OBJECTIVES: Purification and properties of human dihydrofolate reductases, and development of new inhibitors of this enzyme. Studies of the mechanisms of control of folate enzymes by substrates and analogs, with particular emphasis on dihydrofolate reductase, methionine synthetase, and thymidylate synthetase. Studies of DNA polymerases of human leukemia cells, including separation and purification. Development of new folate antagonists based on differential inhibition of dihydrofolate reductase, or differentiated uptake of the drug.