. 2011;29(27):3611–9.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Kubo H et al. Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. Hum Gene Ther. 2003;14(3):227–41.PubMedGoogle Scholar
  36. 36.
    Sangro B et al. A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma. Cancer Gene Ther. 2010;17(12):837–43.PubMedGoogle Scholar
  37. 37.
    Springer CJ, Niculescu-Duvaz I. Gene-directed enzyme prodrug therapy (GDEPT): choice of prodrugs. Adv Drug Deliv Rev. 1996;22(3):351–64.Google Scholar
  38. 38.
    Kurozumi K et al. Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus. J Neurooncol. 2004;66(1–2):117–27.PubMedGoogle Scholar
  39. 39.
    Li Z et al. Enzyme/prodrug gene therapy approach for breast cancer using a recombinant adenovirus expressing Escherichia coli cytosine deaminase. Cancer Gene Ther. 1997;4(2):113–7.PubMedGoogle Scholar
  40. 40.
    Topf N et al. Regional ‘pro-drug’ gene therapy: intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinoma. Gene Ther. 1998;5(4):507–13.PubMedGoogle Scholar
  41. 41.
    O’Keefe DS et al. Prostate-specific suicide gene therapy using the prostate-specific membrane antigen promoter and enhancer. Prostate. 2000;45(2):149–57.PubMedGoogle Scholar
  42. 42.
    Huber BE, Richards CA, Austin EA. VDEPT: an enzyme/prodrug gene therapy approach for the treatment of metastatic colorectal cancer. Adv Drug Deliv Rev. 1995;17:279–92.Google Scholar
  43. 43.
    Kuriyama S et al. 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. 1999;34(10):1033–41.PubMedGoogle Scholar
  44. 44.
    Shirakawa T et al. Cytotoxicity of adenoviral-mediated cytosine deaminase plus 5-fluorocytosine gene therapy is superior to thymidine kinase plus acyclovir in a human renal cell carcinoma model. J Urol. 1999;162(3 Pt 1):949–54.PubMedGoogle Scholar
  45. 45.
    Trinh QT et al. Enzyme/prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line. Cancer Res. 1995;55(21):4808–12.PubMedGoogle Scholar
  46. 46.
    Adachi Y 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. 2000;11(1):77–89.PubMedGoogle Scholar
  47. 47.
    Koyama F et al. Combined suicide gene therapy for human colon cancer cells using adenovirus-mediated transfer of Escherichia coli cytosine deaminase gene and Escherichia coli uracil phosphoribosyltransferase gene with 5-fluorocytosine. Cancer Gene Ther. 2000;7(7):1015–22.PubMedGoogle Scholar
  48. 48.
    Richard C et al. Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy. Cancer Gene Ther. 2007;14(1):57–65.PubMedGoogle Scholar
  49. 49.
    Aghi M et al. Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies. J Natl Cancer Inst. 1998;90(5):370–80.PubMedGoogle Scholar
  50. 50.
    Rogulski KR et al. Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Hum Gene Ther. 1997;8(1):73–85.PubMedGoogle Scholar
  51. 51.
    Hanna NN et al. Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts. Cancer Res. 1997;57(19):4205–9.PubMedGoogle Scholar
  52. 52.
    Pederson LC et al. Molecular chemotherapy combined with radiation therapy enhances killing of cholangiocarcinoma cells in vitro and in vivo. Cancer Res. 1997;57(19):4325–32.PubMedGoogle Scholar
  53. 53.
    Gabel M et al. Selective in vivo radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells transduced with the E. coli cytosine deaminase (CD) gene. Int J Radiat Oncol Biol Phys. 1998;41(4):883–7.PubMedGoogle Scholar
  54. 54.
    Mullen CA et al. 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. 1994;54(6):1503–6.PubMedGoogle Scholar
  55. 55.
    Huber BE et al. 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. 1994;91(17):8302–6.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Huber BE et al. In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. Cancer Res. 1993;53(19):4619–26.PubMedGoogle Scholar
  57. 57.
    Ohwada A, Hirschowitz EA, Crystal RG. Regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver. Hum Gene Ther. 1996;7(13):1567–76.PubMedGoogle Scholar
  58. 58.
    Kanai F et al. In vivo gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine deaminase gene. Cancer Res. 1997;57(3):461–5.PubMedGoogle Scholar
  59. 59.
    Bentires-Alj M et al. Cytosine deaminase suicide gene therapy for peritoneal carcinomatosis. Cancer Gene Ther. 2000;7(1):20–6.PubMedGoogle Scholar
  60. 60.
    Ichikawa T et al. In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus. Cancer Gene Ther. 2000;7(1):74–82.PubMedGoogle Scholar
  61. 61.
    Consalvo M et al. 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(10):5302–12.PubMedGoogle Scholar
  62. 62.
    Pandha HS et al. Genetic prodrug activation therapy for breast cancer: a phase I clinical trial of erbB-2-directed suicide gene expression. J Clin Oncol. 1999;17(7):2180–9.PubMedGoogle Scholar
  63. 63.
    Nemunaitis J et al. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther. 2003;10(10):737–44.PubMedGoogle Scholar
  64. 64.
    Freytag SO 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. 2003;63(21):7497–506.PubMedGoogle Scholar
  65. 65.
    Kan O et al. Direct retroviral delivery of human cytochrome P450 2B6 for gene-directed enzyme prodrug therapy of cancer. Cancer Gene Ther. 2001;8(7):473–82.PubMedGoogle Scholar
  66. 66.
    Roy P, Waxman DJ. Activation of oxazaphosphorines by cytochrome P450: application to gene-directed enzyme prodrug therapy for cancer. Toxicol In Vitro. 2006;20(2):176–86.PubMedGoogle Scholar
  67. 67.
    Karle P et al. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Cancer Gene Ther. 2001;8(3):220–30.PubMedGoogle Scholar
  68. 68.
    Schwartz PS, Waxman DJ. Cyclophosphamide induces caspase 9-dependent apoptosis in 9L tumor cells. Mol Pharmacol. 2001;60(6):1268–79.PubMedGoogle Scholar
  69. 69.
    Tychopoulos M et al. A virus-directed enzyme prodrug therapy (VDEPT) strategy for lung cancer using a CYP2B6/NADPH-cytochrome P450 reductase fusion protein. Cancer Gene Ther. 2005;12(5):497–508.PubMedGoogle Scholar
  70. 70.
    Ross AD et al. Effect of propylthiouracil treatment on NADPH-cytochrome P450 reductase levels, oxygen consumption and hydroxyl radical formation in liver microsomes from rats fed ethanol or acetone chronically. Biochem Pharmacol. 1995;49(7):979–89.PubMedGoogle Scholar
  71. 71.
    Schwartz PS, Chen CS, Waxman DJ. Enhanced bystander cytotoxicity of P450 gene-directed enzyme prodrug therapy by expression of the antiapoptotic factor p35. Cancer Res. 2002;62(23):6928–37.PubMedGoogle Scholar
  72. 72.
    Braybrooke JP et al. Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma. Clin Cancer Res. 2005;11(4):1512–20.PubMedGoogle Scholar
  73. 73.
    Denny WA. Nitroreductase-based GDEPT. Curr Pharm Des. 2002;8(15):1349–61.PubMedGoogle Scholar
  74. 74.
    Bridgewater JA et al. The bystander effect of the nitroreductase/CB1954 enzyme/prodrug system is due to a cell-permeable metabolite. Hum Gene Ther. 1997;8(6):709–17.PubMedGoogle Scholar
  75. 75.
    Patel P et al. A phase I/II clinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984]. Mol Ther. 2009;17(7):1292–9.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Palmer DH et al. Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. J Clin Oncol. 2004;22(9):1546–52.PubMedGoogle Scholar
  77. 77.
    Dachs GU et al. Bystander or no bystander for gene directed enzyme prodrug therapy. Molecules. 2009;14(11):4517–45.PubMedGoogle Scholar
  78. 78.
    Freeman SM et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 1993;53(21):5274–83.PubMedGoogle Scholar
  79. 79.
    Duarte S et al. Suicide gene therapy in cancer: where do we stand now? Cancer Lett. 2012;324(2):160–70.PubMedGoogle Scholar
  80. 80.
    Domin BA, Mahony WB, Zimmerman TP. Transport of 5-fluorouracil and uracil into human erythrocytes. Biochem Pharmacol. 1993;46(3):503–10.PubMedGoogle Scholar
  81. 81.
    Mesnil M, Yamasaki H. Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res. 2000;60(15):3989–99.PubMedGoogle Scholar
  82. 82.
    Garcia-Rodriguez L et al. E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models. Gene Ther. 2011;18(1):73–81.PubMedGoogle Scholar
  83. 83.
    Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res. 1986;46(10):5276–81.PubMedGoogle Scholar
  84. 84.
    Wei J et al. Embryonic endothelial progenitor cells armed with a suicide gene target hypoxic lung metastases after intravenous delivery. Cancer Cell. 2004;5(5):477–88.PubMedGoogle Scholar
  85. 85.
    Kucerova L et al. Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res. 2007;67(13):6304–13.PubMedGoogle Scholar
  86. 86.
    Bi W et al. An HSVtk-mediated local and distant antitumor bystander effect in tumors of head and neck origin in athymic mice. Cancer Gene Ther. 1997;4(4):246–52.PubMedGoogle Scholar
  87. 87.
    Kianmanesh AR et al. A “distant” bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Hum Gene Ther. 1997;8(15):1807–14.PubMedGoogle Scholar
  88. 88.
    Wilson KM et al. HSV-tk gene therapy in head and neck squamous cell carcinoma. Enhancement by the local and distant bystander effect. Arch Otolaryngol Head Neck Surg. 1996;122(7):746–9.PubMedGoogle Scholar
  89. 89.
    Wei MX et al. Suicide gene therapy of chemically induced mammary tumor in rat: efficacy and distant bystander effect. Cancer Res. 1998;58(16):3529–32.PubMedGoogle Scholar
  90. 90.
    Dilber MS et al. Suicide gene therapy for plasma cell tumors. Blood. 1996;88(6):2192–200.PubMedGoogle Scholar
  91. 91.
    Herraiz M et al. Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion. Hum Gene Ther. 2003;14(5):463–72.PubMedGoogle Scholar
  92. 92.
    Pierrefite-Carle V et al. Cytosine deaminase/5-fluorocytosine-based vaccination against liver tumors: evidence of distant bystander effect. J Natl Cancer Inst. 1999;91(23):2014–9.PubMedGoogle Scholar
  93. 93.
    Portsmouth D, Hlavaty J, Renner M. Suicide genes for cancer therapy. Mol Aspects Med. 2007;28(1):4–41.PubMedGoogle Scholar
  94. 94.
    Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med. 2001;7(1):33–40.PubMedGoogle Scholar
  95. 95.
    Kidd S et al. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells. 2009;27(10):2614–23.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Dwyer RM et al. Advances in mesenchymal stem cell-mediated gene therapy for cancer. Stem Cell Res Ther. 2010;1(3):25.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Aboody KS et al. Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci Transl Med. 2013;5(184):184ra59.PubMedGoogle Scholar
  98. 98.
    Metz MZ et al. Neural stem cell-mediated delivery of irinotecan-activating carboxylesterases to glioma: implications for clinical use. Stem Cells Transl Med. 2013;2(12):983–92.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Klopp AH et al. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res. 2007;67(24):11687–95.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Sato H et al. Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors. Cancer Gene Ther. 2005;12(9):757–68.PubMedGoogle Scholar
  101. 101.
    Klopp AH et al. Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2011;29(1):11–9.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Waterman RS, Henkle SL, Betancourt AM. Mesenchymal stem cell 1 (<italic>MSC1</italic>)-based therapy attenuates tumor growth whereas <italic>MSC2-</italic>treatment promotes tumor growth and metastasis. PLoS One. 2012;7(9):e45590.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Zhang T et al. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors. Stem Cell Res Ther. 2013;4(3):70.PubMedCentralPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  1. 1.The U.S. Food and Drug AdministrationSilver SpringUSA
  2. 2.College of PharmacyRoseman University of Health SciencesSouth JordanUSA
  3. 3.Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of UtahSalt Lake CityUSA

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