Abstract
Although there is widespread use of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) in the treatment of acute leukemia, knowledge of the pharmacological mechanism of these drugs is limited. To clarify the cytotoxic mechanism of 6-MP and 6-TG in ML-1 cells and CCRF-CEM cells, intracellular active metabolites were analyzed with HPLC. Intracellular active metabolites of thiopurines were extracted with TCA and neutralized with freon-alamine and analyzed with Waters' HPLC equipped with SAX-10 anion exchange column. The 6-TG was activated to thioguanine mono-, di-, and triphosphate. The intracellular major metabolite of 6-MP was 6-thioinosine monophosphate. No 6-thioinosine di-and triphosphate were detected in cells even at 6-MP concentration up to 1 × 10-4 M. We suggested that the cytotoxic mechanism of 6-TG includes inhibition of both purine pathway and DNA synthesis, and that 6-MP inhibits only the purine pathway.
