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: Carlos A Lopez, Eric T Kimchi, Helena J Mauceri, James O Park, Neil Mehta, Kevin T Murphy, Michael A Beckett, Samuel Hellman, Mitchell C Posner, Donald W Kufe, Ralph R Weichselbaum
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 9 Pg. 1167-75 (Sep 2004) ISSN: 1535-7163 [Print] United States
• PMID: 15367711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• DNA-Binding Proteins
• EGR1 protein, human
• Early Growth Response Protein 1
• Immediate-Early Proteins
• Transcription Factors
• Tumor Necrosis Factor-alpha
• Doxorubicin
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Adenoviridae (genetics)
• Animals
• Antibiotics, Antineoplastic (pharmacology, therapeutic use)
• Cell Line, Tumor
• Combined Modality Therapy
• DNA-Binding Proteins (genetics)
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm
• Early Growth Response Protein 1
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Immediate-Early Proteins (genetics)
• Male
• Neoplasms (drug therapy, pathology, therapy)
• Neovascularization, Pathologic (therapy)
• Promoter Regions, Genetic (genetics)
• Prostatic Neoplasms (pathology, therapy)
• Rats
• Transcription Factors (genetics)
• Tumor Necrosis Factor-alpha (analysis, genetics, metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays