Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Clin Cancer Res. 2016 Jun 1;22(11):2709-20. doi: 10.1158/1078-0432.CCR-15-1888. Epub 2016 Jan 22.
Itraconazole is a triazole antifungal drug that has recently been found to inhibit angiogenesis. Itraconazole is a relatively well-tolerated drug but shows hepatotoxicity in a small subset of patients. Itraconazole contains three chiral centers and the commercial itraconazole is composed of four cis-stereoisomers (named IT-A, IT-B, IT-C, and IT-D). We sought to determine whether the stereoisomers of itraconazole might differ in their antiangiogenic activity and hepatotoxicity.
We assessed in vitro antiangiogenic activity of itraconazole and each stereoisomer using human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. We also determined their hepatotoxicity using primary human hepatocytes in vitro and a mouse model in vivo Mouse Matrigel plug and tumor xenograft models were used to evaluate in vivo antiangiogenic and antitumor activities of the stereoisomers.
Of the four stereoisomers contained in commercial itraconazole, we found that IT-A (2S,4R,2'R) and IT-C (2S,4R,2'S) were more potent for inhibition of angiogenesis than IT-B (2R,4S,2'R) and IT-D (2R,4S,2'S). Interestingly, IT-A and IT-B were more hepatotoxic than IT-C and IT-D. In mouse models, IT-C showed more potent antiangiogenic/antitumor activity with lower hepatotoxicity compared with itraconazole and IT-A.
These results demonstrate the segregation of influence of stereochemistry at different positions of itraconazole on its antiangiogenic activity and hepatotoxicity, with the 2 and 4 positions affecting the former and the 2' position affecting the latter. They also suggest that IT-C may be superior to the racemic mixture of itraconazole as an anticancer drug candidate due to its lower hepatotoxicity and improved antiangiogenic activity. Clin Cancer Res; 22(11); 2709-20. ©2016 AACR.
伊曲康唑是一种三唑类抗真菌药物，最近发现其具有抑制血管生成的作用。伊曲康唑是一种耐受性良好的药物，但在一小部分患者中会表现出肝毒性。伊曲康唑含有三个手性中心，市售的伊曲康唑由四个顺式立体异构体（命名为 IT-A、IT-B、IT-C 和 IT-D）组成。我们试图确定伊曲康唑的立体异构体在抗血管生成活性和肝毒性方面是否存在差异。
我们使用人脐静脉内皮细胞（HUVEC）增殖和管形成试验评估伊曲康唑及其每个立体异构体的体外抗血管生成活性。我们还使用体外原代人肝细胞和体内小鼠模型来确定它们的肝毒性。使用小鼠 Matrigel plugs 和肿瘤异种移植模型来评估立体异构体的体内抗血管生成和抗肿瘤活性。
在市售伊曲康唑中包含的四个立体异构体中，我们发现 IT-A（2S,4R,2'R）和 IT-C（2S,4R,2'S）比 IT-B（2R,4S,2'R）和 IT-D（2R,4S,2'S）更能抑制血管生成。有趣的是，IT-A 和 IT-B 比 IT-C 和 IT-D 更具肝毒性。在小鼠模型中，与伊曲康唑和 IT-A 相比，IT-C 表现出更强的抗血管生成/抗肿瘤活性，同时具有更低的肝毒性。
这些结果表明，伊曲康唑立体化学在不同位置的影响可分离其抗血管生成活性和肝毒性，其中 2 位和 4 位影响前者，而 2' 位影响后者。它们还表明，与伊曲康唑外消旋混合物相比，IT-C 可能作为一种抗癌药物候选物更具优势，因为其肝毒性更低且抗血管生成活性得到改善。Clin Cancer Res; 22(11); 2709-20. ©2016 AACR.
