Transcriptional targeting of adenovirally delivered tumor necrosis factor alpha by temozolomide in experimental glioblastoma.
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-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-alpha and systemic temozolomide significantly prolongs survival in an experimental glioblastoma multiforme model.
Yamini
Bakhtiar
B
Department of Surgery, Section of Neurosurgery and Department of Radiation and Cellular Oncology, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637, USA. byamini@surgery.bsd.uchicago.edu
Yu
Xiaohong
X
Gillespie
G Yancey
GY
Kufe
Donald W
DW
Weichselbaum
Ralph R
RR
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000077204:Temozolomide; D014158:Transcription, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D003606:Dacarbazine; D000077204:Temozolomide