Retroviral vector design for gene therapy of cancer: Specific inhibition and tagging of BCR-ABL(p190) cells

Abstract

Background: The main difficulty in providing effective treatment of patients with cancer is distinguishing between tumor and normal cells. The chimeric molecules created by cancer-associated chromosomal abnormalities (such as the BCR-ABL fusion protein) represent ideal therapeutic targets since they are unique to the disease state. A major challenge, however, is how to deliver the specific anti-tumor agent into every tumor cell. Material and Methods: In this report we describe the use of a novel strategy to introduce specific anti-tumor reagents into every tumor cell. It uses retroviral vectors encoding both antisense transcripts specific for the BCR- ABL(p190) fusion junction (the specific anti-tumor drug) and a truncated human CD5 cDNA, which allows selection of the infected cells. In order to coexpress the antisense molecule with the truncated human CD5 gene, the picornavirus internal ribosome-entry site was incorporated in the constructs. Results: When the antisense transcripts in the CD5 retroviral vector were introduced into Ba/F3+p190 cells rendered interleukin 3 (IL-3) independent by expression of the BCR-ABL sequences, the cells died upon IL-3 withdrawal, as measured by the absence of CD5-positive cells. Control Ba/F3+p210 cells infected with the same virus did not die in the absence of IL-3. Conclusions: These data suggest a novel strategy for cancer treatment which incorporates the use of a retrovirus coexpressing both a selectable surface marker and a tumor-specific agent.