title: Dual induction of the Epo-Egr-TNF-alpha- plasmid in hypoxic human colon adenocarcinoma produces tumor growth delay.
abstract: Gene therapy is a modality for the treatment of solid tumors that involves the introduction of a suicide gene into the tumor cells. Genetic radiotherapy involves the placement of a radiation-sensitive promoter upstream from a suicide gene. Because of their irregular vasculature some solid tumors are chronically hypoxic and hence are resistant to conventional treatment with chemotherapy and ionizing radiation (IR). The purpose of this study was to demonstrate that regional tumor hypoxia could be exploited to improve local tumor control. The cDNA coding the erythropoietin hypoxia-responsive element (EPO) was placed upstream from the Egr-TNF-alpha construct. WIDR human colon adenocarcinoma cells were injected into the right hind limb of nude mice and treated with Epo-Egr-TNF-alpha plasmid with or without IR. Tumor volumes were measured by calipers and tumor necrosis factor (TNF)-alpha content of the tumor was determined by enzyme-linked immunosorbent assay. Treatment with the combined regimen of Epo-Egr-TNF-alpha plasmid + IR resulted in significant tumor growth delay. Tumor TNF-alpha content was increased by 30 per cent in the combined treatment group compared with each treatment alone. Regional tumor hypoxia can be exploited successfully to induce tumor growth delay, enhance local control, and enhance the therapeutic ratio.
authors.affiliation: Department of Surgery, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, New York 14642-8410, USA.
authors.forename: Rabih M
authors.initials: RM
authors.lastname: Salloum
authors.forename: Mark P
authors.initials: MP
authors.lastname: Saunders
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: Nader N
authors.initials: NN
authors.lastname: Hanna
authors.forename: David H
authors.initials: DH
authors.lastname: Gorski
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Posner
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D000818:Animals; D015687:Cell Hypoxia; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D004921:Erythropoietin / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*; D010957:Plasmids; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D010100:Oxygen