OLIGONUCLEOTIDE MANIPULATION OF TUMOR CELL RADIORESISTANCE

放射治疗是癌症的一种重要治疗方式。然而， 由于某些肿瘤对药物的抵抗力，其疗效有限。 电离辐射。尽管多种因素决定了细胞的反应 对于辐射，本研究将重点放在产品的重要性上 人原癌基因c-raf-1(Raf-1)在体内外肿瘤中的表达 对伽马辐射的反应。我们之前已经演示了 反义RAF寡核苷酸作为Raf-1序列特异性抑制物的可能性 表达和活性，以及体外放射增敏剂。我们会 扩展这些观察以进一步研究自由和 脂质体包裹的反义寡核苷酸(bFGF，ras，raf)作为序列- 基因表达的特异性抑制物和作为放射增敏剂。在……里面 此外，我们将检验反义RAF寡核苷酸的假设 在体内抑制Raf-1蛋白的表达，并增强对 实体瘤对辐射的影响。总体而言，这些研究应(I)产生 更好地理解反义寡核苷酸的新型放射增敏特性 RAF寡核苷酸，首次在啮齿动物系统中，以及(Ii) 为未来的翻译提供先进的技术和科学基础 反义RAF寡核苷酸的应用。

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.