Prediction of active drug plasma concentrations achieved in cancer patients by pharmacodynamic biomarkers identified from the geo human colon carcinoma xenograft model.
Clin Cancer Res
; 11(15): 5558-65, 2005 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-16061873
ABSTRACT
PURPOSE:
Epidermal growth factor receptor (EGFR), a protein tyrosine kinase expressed in many types of human cancers, has been strongly associated with tumor progression. Cetuximab is an IgG(1) anti-EGFR chimeric mouse/human monoclonal antibody that has been approved for the treatment of advanced colon cancer. Using human tumor xenografts grown in nude mice, we have determined the in vivo pharmacodynamic response of cetuximab at efficacious doses. Three pharmacodynamic end points were evaluated tumoral phospho-EGFR, tumoral mitogen-activated protein kinase (MAPK) phosphorylation, and Ki67 expression. EXPERIMENTALDESIGN:
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biomarcadores Tumorais
/
Neoplasias do Colo
/
Ensaios Antitumorais Modelo de Xenoenxerto
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article