Adenoviral TNF-alpha gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft

Gene Ther. 1998 Mar;5(3):293-300. doi: 10.1038/sj.gt.3300594.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Combined Modality Therapy
  • DNA-Binding Proteins / genetics
  • Early Growth Response Protein 1
  • Female
  • Genetic Therapy*
  • Genetic Vectors
  • Glioma / radiotherapy
  • Glioma / therapy*
  • Humans
  • Immediate-Early Proteins*
  • In Situ Hybridization
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Recombinant Proteins / pharmacology
  • Transcription Factors / genetics
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Zinc Fingers / genetics

Substances

  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Immediate-Early Proteins
  • Recombinant Proteins
  • Transcription Factors
  • Tumor Necrosis Factor-alpha