Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia
Document Type
Article
Abstract
Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. Summary: Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult-onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound-induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.
Keywords
activin receptors, anemia, angiogenesis inhibitors, arteriovenous malformation, hereditary hemorrhagic, telangiectasia
Publication Date
6-1-2017
Publication Title
Journal of Thrombosis and Haemostasis
ISSN
15387933
E-ISSN
15387836
Volume
15
Issue
6
First Page
1095
Last Page
1102
PubMed ID
28339142
Digital Object Identifier (DOI)
10.1111/jth.13683
Recommended Citation
Kim, Y. H.; Kim, M. J.; Choe, S. W.; Sprecher, D.; Lee, Y. J.; and P. Oh, S., "Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia" (2017). Translational Neuroscience. 1025.
https://scholar.barrowneuro.org/neurobiology/1025