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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

Tumor penetration and epidermal growth factor receptor saturation by panitumumab correlate with antitumor activity in a preclinical model of human cancer

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Daniel J Freeman, Kevin McDorman, Selam Ogbagabriel, Carl Kozlosky, Bing-Bing Yang, Sameer Doshi, Juan Jose Perez-Ruxio, William Fanslow, Charlie Starnes, Robert Radinsky
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-47) contains supplementary material, which is available to authorized users.

Competing interests

DJF, SO, B-BY, SD, JJP-R, WF, CS, and RR are employees of and shareholders in Amgen Inc. KM and CK were employees of and shareholders in Amgen Inc. at the time this research was conducted. This study was funded by Amgen Inc.

Authors’ Contributions

DJF conceived of the study, and participated in its design and coordination, and helped draft the manuscript. KM performed the pathology analysis and interpretation and helped draft the manuscript. SO performed the molecular analysis. CK performed the in vivo pharmacodynamic analysis. B-BY performed the in vivo pharmacokinetic analysis. SD performed the pharmacokinetic modeling. JJP-R carried out the pharmacokinetic/pharmacodynamic/efficacy modeling. WF carried out the tumor saturation analysis and interpretation. CS developed the in vivo efficacy model. RR participated in design and coordination of the study and helped draft the manuscript. All authors read and approved the final manuscript.

Abstract

Background

Successful treatment of solid tumors relies on the ability of drugs to penetrate into the tumor tissue.

Methods

We examined the correlation of panitumumab (an anti-epidermal growth factor [EGFR] antibody) tumor penetration and EGFR saturation, a potential obstacle in large molecule drug delivery, using pharmacokinetics, pharmacodynamics, and tumor growth rate in an A431 epidermoid carcinoma xenograft model of human cancer. To determine receptor saturation, receptor occupancy, and levels of proliferation markers, immunohistochemical and flow cytometric methods were used. Pharmacokinetic data and modeling were used to calculate growth characteristics of panitumumab-treated tumors.

Results

Treatment with panitumumab in vivo inhibited pEGFR, Ki67 and pMAPK levels vs control. Tumor penetration and receptor saturation were dose- and time-dependent, reaching 100% and 78%, respectively. Significant tumor inhibition and eradication (p < 0.05) were observed; plasma concentration associated with tumor eradication was estimated to be 0.2 μg/ml. The tumor inhibition model was able to describe the mean tumor growth and death rates.

Conclusions

These data demonstrate that the antitumor activity of panitumumab correlates with its ability to penetrate into tumor tissue, occupy and inhibit activation of EGFR, and inhibit markers of proliferation and MAPK signaling.
Zusatzmaterial
Authors’ original file for figure 1
12943_2012_1039_MOESM1_ESM.pdf
Authors’ original file for figure 2
12943_2012_1039_MOESM2_ESM.pdf
Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Authors’ original file for figure 6
12943_2012_1039_MOESM6_ESM.pdf
Literatur
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