ANTITUMOR-ACTIVITY OF S-P-BROMOBENZYLGLUTATHIONE CYCLOPENTYL DIESTER IN-VITRO AND IN-VIVO - INHIBITION OF GLYOXALASE-I AND INDUCTION OF APOPTOSIS

The glyoxalase I inhibitor diester, S-p-bromobenzyl-glutathione cyclop entyl diester (BrBzGSHCp(2)), inhibited the growth of human leukaemia 60 (HL60) cells in vitro. The median growth inhibitory concentration G C(50) value of BrBzGSHCp(2) was 4.23 +/- 0.01 mu M (n = 21), and the m edian toxic concentration TC50 value was 8.86 +/- 0.01 mu M (n = 21). BrBzGSHCp(2) inhibited DNA synthesis in the third hr of incubation: th e median inhibitory concentration IC50 value was 6.11 +/- 0.02 mu M (n = 8). Incubation of HL60 cells with 10 mu M BrBzGSHCp(2) delivered th e diester into cells: de-esterification of the diester therein lead to formation of the S-p-bromobenzylglutathione, inhibition of glyoxalase 1 activity in situ, increase in the methylglyoxal concentration after 1 hr, and induction of apoptosis after 6 hr. BrBzGSHCp(2) (50-200 mg/ kg) also inhibited the growth of murine adenocarcinoma 15A in vivo. Gl yoxalase I inhibitor diesters may, therefore, inhibit tumour growth by inducing the accumulation of methylglyoxal in tumour cells, and induc tion of apoptosis.