MOLECULAR MECHANISM OF ACTION OF ANTITUMOR ALKYLATING AGENTS

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This project now focusses primarily on cell cycle regulation as a major determinant of cytotoxic responses to alkylating agents and other DNA damaging anticancer drugs. We are utilizing recently developed tools and concepts to investigate the relationships between cell cycle regulation and the ability of cells to survive DNA damage. Our current studies focus on the mechanisms by which recognition of DNA damage is signalled to the molecular checkpoints that govern cell cycle progression from G2 phase into mitosis, and from G1 into S phase. Our long-range objective is apply new knowledge on cell cycle control to future anticancer drug development and therapy. In studies of the G2 checkpoint, we found that G2 arrest in nitrogen mustard treated human lymphoma cells was not due to lack of cdc2 or cyclin B; components of the critical kinase complex that controls cell cycle progression through this checkpoint. Rather, cdc2 kinase activation remains suppressed due to persistence of inhibitory phosphorylations. We are now investigating the mechanism which determines inhibitory phosphorylations, and hope to trace the sequence of events back to the point where DNA damage is recognized. In future studies, special attention will be given to differences among cell types that may explain why some cancer cells are selectively sensitive to DNA damaging drugs. We are also studying the cdk2-cyclin A kinase complex, whose exact role in the cell cycle is still uncertain; we found that, contrary to the cdc2-cyclin B kinase complex, its activity continued to rise in G2-arrested cells. In addition, we are studying the mechanisms by which drugs such as methylxanthines are able to circumvent DNA damage-induced G2 arrest. Compounds that influence cell cycle control may prove useful modulators of DNA damaging chemotherapies.