The pharmacologic basis for the efficacy of high-dose Ara-C and sequential asparaginase in adult acute myelogenous leukemia

Dose-related effects of ara-C include overcoming a relative transport impediment in human leukemia cells. This result then allows intracellular metabolism and incorporation into DNA to proceed to the maximum extent possible. In addition, the increased synthesis of ara-CDP-choline associated with these high doses may serve as an alternate substrate for phosphatidyl choline synthesis, which may contribute to membrane fragility and cell lysis. HiDAC also serves as a "prodrug" for high concentrations of ara-U, which in turn diminishes ara-C catabolism with a prolonged gamma phase of systemic clearance and also causes cytostasis in S-phase with enhanced anabolism and cytotoxicity of subsequent doses of ara-C. This metabolite/drug interaction could be termed "self-potentiation," a feature which contributes to the overall activity of HiDAC. Asparaginase enhances these effects in a schedule-dependent fashion by lowering the cellular pool size of dCTP and consequent enhanced metabolism of ara-C. The therapeutic benefit of these pharmacologic manipulations has been verified in a randomized clinical trial in patients with acute myelogenous leukemia.