Retroviral vector design for gene therapy of cancer: specific inhibition and tagging of BCR-ABLp190 cells

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 1996-01, Vol.2 (1), p.125-133
• Main Authors: García-Hernández, B, Sánchez-García, I
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Base Sequence; CD5 Antigens - genetics; Cell Division - genetics; Cell Line; Flow Cytometry; Fusion Proteins, bcr-abl - chemistry; Fusion Proteins, bcr-abl - metabolism; Gene Expression Regulation - genetics; Genetic Markers - genetics; Genetic Therapy - methods; Genetic Vectors - chemistry; Genetic Vectors - genetics; Humans; Interleukin-3 - pharmacology; Membrane Glycoproteins - metabolism; Molecular Sequence Data; Neoplasms - therapy; Retroviridae - chemistry; Retroviridae - metabolism; RNA, Antisense - genetics; RNA, Antisense - pharmacology; RNA, Messenger - antagonists & inhibitors; Transcription, Genetic - genetics
• ISSN: 1076-1551; 1528-3658
• DOI: 10.1007/BF03402208

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. 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-ABLp190 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. 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. 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.