THE CYTOTOXICITY OF THIOGUANINE VS MERCAPTOPURINE IN ACUTE LYMPHOBLASTIC-LEUKEMIA

The use of mercaptopurine (MP) rather than thioguanine (TG) in the tre atment of childhood acute lymphoblastic leukemia (ALL) has occurred fo r historical reasons, but does not have a pharmacologic basis. The pur pose of this study was to begin to address whether TG would be more ef ficacious than MP in the treatment of childhood ALL, Pre-clinical cyto toxicity studies were performed using human leukemic cell lines and le ukemic cells from patients with ALL. First, the concentration-survival curves for MP and TG in three human leukemic cell lines (MOLT-4, CCRF -CEM and Wilson) were determined. The second group of experiments dete rmined the concentration-time dependence for cytotoxicity of MP and TG . The final group of experiments compared the in vitro cytotoxicity of MP to TG in leukemic cells from patients with ALL. The thiopurines di splayed classical anti-metabolite cytotoxicity profiles, exhibiting a cytotoxicity threshold concentration and demonstrating an increase in cell kill with prolongation of exposure to the drug. For MP, the cytot oxicity threshold was approximately 1 mu M, with maximum cytotoxicity occurring with 10 mu M concentrations. For TG, the threshold was only 0.05 mu M with maximum cytotoxicity occurring at 0.5 mu M. Exposure to MP for more than 8 h was necessary to produce cytotoxicity, whereas e xposures as short as 4 h were required for TG. Leukemic cells from chi ldren with ALL were also more sensitive to TG than to MP. The median I C50 for TG (20 mu M) was significantly lower than that for MP (greater than or equal to 206 mu M). The data presented here provide a strong rationale for evaluating TG in place of MP in the treatment of childho od ALL. The more direct intracellular activation pathway, higher poten cy, and shorter duration of drug exposure necessary for cytotoxicity a ll suggest that TG may have an advantage over MP.