Chemotherapeutic potential of methionine analogue inhibitors of tumor-derived methionine adenosyltransferases.

Two isozymes of ATP:L-methionine S-adenosyltransferase (MAT) were fractionated from rat Novikoff solid hepatoma. Their Km values for L-methionine and/or their inhibition constants for various L-methionine analogues were significantly different from the kinetic constants obtained for three isozymes fractionated from normal rat liver. Ki values for cycloleucine and (+/-)-2-aminobicyclo[2.1.1]hexane-2-carboxylic acid, presented for each tumor and liver isozyme, indicate that (+/-)-2-aminobicyclo[2.1.1]hexane-2-carboxylic acid was the more potent inhibitor. Dixon plots were also used to test a series of amino acid analogues [cycloleucine, 1-aminocyclobutanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, (+/-)-2-aminobicyclo[2.1.1]hexane-2-carboxylic acid, L-2-amino-4-hexynoic acid, (Z)-L-2-amino-5-chloro-trans-4-hexenoic acid, L-ethionine, S-n-propyl-DL-homocysteine, S-n-butyl-DL-homocysteine, and seleno-DL-ethionine] of methionine for inhibitory potency. Fixed L-methionine concentrations were used to determine the concentration of inhibitor necessary to inhibit the MAT reaction by 50%. Differential inhibitory activities of the amino acid analogues were noted between the tumor and rat liver isozymes thus supporting the suggestion that tumor-derived MAT isozymes may provide an exploitable target for cancer chemotherapy.