Reduction of Radiation- or Chemotherapy-Induced Toxicity by Specific Expression of Anti-Apoptotic Molecules in Normal Cells
Abstract
Adjuvant radiation and chemotherapy confer a survival benefit in breast cancer , but both treatments can damage normal tissues in ways that can adversely affect quality of life (e.g., by skin desquamation, mucositis, pulmonary fibrosis, cardiomyopathy, peripheral neuropathy). These effects on normal tissues are generally due to apoptosis (programmed death) of normal cells. We hypothesize that ectopic overexpression of the anti-apoptotic molecule Bcl-2 will inhibit the chemotherapy- and radiation-induced apoptosis of normal cells and thus reduce the toxicity of these treatments. We found that overexpressing Bcl-2 in murine fibroblast NIH3T3 cells and breast epithelial MCF 1 0A cells resulted in resistance to chemotherapy and radiation. We also prepared a heterogeneous plasmid that expresses Bcl-2 cDNA in front of a minimal promoter regulated by multiple wild-type p53 DNA-binding sites. Because cells with wild-type p53-but not p53-mutated or p53-deleted cancer cells-respond to genotoxic damage (e.g., chemotherapy or radiation) by upregulated expression of p53 and Bcl-2, we reasoned that specific transfection of normal cells with a Bcl-2 vector would prevent those cells from undergoing radiation- or chemotherapy- induced apoptosis. Progress is described in generation of the transfectant cell lines and tests of cytotoxicity upon exposure to doxombicin, paclitaxel, and gamma-radiation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2002
- Accession Number
- ADA407406
Entities
People
- Naoto Ueno
Organizations
- The University of Texas MD Anderson Cancer Center