- Tsurushima, H. and Yuan, X. and Dillehay, L. E. and Leong, K. W., Radioresponsive tumor necrosis factor-related apoptosisinducing ligand (TRAIL) gene therapy for malignant brain tumors,
Cancer Gene Therapy, vol. 14 no. 8
pp. 706-716 .
(last updated on 2010/06/11)
Patients with malignant gliomas have a very poor prognosis. To explore a novel and more effective approach for the treatment of malignant gliomas, a strategy that combined tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and radiation treatment (RT) was designed in this study. Plasmid pE4- GFP was constructed by including the radioinducible early growth response gene 1 (Egr-1) promoter, and it yielded the best response with fractionated RT. Plasmid pE4- TRAIL was constructed by including the Egr-1 promoter and evaluated using U251 and U87 glioma cells. In the assay of apoptosis and killing activities, pE4-TRAIL exhibited radioresponse. pE4-TRAIL combined with RT is capable of inducing cell death synergistically. The expression of TRAIL death receptors was evaluated; which may be influenced by RT. Glioma cells with wild- type p53 showed upregulated expression of death receptors, and more synergistic effects on killing activities are expected. pE4-TRAIL was transfected into the subcutaneous U251 glioma cells in nude mice by the in vivo electroporation method. In the mice treated with pE4- TRAIL and RT, apoptotic cells were detected in pathological sections, and a significant difference of tumor volumes was observed when compared with the other groups (P <0.001). Our results indicate that radioresponsive gene therapy may have great potential as a novel therapy because this therapeutic system can be spatially or temporally controlled by exogenous RT and provides specificity and safety.
radioresponsive gene therapy trail gene therapy the combination with gene therapy and radiation therapy malignant brain tumors in vivo electroporation ionizing-radiation in-vivo glioma-cells hepatocellular-carcinoma antitumor-activity egr-1 promoter induction receptor electroporation activation