The cytotoxicity of thioguanine vs mercaptopurine in acute lymphoblastic leukemia

The use of mercaptopurine (MP) rather than thioguanine (TG) in the treatment of childhood acute lymphoblastic leukemia (ALL) has occurred for historical reasons, but does not have a pharmacologic basis. The purpose of this study was to begin to address whether TG would be more efficacious than MP in the treatment of childhood ALL. Pre-clinical cytotoxicity studies were performed using human leukemic cell lines and leukemic 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 determined 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 displayed 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 cytotoxicity threshold was approximately 1 μM, with maximum cytotoxicity occurring with 10 μM concentrations. For TG, the threshold was only 0.05 μM with maximum cytotoxicity occurring at 0.5 μM. Exposure to MP for more than 8 h was necessary to produce cytotoxicity, whereas exposures as short as 4 h were required for TG. Leukemic cells from children with ALL were also more sensitive to TG than to MP. The median IC 50 for TG (20μM) was significantly lower than that for MP (⩾206μM). The data presented here provide a strong rationale for evaluating TG in place of MP in the treatment of childhood ALL. The more direct intracellular activation pathway, higher potency, and shorter duration of drug exposure necessary for cytotoxicity all suggest that TG may have an advantage over MP.