Exploring the possibility that biochemical and molecular strategies that inhibit DNA repair may be useful in reversing resistance of cancer cells to DNA-damaging anti-tumor agents. The research in our laboratory is exploring the possibility that biochemical and molecular strategies that inhibit DNA repair may be useful in reversing resistance of cancer cells to DNA-damaging anti-tumor agents. We are studying biochemical combinations which inhibit the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT), an enzyme responsible for repairing DNA lesions produced by an important class of anti-tumor agents. We are designing ribozymes (catalytic anti-sense RNA molecules) to destroy MGMT mRNA molecules. Additional studies in the laboratory are examining gene-specific DNA damage produced by anti-tumor agents in oncogenes and other transcriptionally active genes. Other studies are aimed at inhibiting the DNA excision repair exinuclease system, a major mechanism for tumor resistance to DNA-damaging anti-tumor agents such as the important agent cis-platinum. All of these studies are aimed at answering the following questions: 1) What events occur in sensitive tumor cells effectively killed by anti-tumor agents? and, 2) What cellular processes are used by resistant tumor cells to avoid being killed by anti-tumor agents?
