BACKGROUND: Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis. METHODS: The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved. RESULTS: Using a non-diabetic rat model of steatohepatitis with choline deficient L-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies. CONCLUSION: Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.
BACKGROUND: Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis. METHODS: The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved. RESULTS: Using a non-diabeticrat model of steatohepatitis with choline deficient L-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies. CONCLUSION: Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.
Authors: Y Nakai; H Isayama; H Ijichi; T Sasaki; N Sasahira; K Hirano; H Kogure; K Kawakubo; H Yagioka; Y Yashima; S Mizuno; K Yamamoto; T Arizumi; O Togawa; S Matsubara; T Tsujino; K Tateishi; M Tada; M Omata; K Koike Journal: Br J Cancer Date: 2010-10-26 Impact factor: 7.640
Authors: D Nakae; H Yoshiji; Y Mizumoto; K Horiguchi; K Shiraiwa; K Tamura; A Denda; Y Konishi Journal: Cancer Res Date: 1992-09-15 Impact factor: 12.701
Authors: Scott M Wilhelm; Christopher Carter; Liya Tang; Dean Wilkie; Angela McNabola; Hong Rong; Charles Chen; Xiaomei Zhang; Patrick Vincent; Mark McHugh; Yichen Cao; Jaleel Shujath; Susan Gawlak; Deepa Eveleigh; Bruce Rowley; Li Liu; Lila Adnane; Mark Lynch; Daniel Auclair; Ian Taylor; Rich Gedrich; Andrei Voznesensky; Bernd Riedl; Leonard E Post; Gideon Bollag; Pamela A Trail Journal: Cancer Res Date: 2004-10-01 Impact factor: 13.312
Authors: Matthias Pinter; Arndt Weinmann; Marcus-Alexander Wörns; Florian Hucke; Simona Bota; Jens U Marquardt; Dan G Duda; Rakesh K Jain; Peter R Galle; Michael Trauner; Markus Peck-Radosavljevic; Wolfgang Sieghart Journal: United European Gastroenterol J Date: 2017-02-26 Impact factor: 4.623
Authors: Kirstine S Tølbøl; Birgit Stierstorfer; Jörg F Rippmann; Sanne S Veidal; Kristoffer T G Rigbolt; Tanja Schönberger; Matthew P Gillum; Henrik H Hansen; Niels Vrang; Jacob Jelsing; Michael Feigh; Andre Broermann Journal: Dig Dis Sci Date: 2018-12-03 Impact factor: 3.199