EVIDENCE SUPPORTING A SIGNAL-TRANSDUCTION PATHWAY LEADING TO THE RADIATION-RESISTANT PHENOTYPE IN HUMAN TUMOR-CELLS

A signal transduction pathway, involving oncogenes and their normal co unterparts the proto-oncogenes, analogous to that for cell growth and differentiation has been proposed to lead to the phenotype of cellular radioresistance (RR). In this report we provide evidence demonstratin g the existence of such a pathway by using antisense oligonucleotides (ASO) to reverse the RR phenotype. Utilizing ASO directed against the raf-1 gene, a central component of this proposed pathway, we were able to reverse the RR phenotype of human tumor cell Lines having elevated HER-2 expression or a mutant form of Ha-ras, two genes upstream of ra f-1 in signal transduction. Additionally, anti-ras ASO were able to ra diosensitize HER-2 overexpressing cells. These results, which verify t he presence of a signaling pathway leading to cellular RR, also have p ossible clinical implications for the use of ASO as a means to sensiti ze radioresistant tumors to radiation therapy. (C) 1997 Academic Press