IRREVERSIBLE ENZYME INHIBITORS . 133 . STUDIES ON DIFFERENTIAL IRREVERSIBLE INHIBITION OF DIHYDROFOLIC REDUCTASE FROM 3 STRAINS OF L1210 LEUKEMIA LIVER SPLEEN AND INTESTINE OF MOUSE

By use of selected irreversible inhibitors it appears that the dihydrofolic reductase from L1210/FR8, L1210/ DF8, and the parent L1210/0 strain are not appreciably different. Contrariwise the dihydrofolic reductase from mouse liver, spleen, and intestine could be shown to be structurally different from each tissue as well as different from the enzyme from the three L1210 strains. These structural differences are most probably outside of the active site. It has been further demonstrated that of two sulfonyl fluoride type inhibitors with almost equal reversible inhibition power, only the one that showed irreversible inhibition of L1210/0 dihydrofolic reductase was effective in giving a life extension of mice bearing L1210/0; from these data, minimum criteria for enzyme activity have been set to determine whether a candidate irreversible inhibitor of dihydrofolic reductase is worthy of in vivo assay against L1210 mouse leukemia. © 1969, American Chemical Society. All rights reserved.