ADENOVIRAL TNF-ALPHA GENE-THERAPY AND RADIATION-DAMAGE TUMOR VASCULATURE IN A HUMAN-MALIGNANT GLIOMA XENOGRAFT

We evaluated the antitumor effects of ionizing radiation and tumor nec rosis factor-alpha (TNF-alpha) gene therapy in human malignant glioma (D54) xenografts. An adenoviral vector (Ad5) containing DNA sequences of the Egr-1 promoter was linked to a cDNA encoding the TNF-alpha gene (Ad.Egr-TNF). Athymic nude mice bearing D54 xenografts received intra tumoral injections of Ad.Egr-TNF or the null vector (Ad.null), with an d without fractionated radiation. 5 gray (Gy) per day for 6 days, a to tal dose of 30 Gy. Administration of Ad.Egr-TNF and 30 Gy resulted in complete tumor regression in 71% of xenografts compared with xenograft s treated with radiation alone (7.4% P = 0.006), Ad.Ggr-TNF alone (0%, P = 0.012) or Ad.null with 30 Gy (0%, P = 0.002). Combined treatment with Ad.Egr-TNF and 30 Gy significantly reduced mean fractional tumor volumes compared with radiation alone (P = 0.002), Ad.Egr-TNF alone (P = 0.002) and Ad.null plus 30 Gy (P = 0.018). Histopathologic analyses of glioma xenografts treated with Ad.Egr-TNF and radiation revealed t umor vessel thrombosis by day 4 and necrosis by day 7. Thrombosis was not observed in tumors treated with Ad.Egr-TNF alone and was significa ntly reduced in all other treatment groups. These studies suggest that in the D54 glioma xenografts model, the antitumor effects of combinin g radiation and Ad.Egr-TNF are medicated, in part, by the destruction of the tumor microvasculature.