title: 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.
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK. jenkins800@hotmail.com
authors.forename: Christopher
authors.initials: C
authors.lastname: Jenkins
authors.forename: Saman
authors.initials: S
authors.lastname: Hewamana
authors.forename: David
authors.initials: D
authors.lastname: Krige
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.forename: Alan
authors.initials: A
authors.lastname: Burnett
mesh_terms: D000328:Adult; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D018929:Cell Culture Techniques; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C558825:CHR-79888; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D003561:Cytarabine; D000626:Aminopeptidases; C531970:tosedostat; D005998:Glycine