Intracellular pharmacodynamic studies of the synergistic combination of 6-mercaptopurine and cytosine arabinoside in human leukemia cell lines.

摘要: Selective combinations of purine and pyrimidine analogs increase remission rates in pediatric patients with relapsed leukemias. The combination 6-mercaptopurine (6-MP) cytosine arabinoside (ara-C) may exhibit synergism similar to that observed for fludarabine ara-C diminish the potential development resistance since two drugs are activated by separate enzymatic pathways. To determine efficacy against human leukemia cells, we investigated time-concentration relationships given alone or resultant cytotoxicity. whether leads enhanced activity deoxycytidine kinase (dCk), ratelimiting enzyme activation, characterized cellular dCk CCRF/CEM/0, CCRF/CEM/ara-C/7A, CCRF/CEM/ara-C/3A monoclonal cells before after treatment 6-MP. CCRF/CEM/0 (wild type), CCRF/CEM/ara-C/7A (≈50% ara-C-resistant as determined sensitivity assay characterization), (≈90% resistant ara-C) were incubated various concentrations 6-MP combination. Cell survival, inhibition DNA synthetic capacity (DSC), ara-CTP anabolism, characteristics studied. Incubation CEM/0 24 h, followed 48 increased cell-growth approximately 0.5–1 log10, corresponding 5- 10-fold synergism, compared identical drug incubation all cell lines. Simultaneous administration showed no whereas reversal sequence produced an antagonistic effect. levels 2-to 3.5-fold 3- 5-fold higher CEM/ara-C/7A respectively, exposed than those at same concentrations. Furthermore, a progressive was noted increasing 10 20 μM ara-C. A significant decrease DSC upon wild-type ara-Cresistant exhibits sequence-specific both partially also exerts collateral pretreatment play role enhancing thus producing sensitive