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Transcriptional Targeting of Adenovirally Delivered Tumor Necrosis Factor by Temozolomide in Experimental Glioblastoma

¹ Department of Surgery, Section of Neurosurgery and ² Department of Radiation and Cellular Oncology, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois; ³ Brain Tumor Research Laboratories, Division of Neurosurgery, Department of Surgery, University of Alabama, Birmingham, Alabama; and ⁴ Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, Massachusetts

Temozolomide is an oral alkylating agent shown to have modest efficacy in the treatment of glioblastoma multiforme. Tumor necrosis factor (TNF-) 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- 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- after infection with Ad.Egr-TNF compared with Ad.Egr-TNF alone at 96 hours (P < 0.02). TNF- 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- and systemic temozolomide significantly prolongs survival in an experimental glioblastoma multiforme model.

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