A model using radiation and plasmid-mediated tumor necrosis factor-alpha gene therapy for treatment of glioblastomas

The efficacy of radiotherapy for cancer is limited by the dose that can be safely delivered to the tumor without causing debilitating side effects. Pr evious studies have shown an additive ol syngeneic reduction in the volume of malignant tumors when tumor necrosis factor a (TNF-alpha) protein is adm inistered prior to radiation. The major goal of the present investigation w as to evaluate the efficacy of pGL1-TNF-alpha, a new plasmid construct that expresses human TNF-alpha protein, together with radiotherapy in the C6 gl ioma/athymic mouse model. Subcutaneously growing tumors were injected with pGL1-TNF-alpha complexed with a cationic polyamine and radiation, singly an d in combination, over an 8-day period The maximum antitumor effect was ach ieved with the combination of polynmine-pG1-TNF-alpha and radiation. Each m odality used alone, including polyamine, modestly slowed tumor growth, In v itro evaluations of blood, spleen, and tumor indicated that the antitumor m echanisms of combination therapy may include, at least partly, the recruitm ent and activation of nonspecific effector cells. The results demonstrate t hat polyamine-pGL1-TNF-alpha can be safely and effectively administered tog ether with radiation under the conditions used.