The broad objective of this project is to delineate the role of oncogenes in the molecular and biochemical mechanism(s) underlying radiation resistance. Specifically, the present investigations will test whether modulation of the oncogene expression in certain human tumor cells results in altered cellular response to ionizing radiation and/or alterations in the levels of repair/resistance associated enzymes. This project has two AIMS.
Aim I is focused on the detailed analysis of the human tumor cell lines available in our laboratory. These experiments include the identification and characterization of oncogenes, radiation biology and expression of the enzymes glutathione transferases, glutathione peroxidase, beta-polymerase, superoxide dismutases, and the human component of XRCC-1.
AIM II is designed to investigate the molecular, biochemical and biological consequences of the modulation of oncogene function. These experiments will utilize genetically engineered sense and antisense oncogene containing vectors for the introduction of desired oncogene expression into the human tumor cells. The genetically manipulated cancer cells will be analyzed for the regulation of oncogene(s) (RNA/protein), biochemical mediators of repair/resistance and, radiation dose response. The major strength of this project lies in our earlier reports demonstrating the feasibility of the overall experimental design and methodology. New experimentation will address for the first time, whether modulation of the cellular repair-related cascade can be accomplished, indirectly, by down regulation of the specific oncogene function. Taken together, these investigations (AIMS I and II) offer to advance our understanding of the (i) protooncogene function(s), (ii) molecular and biochemical mechanism(s) of radiation resistance, and (iii) antisense oncogene RNA approach to modulate the radiation resistant response of tumors that fail the present radiotherapeutic protocols.
