title: Tumor penetration and epidermal growth factor receptor saturation by panitumumab correlate with antitumor activity in a preclinical model of human cancer.
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.
authors: Amgen Inc, Thousand Oaks, CA, USA.
authors: Daniel J
authors: DJ
authors: Freeman
authors: Kevin
authors: K
authors: McDorman
authors: Selam
authors: S
authors: Ogbagabriel
authors: Carl
authors: C
authors: Kozlosky
authors: Bing-Bing
authors: BB
authors: Yang
authors: Sameer
authors: S
authors: Doshi
authors: Juan Jose
authors: JJ
authors: Perez-Ruxio
authors: William
authors: W
authors: Fanslow
authors: Charlie
authors: C
authors: Starnes
authors: Robert
authors: R
authors: Radinsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000077544:Panitumumab; D010766:Phosphorylation / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008024:Ligands; D000077544:Panitumumab; D066246:ErbB Receptors