[Selective gene therapy of malignant gliomas using brain-specific promoters: its efficacy and basic investigations]

Abstract

Retroviral vector is often used for gene therapy of malignant tumors. The main characteristic of this vector is that it integrates only into the genes of dividing and proliferating cells. Glioma cells proliferate actively, while surrounding normal brain cells rarely divide. Thus, we can expect the recombinant retrovirus modified to express cytotoxic genes to kill glioma cells selectively. However, this characteristic of specific toxicity to the dividing cells is also observed in many chemotherapeutic agents, and it is well known that they cause severe side effects, such as bone marrow suppression or diarrhea caused by simultaneous toxicity of the drugs to proliferating bone marrow cells or intestinal epithelial cells, respectively. We have cloned many genes which are specifically expressed in brain, and identified their promoter regions conferring tissue-specific expression. If we use the brain-specific promoters to regulate the expression of the toxic genes, these genes may not be expressed in the myeloid cells or intestinal epithelial cells, even if they were infected with the retrovirus. Therefore, we searched for brain-specific promoters which are also active in glioma cells to kill glioma cells specifically. Then, MBP promoter showed the strongest promoter activity in mouse glioma cells. These mouse glioma cells transduced with retrovirus containing the MBP promoter directing the herpes simplex virus type 1 thymidine kinase (HTK) gene were extremely sensitive to ganciclovir, even when transduced with the MBP promoter-HTK gene-containing retrovirus. And we could get complete remission in the mouse brain tumor models, which were transfected HTK genes in more than 25% glioma cells, with ganciclovir.(ABSTRACT TRUNCATED AT 250 WORDS)