In vivo Retrovirus‐mediated Herpes Simplex Virus Thymidine Kinase Gene Therapy Approach for Adult T Cell Leukemia in a Rat Model

We have previously demonstrated that human T‐lymphotropic virus type I (HTLV‐tax‐expressing human T cell lines are selectively eliminated in the presence of aciclovir, using a retroviral vector carrying the herpes simplex virus thymidine kinasc (HSV TK) gene under the control of the long terminal repeat (LTR) of HTLV‐I. Based on these findingsin vitro, we investigated whether this system could also be effective in vivo, using a rat model. Following infection of the HTLV‐I‐trans‐formed and tot‐expressing rat T cell line TARS‐1 with this retrovirus (LNLTK virus), high levels of HSV TK expression were observed and resulted in increased susceptibility to ganciclovir (GCV). Tumors were generated by subcutaneous injection of TARS‐1 in newborn syngeneic WKA/H rats. While the tumors derived from infected TARS‐1 cells with control virus, as well as uninfected cells, continued to grow in all the rats with or without administration of GCV, those derived from LNLTK‐infected cells exhibited dramatic regression upon GCV treatment. These results indicate that the HTLV‐I LTR‐HSV TK system also causes selective elimination of HTLV‐I‐transformed, (ax‐expressing T cells in vivo. Therefore, our present study may provide a rationale for clinical gene therapy against adult T cell leukemia.

[1]  D. Curiel.  Methods for Gene Transfer Using DNA-Adenovirus Conjugates. , 1997, Methods in molecular medicine.

[2]  M. Tomonaga,et al.  Rat primary T cells expressing HTLV‐I tax gene transduced by a retroviral vector: In vitro and in vivo characterization , 1996, International journal of cancer.

[3]  K. Ohshima,et al.  Detection of human T‐lymphotrophic virus type‐I DNA and mRNA in the lymph nodes; using polymerase chain reaction in situ hybridization (PCR/ISH) and reverse transcription (RT‐PCR/ISH) , 1996, International journal of cancer.

[4]  H. Wakimoto,et al.  Adenovirus-mediated prodrug gene therapy for carcinoembryonic antigen-producing human gastric carcinoma cells in vitro. , 1996, Cancer research.

[5]  P. Musiani,et al.  Cure of mice with established metastatic friend leukemia cell tumors by a combined therapy with tumor cells expressing both interferon-alpha 1 and herpes simplex thymidine kinase followed by ganciclovir. , 1996, Human gene therapy.

[6]  S. Kaneko,et al.  Adenovirus-mediated gene therapy of hepatocellular carcinoma using cancer-specific gene expression. , 1995, Cancer research.

[7]  K. Sugamura,et al.  Tumorigenicity of human T-cell leukemia virus type I-infected cell lines in severe combined immunodeficient mice and characterization of the cells proliferating in vivo. , 1995, Blood.

[8]  S. Nagataki,et al.  Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus thymidine kinase gene under the control of human alpha-fetoprotein gene promoter. , 1995, Cancer research.

[9]  X. -. Chen,et al.  Combination gene therapy for liver metastasis of colon carcinoma in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Woo,et al.  Adenovirus-mediated gene therapy for human head and neck squamous cell cancer in a nude mouse model. , 1995, Cancer research.

[11]  M. Fujita,et al.  Selective inhibition of human T-lymphotropic virus type I-transformed human T-cell growth by a tax-targeted conditionally cytotoxic recombinant retrovirus , 1994 .

[12]  R. Grossman,et al.  Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Klatzmann,et al.  Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[14]  K. Shimotohno,et al.  Proliferative response of Tax1-transduced primary human T cells to anti-CD3 antibody stimulation by an interleukin-2-independent pathway , 1993, Journal of virology.

[15]  Z. Ram,et al.  In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. , 1993, Cancer research.

[16]  H. Satoh,et al.  Phenotypic progression of a rat lymphoid cell line immortalized by human T-lymphotropic virus type I to induce lymphoma/leukemia-like disease in rats , 1992, Journal of virology.

[17]  Z. Ram,et al.  In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. , 1992, Science.

[18]  K. Shimotohno,et al.  An antigenic structure of the trans-activator protein encoded by human T-cell leukemia virus type-I (HTLV-I), as defined by a panel of monoclonal antibodies. , 1992, AIDS research and human retroviruses.

[19]  C. Richards,et al.  Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[20]  W. Greene,et al.  Molecular biology of the type I human T-cell leukemia virus (HTLV-I) and adult T-cell leukemia. , 1991, The Journal of clinical investigation.

[21]  Y. Tanaka,et al.  Recognition of human T cell leukemia virus type I (HTLV-I) gag and pX gene products by MHC-restricted cytotoxic T lymphocytes induced in rats against syngeneic HTLV-I-infected cells. , 1990, Journal of immunology.

[22]  F. Moolten,et al.  Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. , 1990, Journal of the National Cancer Institute.

[23]  S. Yamaoka,et al.  Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Miller Ad,et al.  Improved Retroviral Vectors for Gene Transfer and Expression , 1989 .

[25]  T. Sugimura,et al.  Detection of mRNA for the tax1/rex1 gene of human T-cell leukemia virus type I in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K. Takatsuki,et al.  Profiles of expression of activated cell antigens on peripheral blood and lymph node cells from different clinical stages of adult T-cell leukemia. , 1989, Blood.

[27]  J. Sodroski,et al.  Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[28]  I. Verma,et al.  c-fos promoter trans-activation by the tax1 protein of human T-cell leukemia virus type I. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Siekevitz,et al.  Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Yoshida.  Expression of the HTLV-1 genome and its association with a unique T-cell malignancy. , 1987, Biochimica et biophysica acta.

[31]  T. Taniguchi,et al.  Induction of interleukin 2 receptor gene expression by p40x encoded by human T‐cell leukemia virus type 1. , 1986, The EMBO journal.

[32]  M. Yoshida,et al.  Direct evidence that p40x of human T‐cell leukemia virus type I is a trans‐acting transcriptional activator. , 1986, The EMBO journal.

[33]  G. Pavlakis,et al.  The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. , 1985, Science.

[34]  T. Taniguchi,et al.  Expression of the pX gene of HTLV-I: general splicing mechanism in the HTLV family. , 1985, Science.

[35]  J. Sodroski,et al.  A transcriptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. , 1985, Science.

[36]  K. Yamaguchi,et al.  Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[37]  T. Yoshiki,et al.  Rat lymphoid cell lines with human T cell leukemia virus production. I. Biological and serological characterization , 1984, The Journal of experimental medicine.

[38]  J. D. Karkas,et al.  9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Y. Yamada.  Phenotypic and functional analysis of leukemic cells from 16 patients with adult T-cell leukemia/lymphoma. , 1983, Blood.

[40]  M. Yoshida,et al.  Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Y. Ohtsuki,et al.  Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells , 1981, Nature.

[42]  John D. Minna,et al.  Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma , 1980, Proceedings of the National Academy of Sciences.

[43]  J. Yodoi,et al.  Adult T-cell leukemia: clinical and hematologic features of 16 cases. , 1977, Blood.