角质形成细胞
帕唑帕尼
索拉非尼
药理学
医学
血管内皮生长因子
毒性
酪氨酸激酶
血管生成
癌症研究
内科学
生物
受体
血管内皮生长因子受体
体外
癌症
生物化学
舒尼替尼
肝细胞癌
作者
Aya Hasan Al-Shammari,Yusuke Masuo,Ken‐ichi Fujita,Kazuhiro Shimada,Noriho Iida,Tomohiko Wakayama,Yukio Kato
标识
DOI:10.1016/j.bcp.2022.114914
摘要
Tyrosine kinase inhibitors (TKIs) are molecular-targeted anticancer drugs. Their benefits are limited by dermal toxicities, including hand-foot skin reaction (HFSR), which is commonly found in skin areas subjected to friction. The present study aimed to explain the incidence of HFSR in patients treated with TKIs by focusing on keratinocyte toxicity and inhibition of vascular endothelial growth factor receptor (VEGFR), which plays an essential role in angiogenesis. Mice with gene knockout for the immunosuppressive cytokine interleukin-10 exhibited HFSR-like phenotypes, such as cytotoxicity in keratinocytes and increased number and size of blood vessels after repeated doses of regorafenib, sorafenib, and pazopanib, all of which cause high incidence of HFSR, in combination with tape-stripping mimicking skin damage at the friction site. Comprehensive examination of the direct cytotoxic effects of 21 TKIs on primary cultured human keratinocytes revealed that 18 of them reduced the cell viability dose-dependently. Importantly, the ratio of the trough concentration in patients (Ctrough) to the LC50 values of cell viability reduction was higher than unity for four HFSR-inducing TKIs, suggesting that these TKIs cause keratinocyte toxicity at clinically relevant concentrations. In addition, eight HFSR-inducing TKIs caused inhibition of VEGFR-2 kinase activity, which was validated by their ratios of Ctrough to the obtained IC50,VEGFR-2 of more than unity. All 12 TKIs with no reported incidence of HFSR exhibited less than unity values for both Ctrough/LC50,keratinocytes and Ctrough/IC50,VEGFR-2. These results suggested that a combination of keratinocyte toxicity and VEGFR-2 inhibition may explain the incidence of HFSR upon TKI usage in humans.
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