title: Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity.
abstract: A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)6GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-alpha. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-alpha by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago Hospitals, Center for Advanced Medicine, Room 1329, Mail Code 9006, 5758 South Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Lopez
authors.forename: Eric T
authors.initials: ET
authors.lastname: Kimchi
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: James O
authors.initials: JO
authors.lastname: Park
authors.forename: Neil
authors.initials: N
authors.lastname: Mehta
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Murphy
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beckett
authors.forename: Samuel
authors.initials: S
authors.lastname: Hellman
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Posner
authors.forename: Donald W
authors.initials: DW
authors.lastname: Kufe
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D051766:Early Growth Response Protein 1; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy; D051381:Rats; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D000111:Acetylcysteine