Data from Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole

Abstract

<div>Abstract<p><b>Purpose:</b> 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 <i>cis</i>-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.</p><p><b>Experimental Design:</b> We assessed <i>in vitro</i> 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 <i>in vitro</i> and a mouse model <i>in vivo</i>. Mouse Matrigel plug and tumor xenograft models were used to evaluate <i>in vivo</i> antiangiogenic and antitumor activities of the stereoisomers.</p><p><b>Results:</b> 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 22(11); 2709–20. ©2016 AACR</i>.</p></div>