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

Mol Med. 1996 Jan;2(1):125-33.

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-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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • RNA, Antisense / genetics
  • RNA, Antisense / pharmacology
  • RNA, Messenger / antagonists & inhibitors
  • Retroviridae / chemistry
  • Retroviridae / metabolism*
  • Transcription, Genetic / genetics

Substances

  • Antineoplastic Agents
  • CD5 Antigens
  • Genetic Markers
  • Interleukin-3
  • Membrane Glycoproteins
  • RNA, Antisense
  • RNA, Messenger
  • Fusion Proteins, bcr-abl