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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2005-4-7
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pubmed:abstractText |
Tumor vascularity is correlated with an aggressive disease phenotype in neuroblastoma, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We previously showed that the antiangiogenic compound TNP-470, an irreversible methionine aminopeptidase 2 (MetAP2) inhibitor, suppressed local and disseminated human neuroblastoma growth rates in murine models but had significant associated toxicity at the effective dose. We have recently shown that a novel, reversible MetAP2 inhibitor, A-357300, significantly inhibits CHP-134-derived neuroblastoma s.c. xenograft growth rate with a treatment-to-control (T/C) ratio at day 24 of 0.19 (P < 0.001) without toxicity. We now show that the combination of A-357300 with cyclophosphamide at the maximal tolerated dose sustained tumor regression with a T/C at day 48 of 0.16 (P < 0.001) in the CHP-134 xenograft model. A-357300 also significantly inhibited establishment and growth rate of hematogenous metastatic deposits following tail vein inoculation of CHP-134 cells and increased overall survival (P = 0.021). Lastly, A-357300 caused regression of established tumors in a genetically engineered murine model with progression-free survival in five of eight mice (P < 0.0001). There was no evidence of toxicity. These data show that MetAP2 may be an important molecular target for high-risk human neuroblastomas. We speculate that the growth inhibition may be through both tumor cell intrinsic and extrinsic (antiangiogenic) mechanisms. The potential for a wide therapeutic index may allow for treatment strategies that integrate MetAP2 inhibition with conventional cytotoxic compounds.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/A357300,
http://linkedlifedata.com/resource/pubmed/chemical/Aminopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/Chlorobenzenes,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclophosphamide,
http://linkedlifedata.com/resource/pubmed/chemical/MYCN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Metalloendopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/methionine aminopeptidase 2
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1078-0432
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pubmed:author |
pubmed-author:BarrRosalindR,
pubmed-author:EricksonScott ASA,
pubmed-author:KingRebeccaR,
pubmed-author:MarisJohn MJM,
pubmed-author:MorowitzMichael JMJ,
pubmed-author:PawelBruceB,
pubmed-author:RhodinNicholasN,
pubmed-author:SheppardGeorge SGS,
pubmed-author:ShustermanSuzanneS,
pubmed-author:WangJieyiJ,
pubmed-author:WangQunQ,
pubmed-author:ZhaoHuaqingH
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
11
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2680-5
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:15814649-Aminopeptidases,
pubmed-meshheading:15814649-Animals,
pubmed-meshheading:15814649-Antineoplastic Agents, Alkylating,
pubmed-meshheading:15814649-Chlorobenzenes,
pubmed-meshheading:15814649-Cyclophosphamide,
pubmed-meshheading:15814649-Drug Therapy, Combination,
pubmed-meshheading:15814649-Humans,
pubmed-meshheading:15814649-Metalloendopeptidases,
pubmed-meshheading:15814649-Mice,
pubmed-meshheading:15814649-Mice, Inbred Strains,
pubmed-meshheading:15814649-Mice, Nude,
pubmed-meshheading:15814649-Mice, SCID,
pubmed-meshheading:15814649-Mice, Transgenic,
pubmed-meshheading:15814649-Neuroblastoma,
pubmed-meshheading:15814649-Nuclear Proteins,
pubmed-meshheading:15814649-Oncogene Proteins,
pubmed-meshheading:15814649-Survival Analysis,
pubmed-meshheading:15814649-Treatment Outcome,
pubmed-meshheading:15814649-Tumor Cells, Cultured,
pubmed-meshheading:15814649-Xenograft Model Antitumor Assays
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pubmed:year |
2005
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pubmed:articleTitle |
Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models.
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pubmed:affiliation |
Division of Oncology, Department of Pathology, The Children's Hospital of Philadelphia, PA, USA.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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