title: Comparison of effects of anti-angiogenic agents in the zebrafish efficacy-toxicity model for translational anti-angiogenic drug discovery.
abstract: BACKGROUND
  Anti-angiogenic therapy in certain cancers has been associated with improved control of tumor growth and metastasis. Development of anti-angiogenic agents has, however, been saddled with higher attrition rate due to suboptimal efficacy, narrow therapeutic windows, or development of organ-specific toxicities. The aim of this study was to evaluate the translational ability of the zebrafish efficacy-toxicity model to stratify anti-angiogenic agents based on efficacy, therapeutic windows, and off-target effects to streamline the compound selection process in anti-angiogenic discovery.
  
  
  METHODS
  The embryonic model of zebrafish was employed for studying angiogenesis and toxicity. The zebrafish were treated with anti-angiogenic compounds to evaluate their effects on angiogenesis and zebrafish-toxicity parameters. Angiogenesis was measured by scoring the development of subintestinal vessels. Toxicity was evaluated by calculating the median lethal concentration, the lowest observed effect concentration, and gross morphological changes. Results of efficacy and toxicity were used to predict the therapeutic window.
  
  
  RESULTS
  In alignment with the clinical outcomes, the zebrafish assays demonstrated that vascular endothelial growth factor receptor (VEGFR) inhibitors are the most potent anti-angiogenic agents, followed by multikinase inhibitors and inhibitors of endothelial cell proliferation. The toxicity assays reported cardiac phenotype in zebrafish treated with VEGFR inhibitors and multikinase inhibitors with VEGFR activity suggestive of cardiotoxic potential of these compounds. Several other pathological features were reported for multikinase inhibitors suggestive of off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy-toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds.
  
  
  CONCLUSIONS
  The zebrafish efficacy-toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics.
authors.affiliation: Department of Pharmacology, Piramal Life Sciences Limited, Mumbai, India.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Chimote
authors.affiliation: Department of Pharmacology, Piramal Life Sciences Limited, Mumbai, India.
authors.forename: Jayasree
authors.initials: J
authors.lastname: Sreenivasan
authors.affiliation: Department of Pharmacology, Piramal Life Sciences Limited, Mumbai, India.
authors.forename: Nilambari
authors.initials: N
authors.lastname: Pawar
authors.affiliation: Department of Modeling and Simulation, Piramal Life Sciences Limited, Mumbai, India.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Subramanian
authors.affiliation: Department of Medicinal Chemistry, Piramal Life Sciences Limited, Mumbai, India.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Sivaramakrishnan
authors.affiliation: Department of Pharmacology, Piramal Life Sciences Limited, Mumbai, India ; Department of Medicinal Chemistry, Piramal Life Sciences Limited, Mumbai, India.
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D007928:Lethal Dose 50; D023421:Models, Animal; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D018675:Toxicity Tests / Q000379:methods; D057170:Translational Research, Biomedical / Q000379:methods*; D015027:Zebrafish / Q000196:embryology
chemical_list: D020533:Angiogenesis Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: VEGFR inhibitors; angiogenesis; therapeutic window; zebrafish toxicity assay