STUDIES ON NORMAL AND LEUKEMIC LEUKOCYTES. IV. TETRAHYDROFOLATE-DEPENDENT ENZYME SYSTEMS AND DIHYDROFOLIC REDUCTASE*

Abstract

A number of investigations (3-6) have been concerned with biochemical characteristics of normal and leukemic leukocytes with special reference to enzymatic reactions that might represent potential targets for chemotherapeutic agents.Tetrahydrofolate-dependent enzyme systems provide a particularly promising area for this approach, since they mediate reactions in which 1-carbon units are incorporated into precursors of nucleic acids and proteins, namely, inosinate, thymidylate, methionine, histidine, and serine (7-9).Further support for this reasoning is provided by other experimental facts: a) the levels of folic acid and folinic acid are considerably higher in acute leukemia cells than in normal cells (10); b) the folic acid antagonists (aminopterin, amethopterin, and dichloroamethopterin) frequently produce transient remissions in patients with acute leukemia; and c) the rate of incorporation of C14formate and C14-formaldehyde into purines and into DNA-thymine is markedly increased in chronic myelocytic leukemic cells as compared with normal cells, and these processes are inhibited by aminopterin and amethopterin (11-13).In the present investigation several tetrahydrofolate-dependent enzymes and dihydrofolic re- ductase ( 14) have been studied in circulating hu- nman leukocytes.A comparison has been made of the level of these enzymes in normal cells and in