Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity.
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.
Lopez
Carlos A
CA
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.
Kimchi
Eric T
ET
Mauceri
Helena J
HJ
Park
James O
JO
Mehta
Neil
N
Murphy
Kevin T
KT
Beckett
Michael A
MA
Hellman
Samuel
S
Posner
Mitchell C
MC
Kufe
Donald W
DW
Weichselbaum
Ralph R
RR
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
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