RT Journal Article
SR Electronic
T1 Prediction of Active Drug Plasma Concentrations Achieved in Cancer Patients by Pharmacodynamic Biomarkers Identified from the Geo Human Colon Carcinoma Xenograft Model
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5558
OP 5565
DO 10.1158/1078-0432.CCR-05-0368
VO 11
IS 15
A1 Luo, Feng R.
A1 Yang, Zheng
A1 Dong, Huijin
A1 Camuso, Amy
A1 McGlinchey, Kelly
A1 Fager, Krista
A1 Flefleh, Christine
A1 Kan, David
A1 Inigo, Ivan
A1 Castaneda, Stephen
A1 Wong, Tai W.
A1 Kramer, Robert A.
A1 Wild, Robert
A1 Lee, Francis Y.
YR 2005
UL http://clincancerres.aacrjournals.org/content/11/15/5558.abstract
AB 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 IgG1 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. 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 μg/mL. Conclusions: Phospho-EGFR/phospho-MAPK could be useful clinical biomarkers to assess EGFR inhibition by cetuximab.