OLIGONUCLEOTIDE MANIPULATION OF TUMOR CELL RADIORESISTANCE

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Radiation Therapy is an important treatment modality of cancer. However, its effectiveness is limited due to the resistance of certain tumors to ionizing radiation. Although diverse factors dictate the cellular response to radiation, this study will focus on the importance of the product of the human proto-oncogene c-raf-1 (Raf-1) in the in vitro and in vivo tumor responses to gamma radiation. We have previously demonstrated the potential of antisense raf oligo as a sequence-specific inhibitor of Raf-1 expression and activity, as well as in vitro radiosensitizer. We will extend these observations to further investigate the potential of free and liposome-encapsulated antisense oligos (bFgf, ras, raf) as sequence- specific inhibitors of gene expression and as radiosensitizers. In addition, we will test the hypothesis that antisense raf oligonucleotide inhibits Raf-1 protein expression in vivo, and enhances the response of solid tumors to radiation. Overall, these studies should (i) generate a better understanding of the novel radiosensitizing property of antisense raf oligonucleotide, for the first time in a rodent system, and (ii) advance technological and scientific bases for the future translational application of antisense raf oligonucleotide.