Polyamine Metabolism; DNA Repair

Research is being carried out on the cellular physiology of polyamines. Polyamines are small basic molecules essential for cell growth and differentiation. Their concentration is very tightly regulated within the cell and is altered by endocrine and other factors having trophic effects. The research is aimed at understanding metabolic pathways responsible for polyamine biosynthesis, degradation, and interconversion; factors responsible for regulating polyamine levels; polyamine roles in growth and differentiation; and design and application of specific inhibitors of polyamine production. Such inhibitors have already been shown to have potential therapeutic value and to be useful as research tools in studying polyamine function.

A second area of research concerns DNA repair enzymes' role in protecting against carcinogenesis by N-nitroso-compounds and other alkylating agents. An alkyltransferase, which removes alkyl groups from DNA, has been isolated and it has been shown that the level of this protein is both species and cell specific. There is a good correlation between the alkyltransferase content and resistance to carcinogenesis and mutagenesis by alkylating agents. Current research is aimed at studying the specificity of this system, factors controlling its activity, and investigating whether it is missing or reduced in certain hereditary conditions. Also, the possibility that transient inactivation of this DNA repair function can be used for cancer chemotherapy to augment the action of therapeutic alkylating agents is being investigated. A potent inhibitor, O⁶-benzylguanine, has been developed in Dr. Pegg's laboratory and in Phase 1 trials has been shown to be effective in depleting tumor cell alkyltransferase activity in patients with cancer. It is currently undergoing Phase 2 trials to determine its efficacy in improving chemotherapy.