AT LEAST 2 WAYS TO APOPTOSE - THE 2-CHLORODEOXYADENOSINE-INDUCED CELL-DEATH SIGNALING PATHWAY IN HUMAN THYMOCYTES IS DIFFERENT FROM THAT INDUCED BY 2-CHLOROADENOSINE - COMMENT

2-Chloroadenosine induced DNA fragmentation and cell death in human th ymocytes primarily by Ca2(-)-dependent mechanisms. Incubation of human thymocytes with 2-chlorodeoxyadenosine (5-1000nM) also induced cell d eath (apoptosis) which was dependent on macromolecule synthesis and in volved activation of an endonuclease which was inhibited by Zn2-. The effect of 2-chlorodeoxyadenosine was prevented by addition of dipyrida mole, a strong nucleoside transport inhibitor, or of deoxycytidine, pr eviously shown to compete for uptake by deoxycytidine kinase. 2-Chloro deoxyadenosine-induced apoptosis did not involve increases in the cyto solic Ca2- concentration, but required the presence of intracellular C a2-. It was not inhibited by activators of protein kinase C previously shown to inhibit Ca2--dependent cell death. Addition of 2-chlorodeoxy adenosine induced an increase in the amount of p53 in human thymocytes , while 2-chloroadenosine had no effect. These data suggest that 2-chl oroadenosine and 2-chlorodeoxyadenosine induce cell death in human thy mocytes via different signalling pathways.