抄録
Mechanism of action of 6-mercaptopurine (6-MP) and 6thioguanine (6-TG) were investigated in cultured L-1210mouse leukemia cells and human leukemic leukocytes. In L-1210 cells,6-MP and 6-TG were catalyzed by HGPRTase to 6-TIMP and 6-TGMP, respectively.6-TG was a competitive inhibitor of hypoxanthine in the presence of PRPP as fixed substrate and the inhibition coefficient (Ki) was 240μM. Also,6-TG inhibition was competitive against guanine with the Ki value of 60μM. The inhibitory effect of 0.2 mM of 6-TG on the IMP synthesis was similar to that of 2.5mM of 6-MP in human leukemic leukocytes. The HGPRTase activity of leukocytes obtained from 10 normal subjects,8 patients with chronic leukemia and 9 patients with acute leukemia were determined. When the HGPRTase activity was expressed as the μmole of synthesized IMP/hr/2×107 cells, the HGPRTase activity of normal leukocytes, chronic leukemia cells and acute leukemia cells were 0.193 ± 0.114,0.230 ± 0.086and 0.172 ± 0.068μmoles, respectively. The mean value of HGPRTase activity of chronic leukemia cells was significantly increased than that of acute leukemia cells. The inhibitory effect of 6-MP on IMP synthesis correlated to the HGPRTase activity significantly in both types of leukemias. The inhibitory effect of 6-TG correlated to the HGPRTase activity significantly in acute leukemia but not in chronic leukemia. The correlation between the inhibitory effect of drugs and percentage of immature leukemia cells was not obtained. It appeared that the HGPRTase activity played an important role in inhibitory effect of 6-MP and 6-TG as well as the concentration of intracellular PRPP.
