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Circulating vascular endothelial growth factor receptor 2/pAkt-positive cells as a functional pharmacodynamic marker in metastatic colorectal cancers treated with antiangiogenic agent

Title
 Circulating vascular endothelial growth factor receptor 2/pAkt-positive cells as a functional pharmacodynamic marker in metastatic colorectal cancers treated with antiangiogenic agent
Authors
 Sang Joon Shin; Jee Won Hwang; Hyun Cheol Chung; Jae Kyung Roh; Sun Young Rha; Joong Bae Ahn
Issue Date
2013
Journal Title
 Investigational New Drugs
ISSN
 0167-6997
Citation
 Investigational New Drugs, Vol.31(1) : 1~13, 2013
Abstract
OBJECTIVE: The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has received considerable attention as a first-line treatment of advanced colorectal cancers. Difficulties associated with effectively monitoring the activity of this drug have prompted us to seek a pharmacodynamic marker suitable for defining the optimum biological dose and schedule of bevacizumab administration against colon cancer in early clinical trials. METHODS: We evaluated inhibitory effects of bevacizumab on VEGF signaling and tumor growth in vitro and in vivo, and assessed phosphorylation of VEGF receptor 2 (VEGFR2) and downstream signaling in endothelial cells as pharmacodynamic markers using phospho-flow cytometry. We also validated markers in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy. RESULTS: In in vitro studies, bevacizumab inhibited proliferation of human umbilical vein endothelial cells in association with reduced VEGF signaling. Notably, bevacizumab inhibited VEGF-induced phosphorylation of VEGFR-2, Akt, and extracellular signal-regulated kinase (ERK). In vivo, treatment with bevacizumab inhibited growth of xenografted tumors and attenuated VEGF-induced phosphorylation of Akt and ERK. The median percentages of VEGFR2 + pAkt + and VEGFR2 + pERK + cells, determined by phospho-flow cytometry, were approximately 3-fold higher in mCRC patients than in healthy controls. Bevacizumab treatment decreased VEGFR2 + pAkt + cells in 18 of 24 patients on day 3. CONCLUSION: Bevacizumab combined with chemotherapy decreased the number of VEGFR2 + pAkt + cells, reflecting impaired VEGFR2 signaling. Together, these data suggest that changes in the proportion of circulating VEGFR2 + pAkt + cells may be a potential pharmacodynamic marker of the efficacy of antiangiogenic agents, and could prove valuable in determining drug dosage and administration schedule.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/86208
DOI
10.1007/s10637-012-9817-7
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Internal Medicine
1. 연구논문 > 1. College of Medicine > Medical Research Center
Yonsei Authors
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Link
 http://link.springer.com/article/10.1007%2Fs10637-012-9817-7
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