Transcriptional targeting of adenovirally delivered tumor necrosis factor α by temozolomide in experimental glioblastoma

Academic Article

Abstract

  • Temozolomide is an oral alkylating agent shown to have modest efficacy in the treatment of glioblastoma multiforme. Tumor necrosis factor α (TNF-α) is a polypeptide cytokine with synergistic antitumor activity in combination therapy with alkylating agents. We investigated the combined use of Ad.Egr-TNF, a replication-defective adenoviral vector encoding the cDNA for TNF-α under the control of chemo-inducible elements of the egr1 gene promoter, and intraperitoneal temozolomide in an intracranial human malignant glioma model. In hind limb U87MG xenografts, temozolomide produced a 6.4-fold greater induction of TNF-α after infection with Ad.Egr-TNF compared with Ad.Egr-TNF alone at 96 hours (P < 0.02). TNF-α and temozolomide combination leads to a synergistic decrease in U87 cell viability at 72 hours compared with either treatment alone (P < 0.001). Median survival for animals treated with Ad.Egr-TNF alone, temozolomide alone, and Ad.Egr-TNF/temozolomide was 21, 28, and 74 days, respectively (P < 0.001 by log-rank). Flow cytometric assessment of apoptosis revealed a synergistic increase in U87 cell apoptosis in vitro at 72 hours (P < 0.05), and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) evaluation of tumor sections revealed significantly increased TUNEL-positive cells after combination treatment compared with either treatment alone (P < 0.05). In conclusion, combination treatment with transcriptionally activated intratumoral TNF-α and systemic temozolomide significantly prolongs survival in an experimental glioblastoma multiforme model.
  • Published In

  • Cancer Research  Journal
  • Digital Object Identifier (doi)

    Author List

  • Yamini B; Yu X; Gillespie GY; Kufe DW; Weichselbaum RR
  • Start Page

  • 6381
  • End Page

  • 6384
  • Volume

  • 64
  • Issue

  • 18