Abstract | PURPOSE: EXPERIMENTAL DESIGN: HT-29 CRC cell line xenografts were treated with either vehicle or ENMD-2076 (100 or 200 mg/kg) orally daily for 28 days. Tumor growth inhibition, dynamic contrast-enhanced magnetic resonance imaging, and (18)FDG-positron emission tomography were conducted to assess the antiproliferative, antiangiogenic, and antimetabolic responses, respectively. Effects on proliferation were also analyzed by immunohistochemical methods. Additionally, three patient-derived xenografts from primary and metastatic sites were treated with ENMD-2076 (100 mg/kg) and assessed for tumor growth inhibition. RESULTS: In the HT-29 xenograft model, ENMD-2076 induced initial tumor growth inhibition followed by regression. Treatment was associated with significant tumor blanching, indicating a loss of vascularity and substantial reductions in tumor vascular permeability and perfusion as measured by dynamic contrast-enhanced magnetic resonance imaging. Positron emission tomography scanning showed significant decreases in (18)FDG uptake at days 3 and 21 of treatment, which was associated with a marked reduction in proliferation as assessed by Ki-67. All three of the patient-derived xenografts tested were sensitive to treatment with ENMD 2076 as measured by tumor growth inhibition. CONCLUSIONS:
ENMD-2076 showed robust antitumor activity against cell line and patient-derived xenograft models of CRC that is detectable by functional imaging, supporting clinical investigation of this agent in CRC.
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Authors | John J Tentler, Erica L Bradshaw-Pierce, Natalie J Serkova, Kendra M Hasebroock, Todd M Pitts, Jennifer R Diamond, Graham C Fletcher, Mark R Bray, S Gail Eckhardt |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 16
Issue 11
Pg. 2989-2998
(Jun 01 2010)
ISSN: 1557-3265 [Electronic] United States |
PMID | 20406842
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright 2010 AACR. |
Chemical References |
- Antineoplastic Agents
- ENMD 2076
- Ki-67 Antigen
- Protein Kinase Inhibitors
- Pyrazoles
- Pyrimidines
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Topics |
- Animals
- Antineoplastic Agents
(therapeutic use)
- Capillary Permeability
(drug effects)
- Cell Proliferation
(drug effects)
- Colorectal Neoplasms
(blood supply, drug therapy)
- Female
- HT29 Cells
- Humans
- Ki-67 Antigen
(analysis)
- Mice
- Mice, Nude
- Positron-Emission Tomography
- Protein Kinase Inhibitors
(therapeutic use)
- Pyrazoles
(therapeutic use)
- Pyrimidines
(therapeutic use)
- Xenograft Model Antitumor Assays
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