The goal of this project is to investigate the contribution of oncogenes to tumor radioresistance in pursuit of identifying sensitive target(s) for pharmacological intervention. The major observations are: 1. Oncogenes and Radioresistance. Using ras-transformed mouse and human tumor cell lines we demonstrated: (a)dosage-dependent correlation between the amounts of ras-encoded protein, p21ras, and radioresistance; and (b)localization of 2lras to the inner side of the plasma membrane is critical for maintenance of the radioresistant phenotype. 2. p2lras As A Therapeutic Target. Isoprenylation is obligatory for its membrane localization and biological activity. Our studies indicate that inhibitors of HMGCoA reductase, including lovastatin and limonene, prevent p21ras attachment to the cell membrane with subsequent reduction in tumor radioresistance. We found that gluthathione inhibitors can down regulate ras expression at the posttranscriptional level, leading to radiosensitization. It appears that inhibitors of protein isoprenylation as well as gluthathione modulators could improve the efficacy of radiotherapy of tumor with ras overexpression, e.g., breast, lung, and colon carcinomas.
