title: Raf inhibition causes extensive multiple tissue hyperplasia and urinary bladder neoplasia in the rat.
abstract: Seven novel and potent Raf small molecule kinase inhibitors (C1-7) were evaluated in seven-day oral repeat dose rat toxicity studies. All compounds tested induced hyperplasia in multiple tissues. Consistently affected was stratified squamous epithelium at a number of sites and transitional epithelium of urinary bladder and kidney. A seven-day time course study in rats showed morphologic evidence of epithelial proliferation in the nonglandular stomach within four to five hours after a single dose of C-1. Similar indications of cellular proliferation were observed in the urinary bladder by day 2 and in the heart, kidney, and liver by day 3. Transcriptional evidence of proliferation in the urinary bladder was detected within four to five hours after a single dose consistent with activation of the PI3K/AKT and ERK/MAPK pathways. In a twenty-eight-day rat toxicity study of C-1, hyperplasia was observed in the esophagus, nonglandular stomach, skin, urinary bladder, kidney, and heart. Hyperplasia of transitional epithelium of the urinary bladder was particularly severe and in one female rat was accompanied by the presence of a transitional cell carcinoma. These results suggest that these Raf inhibitors induce early transcriptional changes driving unchecked cell proliferation, resulting in marked tissue hyperplasia that can progress to carcinoma within a short time frame.
authors.affiliation: Comparative Biology Safety Sciences, Amgen Inc., Thousand Oaks, CA 91320-1799, USA. jwisler@amgen.com
authors.forename: John A
authors.initials: JA
authors.lastname: Wisler
authors.forename: Cynthia
authors.initials: C
authors.lastname: Afshari
authors.forename: Mark
authors.initials: M
authors.lastname: Fielden
authors.forename: Cameron
authors.initials: C
authors.lastname: Zimmermann
authors.forename: Scott
authors.initials: S
authors.lastname: Taylor
authors.forename: Josette
authors.initials: J
authors.lastname: Carnahan
authors.forename: Steven
authors.initials: S
authors.lastname: Vonderfecht
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D005260:Female; D006651:Histocytochemistry; D006965:Hyperplasia; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D014018:Tissue Distribution; D036401:Toxicity Tests, Chronic; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology
chemical_list: D047428:Protein Kinase Inhibitors; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf