INHIBITION OF HUMAN LEUKEMIA-60 CELL-GROWTH BY S-D-LACTOYLGLUTATHIONEIN-VITRO - MEDIATION BY METABOLISM TO N-D-LACTOYLCYSTEINE AND INDUCTION OF APOPTOSIS

The inhibition of human leukaemia 60 cell growth by S-D-lactoylglutath ione in vitro is mediated by the inhibition of de novo pyrimidine synt hesis, When S-D-lactoylglutathione was added to human leukaemia 60 cel ls in culture, it was hydrolysed by thiolesterase activity to reduced glutathione and D-lactate but also converted to N-D-lactoylcysteinylgl ycine and N-D-lactoylcysteine by gamma-glutamyl transferase and dipept idase. The N-D-lactoylcysteine inhibited human leukaemia 60 cell growt h: the median growth inhibitory concentration IC50 value was 46.7 +/- 0.9 (N = 30) and the median toxic concentration TC50 value was 103 +/- 1 mu M. Other N-(R)2-hydroxyacylcysteine derivatives, N-D-mandelylcys teine a nd N-L-glyceroylcysteine, were less effective inhibitors of hu man leukaemia 60 cell growth, whereas N-D-lactoylcysteine ethyl ester was more effective: the IC50 value was 16.5 +/- 1.5 mu M (N = 8). Cyto toxic concentrations of S-D-lactoylglutathione-induced apoptosis in hu man leukaemia 60 cells, The S-D-lactoylglutathione was not toxic to pe ripheral human lymphocytes at the same concentrations but rather induc ed growth arrest. The expected mechanism of action of N-D-lactoylcyste ine is inhibition of dihydro-orotase, which is particularly susceptibl e to inhibition by cysteine derivatives.