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...

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Bibliographic Details
Published in:Leukemia research 2011-05, Vol.35 (5), p.677-681
Main Authors: Jenkins, Christopher, Hewamana, Saman, Krige, David, Pepper, Chris, Burnett, Alan
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Adult
Aminopeptidases
Aminopeptidases - antagonists & inhibitors
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - pharmacology
CD13
Cell Culture Techniques
CHR-2797
Cytarabine - administration & dosage
Cytarabine - pharmacology
Drug Evaluation, Preclinical
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Female
Glycine - analogs & derivatives
Glycine - pharmacology
Glycine - therapeutic use
Hematology, Oncology and Palliative Medicine
Humans
Hydroxamic Acids - pharmacology
Hydroxamic Acids - therapeutic use
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - enzymology
Leukemia, Myeloid, Acute - pathology
Male
Metalloenzymes
Middle Aged
Molecular therapeutics
Tosedostat
Tumor Cells, Cultured
Young Adult
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Summary: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.
ISSN:0145-2126
1873-5835
DOI:10.1016/j.leukres.2010.10.030