RETROVIRAL VECTOR DESIGN FOR GENE-THERAPY OF CANCER - SPECIFIC-INHIBITION AND TAGGING OF BCR-ABL(P190) CELLS

Background: The main difficulty in providing effective treatment of pa tients with cancer is distinguishing between tumor and normal cells. T he chimeric molecules created by cancer-associated chromosomal abnorma lities (such as the BCR-ABL fusion protein) represent ideal therapeuti c targets since they are unique to the disease slate. A major challeng e, 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 eve ry tumor cell. It uses retroviral vectors encoding both antisense tran scripts specific for the BCR-ABL(p190) fusion junction (the specific a nti-tumor drug) and a truncated human CD5 cDNA, which allows selection of the infected cells. In order to coexpress the anti-sense molecule with the truncated human CD5 gene, the picornavirus internal ribosome- entry site was incorporated in the constructs. Results: When the antis ense 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 meas ured by the absence of CDS-positive cells. Control Ba/F3+p210 cells in fected with the same virus did not die in the absence of IL-3. Conclus ions: These data suggest a novel strategy for cancer treatment which i ncorporates the use of a retrovirus coexpressing both a selectable sur face marker and a tumor-specific agent.