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 counterparts 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 demonstrating 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 raf-1 in signal transduction. Additionally, anti-ras ASO were able to radiosensitize HER-2 overexpressing cells. These results, which verify the presence of a signaling pathway leading to cellular RR, also have possible clinical implications for the use of ASO as a means to sensitize radioresistant tumors to radiation therapy.
Pirollo
K F
KF
Department of Surgery, Stanford University Medical Center, California 94305-5328, USA.
Hao
Z
Z
Rait
A
A
Ho
C W
CW
Chang
E H
EH
D001940:Breast; D002294:Carcinoma, Squamous Cell; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays; D011905:Genes, ras; D006258:Head and Neck Neoplasms; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009857:Oncogenes; D010051:Ovarian Neoplasms; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf; D011519:Proto-Oncogenes; D011836:Radiation Tolerance / Q000187:drug effects; D015398:Signal Transduction; D013873:Thionucleotides; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms
D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D013873:Thionucleotides; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf