Dual Induction of the Epo-Egr-TNF-α Plasmid in Hypoxic Human Colon Adenocarcinoma Produces Tumor Growth Delay

Abstract

Gene therapy is a modality for the treatment of solid tumors that involves the introduction of a suicide gene into the tumor cells. Genetic radiotherapy involves the placement of a radiation-sensitive promoter upstream from a suicide gene. Because of their irregular vasculature some solid tumors are chronically hypoxic and hence are resistant to conventional treatment with chemotherapy and ionizing radiation (IR). The purpose of this study was to demonstrate that regional tumor hypoxia could be exploited to improve local tumor control. The cDNA coding the erythropoietin hypoxia-responsive element (EPO) was placed upstream from the Egr-TNF-α construct. WIDR human colon adenocarcinoma cells were injected into the right hind limb of nude mice and treated with Epo-Egr-TNF-α plasmid with or without IR. Tumor volumes were measured by calipers and tumor necrosis factor (TNF)-α content of the tumor was determined by enzyme-linked immunosorbent assay. Treatment with the combined regimen of Epo-Egr-TNF-α plasmid + IR resulted in significant tumor growth delay. Tumor TNF-α content was increased by 30 per cent in the combined treatment group compared with each treatment alone. Regional tumor hypoxia can be exploited successfully to induce tumor growth delay, enhance local control, and enhance the therapeutic ratio.