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

Cancer Research
Bakhtiar YaminiRalph R Weichselbaum

Abstract

Temozolomide is an oral alkylating agent shown to have modest efficacy in the treatment of glioblastoma multiforme. Tumor necrosis factor alpha (TNF-alpha) 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-alpha 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-alpha after infection with Ad.Egr-TNF compared with Ad.Egr-TNF alone at 96 hours (P < 0.02). TNF-alpha 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...Continue Reading

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Citations

Aug 6, 2005·Cancer Gene Therapy·J J MezhirR R Weichselbaum
Oct 14, 2005·Anti-cancer Drugs·James J MezhirRalph R Weichselbaum
Jul 3, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Marianela CandolfiMaria G Castro
Sep 23, 2014·Human Gene Therapy. Clinical Development·Michael E EggerJorge G Gomez-Gutierrez
Oct 4, 2005·Neurological Research·Christian W Sikorski, Maciej S Lesniak
Apr 21, 2006·Expert Review of Neurotherapeutics·Maciej S Lesniak
May 6, 2009·Journal of Neuro-oncology·Tara A BaroneRobert J Plunkett
Oct 20, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bakhtiar YaminiRalph R Weichselbaum
Mar 13, 2021·Scientific Reports·David J VoceBakhtiar Yamini
Nov 21, 2007·Surgical Oncology Clinics of North America·Medina C KushenMaciej S Lesniak

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis