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Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models.

Abstract
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.
AuthorsMichael J Morowitz, Rosalind Barr, Qun Wang, Rebecca King, Nicholas Rhodin, Bruce Pawel, Huaqing Zhao, Scott A Erickson, George S Sheppard, Jieyi Wang, John M Maris, Suzanne Shusterman
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 7 Pg. 2680-5 (Apr 1 2005) ISSN: 1078-0432 [Print] United States
PMID15814649 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • A357300
  • Antineoplastic Agents, Alkylating
  • Chlorobenzenes
  • MYCN protein, human
  • Nuclear Proteins
  • Oncogene Proteins
  • Cyclophosphamide
  • Aminopeptidases
  • methionine aminopeptidase 2
  • Metalloendopeptidases
Topics
  • Aminopeptidases (antagonists & inhibitors)
  • Animals
  • Antineoplastic Agents, Alkylating (therapeutic use)
  • Chlorobenzenes (pharmacology, therapeutic use)
  • Cyclophosphamide (therapeutic use)
  • Drug Therapy, Combination
  • Humans
  • Metalloendopeptidases (antagonists & inhibitors)
  • Mice
  • Mice, Inbred Strains
  • Mice, Nude
  • Mice, SCID
  • Mice, Transgenic
  • Neuroblastoma (pathology, prevention & control)
  • Nuclear Proteins (genetics, metabolism)
  • Oncogene Proteins (genetics, metabolism)
  • Survival Analysis
  • Treatment Outcome
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays (methods)

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