Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies
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- Bruno Morgan
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Anne L. Thomas
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Joachim Drevs
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Juergen Hennig
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Martin Buchert
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Asvina Jivan
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Mark A. Horsfield
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Klauss Mross
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Howard A. Ball
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Lucy Lee
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- William Mietlowski
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Stefan Fuxius
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Clemens Unger
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Ken O’Byrne
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Andrew Henry
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Graham R. Cherryman
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Dirk Laurent
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Margaret Dugan
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- Dieter Marmé
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
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- William P. Steward
- From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
抄録
<jats:p> Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. </jats:p><jats:p> Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. </jats:p><jats:p> Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. </jats:p><jats:p> Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. </jats:p>
収録刊行物
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- Journal of Clinical Oncology
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Journal of Clinical Oncology 21 (21), 3955-3964, 2003-11-01
American Society of Clinical Oncology (ASCO)
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詳細情報
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- CRID
- 1363670318275833088
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- NII論文ID
- 30022789261
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- ISSN
- 15277755
- 0732183X
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- データソース種別
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