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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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| Published in: | Leukemia research 2011-05, Vol.35 (5), p.677-681 |
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| cites | cdi_FETCH-LOGICAL-c451t-66e63434a623904aedd89b85b772afc3eca0377728e01a22c733afbb4ecc3a413 |
| container_end_page | 681 |
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| container_title | Leukemia research |
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| creator | Jenkins, Christopher Hewamana, Saman Krige, David Pepper, Chris Burnett, Alan |
| description | 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. |
| doi_str_mv | 10.1016/j.leukres.2010.10.030 |
| format | article |
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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.</description><identifier>ISSN: 0145-2126</identifier><identifier>EISSN: 1873-5835</identifier><identifier>DOI: 10.1016/j.leukres.2010.10.030</identifier><identifier>PMID: 21145592</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>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</subject><ispartof>Leukemia research, 2011-05, Vol.35 (5), p.677-681</ispartof><rights>Elsevier Ltd</rights><rights>2010 Elsevier Ltd</rights><rights>Copyright © 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-66e63434a623904aedd89b85b772afc3eca0377728e01a22c733afbb4ecc3a413</citedby><cites>FETCH-LOGICAL-c451t-66e63434a623904aedd89b85b772afc3eca0377728e01a22c733afbb4ecc3a413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21145592$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jenkins, Christopher</creatorcontrib><creatorcontrib>Hewamana, Saman</creatorcontrib><creatorcontrib>Krige, David</creatorcontrib><creatorcontrib>Pepper, Chris</creatorcontrib><creatorcontrib>Burnett, Alan</creatorcontrib><title>Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia</title><title>Leukemia research</title><addtitle>Leuk Res</addtitle><description>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.</description><subject>Acute myeloid leukemia</subject><subject>Adult</subject><subject>Aminopeptidases</subject><subject>Aminopeptidases - antagonists & inhibitors</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>CD13</subject><subject>Cell Culture Techniques</subject><subject>CHR-2797</subject><subject>Cytarabine - administration & dosage</subject><subject>Cytarabine - pharmacology</subject><subject>Drug Evaluation, Preclinical</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Female</subject><subject>Glycine - analogs & derivatives</subject><subject>Glycine - pharmacology</subject><subject>Glycine - therapeutic use</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Hydroxamic Acids - therapeutic use</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - enzymology</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Male</subject><subject>Metalloenzymes</subject><subject>Middle Aged</subject><subject>Molecular therapeutics</subject><subject>Tosedostat</subject><subject>Tumor Cells, Cultured</subject><subject>Young Adult</subject><issn>0145-2126</issn><issn>1873-5835</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqFUk1v1DAUtBCIbgs_AeQbcMjWH4mTXEDVitJKlSrxcbYc54V669jBdirl3-N0Fw699GBZfp438_RmEHpHyZYSKs73WwvzfYC4ZeSxtiWcvEAb2tS8qBpevUQbQsuqYJSJE3Qa454QUrW0fY1OGM0_Vcs2yF6MxvkJpmR6FQEbd2c6k4x3uFtwugPs_ANYrH6DS3h39b1gdVvjj8lH6H1MKn3Cgw-PyHyCmhbsB6z0nACPC1hverxOCqNRb9CrQdkIb4_3Gfp1-fXn7qq4uf12vbu4KXRZ0VQIAYKXvFSC8ZaUCvq-abum6uqaqUFz0IrwOj8aIFQxpmvO1dB1JWjNVUn5Gfpw4J2C_zNDTHI0UYO1yoGfo2zqkmbipnweKZjIWoJnZHVA6uBjDDDIKZhRhUVSIldH5F4eHZGrI2s5O5L73h8V5m6E_n_XPwsy4MsBAHkjDwaCjNqA09CbADrJ3ptnJT4_YdDWOKOVvYcF4t7PweV1Syojk0T-WGOxpoKugWCZ4C9oV7PF</recordid><startdate>20110501</startdate><enddate>20110501</enddate><creator>Jenkins, Christopher</creator><creator>Hewamana, Saman</creator><creator>Krige, David</creator><creator>Pepper, Chris</creator><creator>Burnett, Alan</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20110501</creationdate><title>Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia</title><author>Jenkins, Christopher ; Hewamana, Saman ; Krige, David ; Pepper, Chris ; Burnett, Alan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-66e63434a623904aedd89b85b772afc3eca0377728e01a22c733afbb4ecc3a413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Acute myeloid leukemia</topic><topic>Adult</topic><topic>Aminopeptidases</topic><topic>Aminopeptidases - antagonists & inhibitors</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>CD13</topic><topic>Cell Culture Techniques</topic><topic>CHR-2797</topic><topic>Cytarabine - administration & dosage</topic><topic>Cytarabine - pharmacology</topic><topic>Drug Evaluation, Preclinical</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Female</topic><topic>Glycine - analogs & derivatives</topic><topic>Glycine - pharmacology</topic><topic>Glycine - therapeutic use</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Hydroxamic Acids - therapeutic use</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - enzymology</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Male</topic><topic>Metalloenzymes</topic><topic>Middle Aged</topic><topic>Molecular therapeutics</topic><topic>Tosedostat</topic><topic>Tumor Cells, Cultured</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jenkins, Christopher</creatorcontrib><creatorcontrib>Hewamana, Saman</creatorcontrib><creatorcontrib>Krige, David</creatorcontrib><creatorcontrib>Pepper, Chris</creatorcontrib><creatorcontrib>Burnett, Alan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Leukemia research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jenkins, Christopher</au><au>Hewamana, Saman</au><au>Krige, David</au><au>Pepper, Chris</au><au>Burnett, Alan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia</atitle><jtitle>Leukemia research</jtitle><addtitle>Leuk Res</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>35</volume><issue>5</issue><spage>677</spage><epage>681</epage><pages>677-681</pages><issn>0145-2126</issn><eissn>1873-5835</eissn><abstract>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.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>21145592</pmid><doi>10.1016/j.leukres.2010.10.030</doi><tpages>5</tpages></addata></record> |
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| 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 |
| title | Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia |
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