Reduction of Radiation or Chemotherapy-Induced Toxicity by Specific Expression of Anti-Apoptotic Molecules in Normal Cells

摘要

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 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 resulted in resistance to radiation. Heterogeneous plasmid that expresses Bcl-2 cDNA in front of a minimal promoter regulated by multiple wild-type p53 DNA-binding sites protects specifically cells with wild-type p53-but not p53-mutated or p53-deleted cancer cells from genotoxic damage (e.g., radiation) by upregulated expression of p53 and Bcl-2. Progress is described the results of specific aim 2 and 3 that allowed to development of preclinical animal model.