6-MERCAPTOPURINE DECREASES THE BCL-2 BAX RATIO AND INDUCES APOPTOSIS IN ACTIVATED SPLENIC B-LYMPHOCYTES/

6-Mercaptopurine and related purine antimetabolites are used in the tr eatment of several B cell disorders. These drugs inhibited the prolife ration of mature splenic B cells after being triggered with polyclonal mitogens. In addition to the antiproliferative effects, B-mercaptopur ine, 2-mercaptopurine, and aminoguanidine evoked a rapid apoptotic cel l death in activated B cells that started at 6 hr after drug treatment and therefore preceded DNA synthesis. Incubation of activated B lymph ocytes with 8-mercaptopurine blocked the low but sustained nitric oxid e release observed in these cells that contributes to the prevention o f apoptotic cell death; the addition of chemical nitric oxide donors s ignificantly antagonized the apoptosis elicited by these drugs. The in hibition of nitric oxide synthesis elicited by mercaptopurines correla ted with a decrease in the release of nitric oxide-derived species to the culture medium and in the intracellular levels of cGMP. The ratio between the amounts of Bcl-2 and Bar, two proteins involved in the con trol of apoptosis in mature B cells, markedly decreased as result of m ercaptopurine treatment.