Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Joong Sup ShimJun O Liu

Abstract

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/antitumo...Continue Reading

References

Jul 1, 1992·Annals of the Rheumatic Diseases·P R Colville-Nash, D L Scott
Oct 1, 1990·The Journal of Antimicrobial Chemotherapy·R M TuckerD A Stevens
Jan 1, 1989·Mycoses·J HeykantsG Cauwenbergh
Jan 1, 1988·Journal of Biochemical Toxicology·C S BoyerD R Petersen
Feb 1, 1971·The Journal of Experimental Medicine·J FolkmanG Williams
May 1, 1970·British Medical Bulletin·N Ashton
Nov 18, 1971·The New England Journal of Medicine·J Folkman
Nov 1, 1996·Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology·B G Lake, P Grasso
Jan 1, 1997·Dermatologic Clinics·A K GuptaP De Doncker
Nov 25, 1997·Current Opinion in Oncology·P Twardowski, W J Gradishar
Jun 21, 2005·Nature Reviews. Drug Discovery·Lee M Ellis
Jan 18, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kent L KunzeNina Isoherranen
Apr 17, 2007·ACS Chemical Biology·Curtis R ChongJun O Liu
Jul 25, 2008·The New England Journal of Medicine·Josep M LlovetUNKNOWN SHARP Investigators Study Group
Oct 18, 2008·Journal of Pharmaceutical and Biomedical Analysis·Wei ChenXiangming Guan
Feb 24, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jing XuJun O Liu
Nov 20, 2010·Journal of the National Cancer Institute·Joong Sup ShimJun O Liu
Jun 29, 2011·The International Journal of Developmental Biology·Domenico RibattiEnrico Crivellato
Sep 8, 2011·Cancer Research·Blake T AftabCharles M Rudin
Nov 23, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Chi-Chi PengNina Isoherranen
Apr 3, 2013·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Charles M RudinJun O Liu
Oct 19, 2013·Arteriosclerosis, Thrombosis, and Vascular Biology·Richard J BodnarAlan Wells
Feb 5, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Daniel J KimJean Y Tang
Feb 12, 2015·Journal of Oncology Pharmacy Practice : Official Publication of the International Society of Oncology Pharmacy Practitioners·Nicholas R LockhartNathan Eric Schrock

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.

Related Papers

Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology
Yan Wang, Jian-hua Shao
Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban
Chun-yan SunLu Zhang
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
David Z QianRoberto Pili
© 2022 Meta ULC. All rights reserved