Abstract | PURPOSE: EXPERIMENTAL DESIGN: The pharmacodynamic study was conducted in nude mice bearing Geo tumors following a single i.p. administration of 0.25 and 0.04 mg. The tumors were analyzed by immunohistochemistry. The levels of phospho-EGFR were quantitated by an ELISA assay. RESULTS: At 0.25 mg, phospho-EGFR was maximally inhibited by 91% at 24 hours, whereas the level of inhibition decreased to 72% by 72 hours. At 0.04 mg, the maximum inhibition of phospho-EGFR was 53% at 24 hours, whereas the level of inhibition decreased to 37% by 72 hours. The time course of phospho-EGFR inhibition and recovery seemed to correlate with the pharmacokinetics of cetuximab. Immunohistochemical analysis showed that phospho-MAPK and Ki67 expression were inhibited between 24 and 72 hours at 0.25 and 0.04 mg. A pharmacokinetic/pharmacodynamic model was established and predicted that the plasma concentration of cetuximab required to inhibit 90% of phospho-EGFR was 67.5 mug/mL. CONCLUSIONS: Phospho-EGFR/phospho-MAPK could be useful clinical biomarkers to assess EGFR inhibition by cetuximab.
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Authors | Feng R Luo, Zheng Yang, Huijin Dong, Amy Camuso, Kelly McGlinchey, Krista Fager, Christine Flefleh, David Kan, Ivan Inigo, Stephen Castaneda, Tai W Wong, Robert A Kramer, Robert Wild, Francis Y Lee |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 11
Issue 15
Pg. 5558-65
(Aug 01 2005)
ISSN: 1078-0432 [Print] United States |
PMID | 16061873
(Publication Type: Journal Article)
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Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Biomarkers, Tumor
- Immunoglobulin G
- Ki-67 Antigen
- ErbB Receptors
- Cetuximab
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Topics |
- Animals
- Antibodies, Monoclonal
(chemistry, pharmacology)
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
(pharmacokinetics)
- Biomarkers, Tumor
- Cell Line, Tumor
- Cetuximab
- Colonic Neoplasms
(drug therapy, pathology)
- Enzyme-Linked Immunosorbent Assay
- ErbB Receptors
(metabolism)
- Female
- Humans
- Immunoglobulin G
(chemistry)
- Immunohistochemistry
- Ki-67 Antigen
(biosynthesis)
- MAP Kinase Signaling System
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Phosphorylation
- Time Factors
- Xenograft Model Antitumor Assays
(methods)
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