MODULATION OF THE CELLULAR-METABOLISM OF CYTARABINE AND FLUDARABINE BY GRANULOCYTE-COLONY-STIMULATING FACTOR DURING THERAPY OF ACUTE MYELOGENOUS LEUKEMIA

Previous in vitro investigations demonstrated that human leukemia cell s, when incubated with hematopoietic growth factors such as granulocyt e-colony-stimulating factor (G-CSF), augment the accumulation of the t riphosphate 1-beta-D arabinofuranosylcytosine (ara-C cytarabine), To t est whether G-CSF infusion prior to ara-C infusion would biologically modulate the accumulation of ara-9-beta-D-arabinofuranosylcytosine 5'- triphosphate (ara-CTP) and other ara nucleotides in the leukemia blast s during therapy, protocols were designed to infuse G-CSP prior to flu darabine (9-beta-D-arablnofuranosyl-2-fluoroadenine monophosphate) and ara-C to increase the accumulation of the active triphosphates [9-bet a-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) and a ra-CTP] in acute myelogenous leukemia (AML) blasts during therapy, To complement these in vivo studies, ex vive accumulation of ara-CTP was also investigated before and after G-CSF infusion, Patients (n = 5) tr eated on the fludarabine/ara-C/G-CSF regimen received a 30 mg/m(2) dos e of fludarabine followed by a 2 g/m(2) dose of ara-C infused i.v. for 4 h, Beginning at 24 h, and every day, patients received a 6-h infusi on of 400 mu g/m(2) G-CSF, At 48 h, the fludarabine and ara-C couplet was repeated, Comparison of F-ara-ATP pharmacokinetics in circulating AML cells of patients on the fludarabine/ara- C/G-CSF regimen demonstr ated that the area under concentration time curve (AUG) of F-ara-ATP i ncreased significantly (median, 1.4-fold; range, 0.9-1.5; P = 0.045) a fter G-CSF infusion, This was due to an increased rate of F-ara-ATP ac cumulation by AML cells, The AUC of ara-CTP, on the other hand, was no t affected (median, 1.0-fold; range, 1.0-1.2; P = 0.571) after G-CSF i nfusion, Because fludarabine potentiates the accumulation of ara-CTP, the effect of G-CSF on ara-CTP metabolism may not be evident in the AM L blasts of patients on the fludarabine/ara-C/G-CSF regimen. To determ ine the effect of G-CSF when ara-C was infused alone, four additional patients were treated on a pilot protocol in which ara-C (2 g/m(2)) wa s infused on days 1 and 3 and G-CSF on day 2, The AUC of ara-CTP accum ulation in these patients decreased by a median of 48% after G-CSF inf usion, Consistent,vith these in vive investigations, ex vive ara-CTP a ccumulation was decreased in the AML blasts after G-CSF infusion, Base d on these data it could be concluded that (a) infusion of G-CSF befor e fludarabine augmented the rate of F-ara-ATP synthesis in circulating AML blasts during therapy, suggesting that G-CSF may benefit fludarab ine therapy by biological modulation; (b) G-CSF did not increase ara-C TP accumulation, rather it may have caused it to decrease; and (c) the se data imply that when G-CSF and ara-C are used in combination, admin istration of fludarabine prior to ara-C may maintain the ara-CTP AUG.