| Research Abstract |
Adult T cell leukemia (ATL), which arises from CD4^+T cells, is caused by human T-lymphotropic virus type I (HTLV-I). HTLV-I possesses a unique 3'region in its genome, designated as pX,which encodes the viral transactivator tax protein. tax can transactivate not only its own long terminal repeat (LTR), but also cellular gene promoters including several proto-oncogenes and lymphokines and their receptor genes, such as interleukin 2 (IL-2) and IL-2 receptor alpha-chain.
Among the various paradigms for cancer gene therapy, one promising approach is virus-mediated transduction of tumor cells with suicide genes. To date, the herpes simplex virus thymidine kinase (HSV TK) gene is the most commonly used suicide gene. Cells transduced with the HSV TK gene become sensitive to nucleoside analogs such as ganciclovir (GCV) and aciclovir (ACV).
We demonstrated that human T-lymphotropic virus type I (HTLV-I) tax-expressing human T cell lines are selectively eliminated in the presence of aciclovir, using a retroviral vector carrying the herpes simplex virus thymidine kinase (HSV TK) gene under the control of the long terminal repeat (LTR) of HTLV-I.Based on these finding in vitro, we also investigated whether this system could also be effective in vivo, using a rat model. Following infection of the HTLV-I-transformed and tax-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). While the tumors derived from infected TARS-1 cells with control virus, as well as unifected 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.
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