The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside-based treatment regimens in acute myeloid leukaemia with ahigh proliferative activity

The current study was initiated to explore the mechanisms underlying the pr eviously demonstrated association between the proliferative activity of leu kaemic blasts and the response to cytosine arabinoside (AraC)-based therapy in de novo acute myeloid leukaemia (AML). The activity of key enzymes of A raC metabolism-deoxycytidine kinase (DCK), cytidine deaminase (DCD) and pol ymerase a (PolyA) were determined in blast cells from 33 patients. In addit ion, formation and retention of intracellular levels of AraC triphosphate ( AraCTP) and DNA incorporation of AraC were measured, as was the proliferati ve activity of leukaemic blasts by [H-3]-TdR incorporation before and after stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte CSF (G-CSF) for 48 h. AraC incorporation into the DNA (medi an 0.60 pmol/10(5) cells) was significantly related to the proliferative ac tivity of AML blasts (r = 0.74, P < 0.001). Similarly, priming with GM-CSF or G-CSF increased both the proliferative activity of AML blasts by a media n of 1.84- and 1.64-fold, respectively and the incorporation of AraC into t he DNA (1.29- and 1.40-fold respectively), In contrast, no relationship was found between the endogenous proliferative activity (EPA) and enzyme activ ities regulating AraC activation (DCK: median 4.70 pmol/min/mg protein), in activation (DCD; median 2.92 pmol/min/mg protein) or inhibitory effects (Po lyA; median 1.50 pmol/min/mg protein), nor the formation or retention of Ar aCTP (median 306.1 ng/10(7) cell and 1.6 h respectively). When samples were grouped according to EPA (more than or less than the median), slowly proli ferating specimens had a higher response to cytokine priming for proliferat ive activity and incorporation of AraC into DNA. Clinical data of 15 patien ts were available. Although all eight patients with a high endogenous proli ferative activity reached complete remission, only four out of seven patien ts with a low proliferative activity responded, whereas the other three pat ients were non-responders (P = 0.077).