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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

DC FieldValueLanguage
dc.contributor.author노재경-
dc.contributor.author라선영-
dc.contributor.author신상준-
dc.contributor.author안중배-
dc.contributor.author정현철-
dc.contributor.author황지원-
dc.date.accessioned2014-12-18T08:23:10Z-
dc.date.available2014-12-18T08:23:10Z-
dc.date.issued2013-
dc.identifier.issn0167-6997-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/86208-
dc.description.abstractOBJECTIVE: 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.-
dc.description.statementOfResponsibilityopen-
dc.relation.isPartOfINVESTIGATIONAL NEW DRUGS-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAdult-
dc.subject.MESHAged-
dc.subject.MESHAngiogenesis Inhibitors/pharmacology-
dc.subject.MESHAngiogenesis Inhibitors/therapeutic use-
dc.subject.MESHAnimals-
dc.subject.MESHAntibodies, Monoclonal, Humanized/pharmacology-
dc.subject.MESHAntibodies, Monoclonal, Humanized/therapeutic use-
dc.subject.MESHBevacizumab-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCell Proliferation/drug effects-
dc.subject.MESHColorectal Neoplasms/drug therapy-
dc.subject.MESHColorectal Neoplasms/metabolism*-
dc.subject.MESHColorectal Neoplasms/pathology-
dc.subject.MESHExtracellular Signal-Regulated MAP Kinases/metabolism-
dc.subject.MESHFemale-
dc.subject.MESHHuman Umbilical Vein Endothelial Cells-
dc.subject.MESHHumans-
dc.subject.MESHMice-
dc.subject.MESHMice, Nude-
dc.subject.MESHMiddle Aged-
dc.subject.MESHProto-Oncogene Proteins c-akt/metabolism*-
dc.subject.MESHTumor Burden/drug effects-
dc.subject.MESHVascular Endothelial Growth Factor A-
dc.subject.MESHVascular Endothelial Growth Factor Receptor-2/metabolism*-
dc.subject.MESHXenograft Model Antitumor Assays-
dc.titleCirculating vascular endothelial growth factor receptor 2/pAkt-positive cells as a functional pharmacodynamic marker in metastatic colorectal cancers treated with antiangiogenic agent-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학)-
dc.contributor.googleauthorSang Joon Shin-
dc.contributor.googleauthorJee Won Hwang-
dc.contributor.googleauthorJoong Bae Ahn-
dc.contributor.googleauthorSun Young Rha-
dc.contributor.googleauthorJae Kyung Roh-
dc.contributor.googleauthorHyun Cheol Chung-
dc.identifier.doi10.1007/s10637-012-9817-7-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA01290-
dc.contributor.localIdA02105-
dc.contributor.localIdA02262-
dc.contributor.localIdA03773-
dc.contributor.localIdA04490-
dc.contributor.localIdA01316-
dc.relation.journalcodeJ01184-
dc.identifier.eissn1573-0646-
dc.identifier.pmid22539090-
dc.identifier.urlhttp://link.springer.com/article/10.1007%2Fs10637-012-9817-7-
dc.subject.keywordVEGFR2-
dc.subject.keywordAkt-
dc.subject.keywordBevacizumab-
dc.subject.keywordPharmacodynamic marker-
dc.subject.keywordPhospho-flow cytometry-
dc.contributor.alternativeNameRoh, Jae Kyung-
dc.contributor.alternativeNameRha, Sun Young-
dc.contributor.alternativeNameShin, Sang Joon-
dc.contributor.alternativeNameAhn, Joong Bae-
dc.contributor.alternativeNameChung, Hyun Cheol-
dc.contributor.alternativeNameHwang, Jee Won-
dc.contributor.affiliatedAuthorRoh, Jae Kyung-
dc.contributor.affiliatedAuthorShin, Sang Joon-
dc.contributor.affiliatedAuthorAhn, Joong Bae-
dc.contributor.affiliatedAuthorChung, Hyun Cheol-
dc.contributor.affiliatedAuthorHwang, Jee Won-
dc.contributor.affiliatedAuthorRha, Sun Young-
dc.rights.accessRightsnot free-
dc.citation.volume31-
dc.citation.number1-
dc.citation.startPage1-
dc.citation.endPage13-
dc.identifier.bibliographicCitationINVESTIGATIONAL NEW DRUGS, Vol.31(1) : 1-13, 2013-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers

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