Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity

Mol Cancer Ther. 2004 Sep;3(9):1167-75.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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