Employment of the mdr1 promoter for the chemotherapy-inducible expression of therapeutic genes in cancer gene therapy

Abstract

Numerous approaches in gene therapy of human cancers are focused on the establishment of cell type specific or inducible expression vectors allowing the targeted and regulated expression of therapeutic genes. Various conditionally active vectors have been created carrying promoters responding to certain factors or therapeutic modalities (eg hormones, irradiation). The promoter of the multidrug resistance gene (mdr1) harbors such responsive elements and two of these elements have been related to drug responsiveness. In earlier studies we and others have characterized the mdr1 drug responsive-element in CAT reporter assays demonstrating its inducibility by MDR-associated drugs. To exploit this property, we linked the mdr1 promoter sequence to the human tumor necrosis factor alpha (TNF) cDNA in a retroviral vector and transduced the vector into human mammary and colon carcinoma cell lines. These cells were treated with various mdr1-associated drugs to induce TNF expression in vitro. We have shown that the mdr1 promoter-driven TNF expression is drug-inducible and that this induction is drug concentration and time dependent. The studies demonstrate the feasibility of the novel vector system for a chemotherapy-inducible expression of a chemosensitizing cytokine that is successful at enhancing cytotoxicity of drugs in cancer therapy.