THE 2-CHLORODEOXYADENOSINE-INDUCED CELL-DEATH SIGNALING PATHWAY IN HUMAN THYMOCYTES IS DIFFERENT FROM THAT INDUCED BY 2-CHLOROADENOSINE

2-Chloroadenosine induced DNA fragmentation and cell death in human th ymocytes primarily by Ca2+-dependent mechanisms. Incubation of human t hymocytes with 2-chlorodeoxyadenosine (5-1000 nM) also induced cell de ath (apoptosis) which was dependent on macromolecule synthesis and inv olved activation of an endonuclease which was inhibited by Zn2+. The e ffect of 2-chlorodeoxyadenosine was prevented by addition of dipyridam ole, a strong nucleoside transport inhibitor, or of deoxycytidine, pre viously shown to compete for uptake by deoxycytidine kinase. 2-Chlorod eoxyadenosine-induced apoptosis did not involve increases in the cytos olic Ca2+ concentration, but required the presence of intracellular Ca 2+. It was not inhibited by activators of protein kinase C previously shown to inhibit Ca2+-dependent cell death. Addition of 2-chlorodeoxya denosine induced an increase in the amount of p53 in human thymocytes, while 2-chloroadenosine had no effect. These data suggest that 2-chlo roadenosine and 2-chlorodeoxyadenosine induce cell death in human thym ocytes via different signalling pathways.