IN-VITRO AND IN-VIVO POTENTIATION OF RADIOSENSITIVITY OF MALIGNANT GLIOMAS BY ANTISENSE INHIBITION OF THE RAD51 GENE

The mammalian RAD51 gene is a homologue of the yeast RAD51 and E. coli RecA genes, which are related to the repair of DNA double-strand brea ks and are also involved in recombination repair and various SOS respo nses to DNA damage by gamma-irradiation and alkylating reagents. In th is study, we investigated both in vitro and in vivo whether inhibition of the RAD51 gene by antisense oligonucleotides (ODNs) enhances the r adiosensitivity of mouse malignant gliomas. A volume of 100 nM of RAD5 1 antisense ODNs inhibited the level of mRNA by more than 95% and redu ced the protein expression by about 70%. Treatment of mouse 203G gliom a cells with 100 nM of RAD51 antisense ODNs significantly enhanced the radiation-induced cell kill compared to control cells, and cells trea ted with sense or scrambled ODNs. When the glioma cells were implanted in the cisterna magna of mice followed by treatment with RAD51 antise nse ODNs, the survival time of the mice was markedly prolonged compare d to that of the untreated group (p<0.001, logrank test). In addition, the combination of antisense ODNs and irradiation extended the surviv al time of the glioma-bearing mice much longer than could be achieved with radiation alone (p<0.0001, logrank test). These results suggest t hat inhibition of RAD51 can be expected to serve as a novel potentiato r for radiation therapy in malignant gliomas by inhibiting DNA double- strand break repair. (C) 1998 Academic Press.