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: l. Oncogenes and Radioresistance. Altered expression of the ras family has been implicated in intrinsic resistance to ionizing radiation. Using ras-transformed tumor cell lines we demonstrated: (a) dosage-dependent correlation between the amounts of ras-coded protein, p2lras, and radioresistance; (b) localization of p2lras to the inner side of the plasma membrane is critical for maintenance of the radioresistant phenotype. 2. P2lras As a Therapeutic Target. Cellular p2l is subject to a series of posttranslational modifications, of which isoprenylation is obligatory for its membrane localization and biological activity. Our studies indicate that inhibitors of protein prenylation, including lovastatin, PA and limonene, prevent p2lras attachment to the cell membrane with subsequent reduction in tumor radioresistance. Moreover, we found that glutathione inhibitors can down regulate ras expression at the post-transcriptional level, leading to radiosensitization. 3. Results obtained with gene-transfer models have been confirmed using tumor cell lines derived from patients with adenocarcinomas of the colon, lung, pancreas and prostate, all of which have elevated ras expression. It appears therefore that inhibitors of protein isoprenylation as well as glutathione modulators could improve the efficacy of radiotherapy, especially in cases involving ras overexpression.
