Brunner's gland lesions in rats induced by a vascular endothelial growth factor receptor inhibitor.
Vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitors are reported to cause reversible mucosal hyperplasia (adenosis) in the duodenum of rats; however, the pathogenesis is not fully elucidated. Using lenvatinib, a VEGF RTK inhibitor, we characterized the histologic time course of this duodenal change in rats. At 4 weeks, there was degeneration and necrosis of Brunner's gland epithelium accompanied by neutrophil infiltration around the affected glands. At 13 weeks, the inflammation was more extensive, and Brunner's gland epithelium was attenuated and flattened and was accompanied by reactive hyperplasia of duodenal epithelium. At 26 weeks, the changes became more severe and chronic and characterized by marked cystic dilation, which extended to the external muscular layer. These dilated glands exhibited morphological characteristics of duodenal crypt epithelium, suggestive of replacement of disappeared Brunner's glands by regenerative duodenal crypt epithelial cells. Similar changes were not present in similar time course studies in dog and monkey studies, suggesting that this is a rodent- or species-specific change. Based on the temporal progression of Brunner's gland lesion, we identify degeneration and necrosis of the Brunner's glands as the primary change leading to inflammation, cystic dilatation, and regeneration with cells that are morphologically suggestive of duodenal crypt epithelium.
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan a-inomata@hhc.eisai.co.jp.
Akira
A
Inomata
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan.
Kyoko
K
Nakano-Ito
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan.
Yasuhiro
Y
Fujikawa
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan.
Jiro
J
Sonoda
Preclinical Safety Research Laboratories, Kawashima Division, Sunplanet, Kagamigahara, Gifu, Japan.
Kazuhiro
K
Hayakawa
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan.
Etsuko
E
Ohta
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan.
Yoshikazu
Y
Taketa
Drug Safety Andover, Eisai, Andover, Massachusetts, USA.
Yvonne
Y
Van Gessel
Drug Safety Andover, Eisai, Andover, Massachusetts, USA.
Sandeep
S
Akare
Drug Safety Andover, Eisai, Andover, Massachusetts, USA.
David
D
Hutto
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan.
Satoru
S
Hosokawa
Drug Safety Tsukuba, Eisai, Tsukuba, Ibaraki, Japan.
Kazuo
K
Tsukidate
D000818:Animals; D002011:Brunner Glands / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D004378:Duodenal Diseases / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008297:Male; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011804:Quinolines / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D010671:Phenylurea Compounds; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; D020794:Receptor Protein-Tyrosine Kinases; C531958:lenvatinib
Brunner’s gland; lenvatinib; nonclinical toxicity.; rats; receptor tyrosine kinase inhibitor; vascular endothelial growth factor