Cellular pharmacodynamics as a guide to leukemia therapy

ARABINOSYLCYTOSINE (ara-C), the most widely used drug for treating acute leukemias, is a pro-drug that must be phosphorylated to the active metabolite ara-CTP to exert cytotoxicity. Previous clinical pharmacology studies have demonstrated a strong relationship between the pharmacokinetics of ara-CTP in leukemia cells and clinical response to ara-C therapy for patients with both newly diagnosed and relapsed acute leukemias. The strategy of using high- dose ara-C to achieve higher intracellular ara-CTP is ineffective. Biochemical modulation of ara-C metabolism with fludarabine is a different strategy that effectively increases the ara-CTP concentration in leukemia cells. Likewise, the action of the DNA-damaging agent mitoxantrone was enhanced by its administration with ara-C. This combination resulted in enhanced DNA damage and an increased cellular concentration of ara-CTP, indicating a synergistic action. A rational extension of these approaches would be to combine both fludarabine and mitoxantrone with ara-C in the treatment of adult leukemias.