Experimental Study Of Retrovirus Vector-HSV-tk-GCV System Gene Therapy For Glioma And Effects Of GCV, Cisplatin On The Induction Of Apoptosis In Transduced And Nontransduced C6 Glioma Cells

Malignant glioma (the glilblastoma multiform, and the anaplastic astrocytomas)is one of the most malignant form of tumor afflicting adultants and children . Its incidence rate amount to 2-3/1000,000 inhabitants. It is the major cause of morbidity and mortality in the population. Its prognosis is particularly grim since only 10% of patients with glioblastoma multiform and 40% patients of anaplastic astrocytomas will survive for more than 2 years following their diagnosis and treatment(surgical resection, adjuvant radiation and chemotherapy). It is necessary to explore new and effective methods to treat the malignant glioma.The transfer of genes into target cell population is being developed to treat a variety of human diseases, including malignant glioma. Drag sensitivity gene therapy (or suicide gene therapy) is one of approach of gene therapy. In this approach, Herpes Simplex virus thymidine kinase(HSV-tk) gene is the most useful target gene. Of nearly 120 submitted the clinical protocols of cancer gene therapy in the end of 1995, 21 use this approach and of the 21 protocols, 12 focus on the malignant glioma. HSV-tk gene can convert the nucleoside analogies, Ganciclovir (GCV), an antiviral drug which has notoxic effect to mammalian cells, into triphospharylated comform, GCVTP [host cellular TK kinases(Cytosol TK)] are needed to convert GCV cooperatively). GCVTP acts as a chain terminator and interferes with DNA synthesis in replicating cells. This eventually will cause cells which contain HSV-tk gene arrest or cells death. At the same time of transduced target cells(HSV-tk~+)dying,the nearby non-transduced cells (HSV-tk) were dead. This feature is called bystander effect, another mechanism to kill tumor cells by this HSV-tk-GCV system. In malignant gliomas , the transfer of target gene is rather specific , because provirus DNA will integration into the genome of actively dividing cells and malignant glioma is growing in an environment of post-mitotic cells. The transfer of HSV-tk gene by retrovirus vector into malignant brain tumors following by GCV administration has recently been proposed as a novel approach for the treatment brain tumors. Recent reports demonstrated the efficacy of this approach in eradicating brain tumor cell lines in vitro , and in vivo. Preliminary clinical case report shows the result of drug -sensitivity gene therapy for malignant...