Elacytarabine, a novel 5′-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia

Cytarabine (ara-C, [1-β-D-arabinofuranosylcytosine]), enters cells primarily as a false substrate through specialized nucleoside transporter proteins, predominantly hENT1 (the human equilibrative nucleoside transporter. Reduced hENT1 expression and activity is associated with adverse therapeutic outcomes and reduced cytotoxicity for patients treated with cytarabine (1, 2). Patients with AML and low hENT1 expression have reduced disease- free survival (1, 3). Elacytarabine (CP-4055) (Figure 1), the lipophilic 5′-elaidic acid ester of cytarabine, enters cells independently of hENT1. Preclinical studies of elacytarabine demonstrate activity in cytarabine-resistant cell lines and in animal models with tumor xenografts (4, 5). Elacytarabine may thus be active in patients with leukemia for whom cytarabine is ineffective (6-8). We conducted a study to determine DLT, establish the pharmacokinetics (PK) and toxicity profiles and to obtain a preliminary assessment of activity of elacytarabine CIV combined with idarubicin in adult patients with refractory AML. Open in a separate window Figure 1 Elacytarabine mechanism of action relative to that of cytarabine (ara-C) The cytotoxic activity of elacytarabine relative to that of cytarabine is mediated through increased cell uptake, decreased deactivation to ara-U, prolonged exposure to ara-CTP and transient inhibition of RNA synthesis.