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

作者：Jenkins Christopher^*; Hewamana Saman; Krige David; Pepper Chris; Burnett Alan

来源：Leukemia Research, 2011, 35(5): 677-681.

DOI：10.1016/j.leukres.2010.10.030

• Aminopeptidases
• Metalloenzymes
• CHR-2797
• Tosedostat
• Acute myeloid leukemia
• CD13
• Molecular therapeutics

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.

• 出版日期2011-5