One obstacle to successful radiotherapy is the elevated resistance to ionizing radiation that many tumors display relative to adjacent normal tissues. Thus the radiosensitivity of normal tissue limits the radiation dose that can be delivered to a tumor. The combined effect of tumor resistance and normal tissue sensitivity can result in incomplete elimination of tumor cells and local recurrence. This grant address this problem by developing a method to specifically sensitize tumor cells to radiation using an approach based on the contribution of ras oncogenes to radiation resistance. Ras oncogenes are frequently mutated in human tumors treated with radiation therapy. These include pancreatic, colon, ovarian, and thyroid carcinomas sarcomas and late stage cervical carcinomas. Ras mutations have furthermore been shown to cause increase radiation resistance in experimental tumor systems. Thus, inhibition of the activity of oncogenic ras might be hypothesized to lead to radiation sensitization of the tumor cells. Since normal cells do not contain oncogenic ras, such an approach should not affect these cells. Farnesyltransferase and geranylgeranyltransferase inhibitors are compounds that specifically inhibit the post-translational prenylation of ras which is required for membrane association and signal transduction activity. The action of farnesyltransferase inhibitors (FTI) appears to be greatest against activated H-ras oncogenes, and consequently little or no effect is seen in normal cells as doses that significantly alter the morphology, growth and radiation-resistance of H-ras transformed cells. Geranylgeranyltransferase inhibitors (GGTI) show selective activity against K-ras prenylation. Both inhibitors have been shown to impede tumor growth, and are thus ideal candidates for combined modality therapy with radiation. The goal of this study is to determine whether the specificity of these inhibitors for the activated ras in tumor cells can be exploited such that these agents can be used as tumor cell radiosensitizers during radiation therapy.
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