Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia.

ABSTRACT

Aminopeptidase enzyme inhibition is thought to deplete the free intracellular amino acids needed by malignant cells for growth and development, resulting in profound anti-proliferative and apoptotic effects. In this study, we investigated the effects of the metalloenzyme-inhibitor CHR-2797 (tosedostat), in primary acute myeloid leukemia (AML) cells. CHR-2797 demonstrated marked in vitro cytotoxicity in AML samples and strong synergy with Cytarabine (Ara-C), but significantly less cytotoxicity to normal marrow progenitors. Furthermore mechanistic investigations revealed that CHR-2797 inhibited the intrinsic nuclear, cytoplasmic and cell surface aminopeptidase function of AML blasts in a dose-dependent manner, demonstrating a promising novel approach for AML therapy.