In vitro and in vivo potentiating the cytotoxic effect of radiation on human U251 gliomas by the c-Met antisense oligodeoxynucleotides

Abstract

C-Met, a receptor tyrosine kinase, and its ligand, hepatocyte growth factor (HGF), are critical in cellular proliferation, motility, and invasion, and are known to be overexpressed in gliomas, which are related to the repair of damaged DNA. In this study, we investigated both in vitro and in vivo whether inhibition of the c-Met gene by antisense oligonucleotides (ODNs) enhances the cytotoxic effect of radiation on human U251 gliomas. A volume of 100 nM of c-Met antisense ODNs inhibited the level of mRNA by more than 95% and reduced the protein expression by about 70%. Treatment of human U251 glioma cells with 100 nM of c-Met antisense ODNs significantly enhanced the radiation-induced cell kill compared to control cells, and cells treated with nonsense ODNs. When the glioma cells were implanted in the cisterna magna of nude mice followed by treatment with c-Met antisense ODNs, the survival time of the nude mice was markedly prolonged compared to that of the untreated group (P < 0.001, logrank test). In addition, the combination of antisense ODNs and irradiation extended the survival time of the glioma-bearing nude mice much longer than could be achieved with radiation alone (P < 0.0001, logrank test). These results suggest that inhibition of c-Met can be expected to serve as a novel potentiator for radiation therapy in human U251 gliomas.