Combination of pGL1-TNF-alpha gene and radiation (proton and gamma-ray) therapy against brain tumor

The major goal of this study was to determine if treatment with the newly c onstructed plasmid vector for tumor necrosis factor-alpha (pGL1-TNF-alpha) could enhance the radiation-induced growth reduction of C6 rat glioma. In. addition, two different forms of ionizing radiation (gamma -rays and proton s) were utilized. Body and spleen mass, leukocyte blastogenesis, and flow c ytometry analysis of cell populations in blood and spleen were performed to detect toxicity, if any, and to identify mechanisms that may correlate wit h the anti-tumor action of combination therapy C6 tumor cells were implante d subcutaneously into athymic mice and allowed to become established before treatment initiation. pGL1-TNF-alpha was injected into the implanted tumor s, which were then irradiated 16-18 hr later; each modality was administer: ed thr ee times over 8-9 days. The addition of pGL1-TNF-alpha significantly enhanced the anti-tumor effect of radiation (p<0.05). The effect was mon t han additive, since pGL1-TNF-<alpha> alone did not slow tumor progression a nd radiation alone had only a modest effect. Administration of pGL1-TNF-alp ha together with proton radiation resulted in tumor volumes that were 23% s maller than those following pGL1-TNF-alpha + gamma -ray treatment; a simila r differential in tumor size was observed in the groups receiving only radi ation. Body weights and blood and spleen cell analyses did not reveal treat ment-related toxicity. High basal proliferation of blood leukocytes and inc reased B cell levels in the spleen were associated with pGL1-TNF-alpha + Co -60 (gamma -radiation) or proton treatment. Overall, the results suggest th at the pGL1-TNF-alpha /radiation combination is effective and safe under th e conditions employed. This is the first study to combine gene and proton r adiation therapy and to show, under controlled experimental conditions, tha t proton radiation may have a greater effect against malignant tumors compa red to the same physical dose of gamma -radiation.