ATM kinase inhibition preferentially sensitizes p53 mutant glioma to ionizing radiation.

摘要: Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival only 12 to 15 months. Current standard treatment consists surgery followed by chemoradiation. The poor patients GBM due aggressive tumor invasiveness, an inability remove all tissue, and innate chemo- radioresistance. Ataxia–telangiectasia mutated (ATM) excellent target for radiosensitizing because its critical role in regulating DNA damage response p53, among other cellular processes. As first step toward this goal, we recently showed that novel ATM kinase inhibitor KU-60019 reduced migration, invasion, growth, potently radiosensitized human glioma cells vitro . Experimental Design: Using orthotopic xenograft models GBM, now show also effective radiosensitizer vivo Human expressing reporter genes monitoring growth dispersal were grown intracranially, was administered intratumorally convection-enhanced delivery or osmotic pump. Results: Our results combined effect radiation significantly increased mice 2- 3-fold over controls. Importantly, mutant p53 much more sensitive radiosensitization than genetically matched wild-type glioma. Conclusions: Taken together, our suggest may be adjuvant therapy cancers. Clin Cancer Res; 19(12); 3189–200. ©2013 AACR