Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53

Malignant gliomas of astrocytic origin have commonly expressed several feat ures such as alterations in the tumor-suppressor gene p53 or p16 or the acq uisition of telomerase activity, which are distinctive from astrocytes. The refore, restoration of the rumor-suppressor gene or telomerase inhibition i s expected to provide a cure for malignant gliomas. We have recently demons trated that the treatment with a 19-mer antisense oligonucleotide against h uman telomerase RNA linked to a 2',5'-oligoadenylate (2-SA-anti-hTR) inhibi ted the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hT R combined with the restoration of p53 or p16 gene. In this study, we evalu ated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21(WAF1/CIP1), Or p16(CDKN2) gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p 53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase -dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against su bcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressin g the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treat ment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic pote ntial for malignant gliomas with mutant p53. For tumors exhibiting wild-typ e p53, it may be useful to treat with 2-5A-anti-hTR.