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 necrosis 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 intratumoral injections of Ad.Egr-TNF or the null vector (Ad.null), with and without fractionated radiation, 5 gray (Gy) per day for 6 days, a total dose of 30 Gy. Administration of Ad.Egr-TNF and 30 Gy resulted in complete tumor regression in 71% of xenografts compared with xenografts treated with radiation alone (7.4%, P = 0.006), Ad.Egr-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 tumor vessel thrombosis by day 4 and necrosis by day 7. Thrombosis was not observed in tumors treated with Ad.Egr-TNF alone and was significantly reduced in all other treatment groups. These studies suggest that in the D54 glioma xenograft model, the antitumor effects of combining radiation and Ad.Egr-TNF are mediated, in part, by the destruction of the tumor microvasculature.
Staba
M J
MJ
Department of Pediatric Hematology/Oncology, University of Chicago Hospitals, IL 60637, USA.
Mauceri
H J
HJ
Kufe
D W
DW
Hallahan
D E
DE
Weichselbaum
R R
RR
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000494:pharmacology; D016335:Zinc Fingers / Q000235:genetics
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha