Scientific and public interest in the role of a """"""""healthy diet"""""""" for prevention of cancer has sparked research on numerous dietary anti-carcinogenesis. However most studies have focused on reduction of mutagenic effects elicited by specific carcinogens. Few investigators have attempted to identify anti-mutagens that are effective in reducing spontaneous mutations may be more relevant to overall lifetime disease prevention than mitigating specific carcinogen effects. Defects in mismatch repair have been identified in patients with hereditary non-polyposis colorectal cancer (HNPCC, Lynch Syndrome II), a condition characterized by an increased spontaneous mutation rate and a high degree of genome instability. This proposal aims to study the ability of several anti- carcinogens, the tomato carotenoid lycopene, soybean extracts, and the green tea polyphenol epigallocatechin-3-gallate (EGCG), to reduce the the high levels of spontaneous mutations observed in mismatch repair deficient human cells. The project uses a novel mismatch repair cell line and a human HNPCC colon cancer cell line to study these agents. Our expertise in measuring low levels of spontaneous mutation rates allows us to investigate the hypothesis that increased spontaneous mutation rates conferred by loss of functional mismatch repair in humans cells may be mitigated by certain dietary components.
In aims 1 and 2 we will directly measure the reduction of spontaneous mutation rates by lycopene, soybean products, and EGCG in two cell lines, each defective in one mismatch repair gene, hPMS2 or Hmlh1.
Aim 3 will determine whether the same anti-carcinogens can also reduce the observed microsatellite instability that is coordinate with high levels of spontaneous mutations in these repair deficient cells.
Aim 4 will evaluate whether our novel hPMS2 mutant cell line has acquired tumorigenic capacity as evidenced by growth in soft agar, and will coordinately evaluate whether this phenotype can be reversed by the addition of anti-carcinogens. These studies will provide scientific evidence that dietary components may have protective effects against an important mutator phenotype that is characteristic of many cancers.
| King, Audrey A; Shaughnessy, Daniel T; Mure, Kanae et al. (2007) Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair. Mutat Res 616:60-9 |
