Comparison of effects of anti-angiogenic agents in the zebrafish efficacy-toxicity model for translational anti-angiogenic drug discovery

• Published in: Drug design, development and therapy Vol. 8; no. default; pp. 1107 - 1123
• Main Authors: Chimote, Geetanjali, Sreenivasan, Jayasree, Pawar, Nilambari, Subramanian, Jyothi, Sivaramakrishnan, Hariharan, Sharma, Somesh
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2014; Taylor & Francis Ltd; Dove Press; Dove Medical Press
• Subjects: Angiogenesis; Angiogenesis inhibitors; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - toxicity; Animals; Antiangiogenic agents; Antiangiogenics; Biological activity; Blood vessels; Cancer therapies; Cell adhesion & migration; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Chemical activity; Danio rerio; Drug Design; Drug discovery; Drug dosages; Drugs; Edema; Effectiveness; Embryos; Endothelial cells; Freshwater; Growth factors; Health aspects; Inhibitors; Kidney cancer; Kinases; Lethal Dose 50; Mathematical models; Metastases; Models, Animal; Morphology; Neoplasms - blood supply; Neoplasms - drug therapy; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Organic chemistry; Original Research; Phenotypes; Physiological aspects; Prediction models; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; therapeutic window; Toxicity; Toxicity Tests - methods; Translation; Translational Medical Research - methods; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; VEGFR inhibitors; Zebra fish; Zebrafish; Zebrafish - embryology; zebrafish toxicity assay; India; United States > US; VEGFR inhibitors; therapeutic window; angiogenesis; zebrafish toxicity assay
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S55621

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. 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. 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. 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.