The specific aims of this proposal are: to examine the relationship between cellular proliferation rates and the relative utilization of S-adenosylmethionine (AdoMet) for transmethylation vs. polyamine synthesis via decarboxylated AdoMet (dcAdoMet); to determine the specific effects of exogenous polyamines on intracellular synthesis and utilization of dcAdoMet; to chemically synthesize N-methylmethionine and Alpha-fluoromethylmethionine and to test these and commercailly available Alpha-methylmethionine both in vitro and in vivo as substrates for synthesis of AdoMet analogs by methionine adenosyltransferase; to chemically (or enzymatically) synthesize N-methylAdoMet, and Alpha-methylAdoMet, and Alpha-fluoromethylAdoMet and to test these in vitro and in vivo as inhibitors of AdoMet decarboxylase. Methods to be used include chemical synthesis, enzymology, metabolic studies using radioisotopes, and high-pressure liquid chromatography. The long-term goals are to more completely understand the regulation of the methionine branch of the polyamine biosynthetic pathway and to apply this understanding to the rational development of chemotherapeutic agents acting by inhibiting enzymes of this pathway. In particular, neoplastic cells have high levels of polyamine synthesis and accumulation and should be particularly sensitive to such agents.