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

  • Leuk Res. 2011 May;35(5):677-81. doi: 10.1016/j.leukres.2010.10.030.
Christopher Jenkins  1 ,  Saman Hewamana ,  David Krige ,  Chris Pepper ,  Alan Burnett
Affiliations
  • 1. Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK. [email protected]
PMID: 21145592 DOI: 10.1016/j.leukres.2010.10.030
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.

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