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.
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Authors | Michael 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 |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 11
Issue 7
Pg. 2680-5
(Apr 01 2005)
ISSN: 1078-0432 [Print] United States |
PMID | 15814649
(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.)
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Chemical References |
- A357300
- Antineoplastic Agents, Alkylating
- Chlorobenzenes
- MYCN protein, human
- N-Myc Proto-Oncogene Protein
- Nuclear Proteins
- Oncogene Proteins
- Cyclophosphamide
- Aminopeptidases
- methionine aminopeptidase 2
- Metalloendopeptidases
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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
- N-Myc Proto-Oncogene Protein
- 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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