Author:

Keywords:

Zebrafish, Anti-angiogenic drug discovery

Abstract:

Abberant angiogenesis has been implicated in tumor survival and metastasis. Angiogenesis related signaling pathways have been established and validated for their role in tumor resistance and spread. However development of anti-angiogenic therapies have taken a protracted course from being first proposed by Judah Folkman in 1971. The reason for protracted development of anti-angiogenic drugs has been multiple concomitant and unpredictable toxicities that were clinically observed with use of anti-angiogenic drugs. This feature emphasizes that generation of new blood vessels is a multifactorial biological process with vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) being the main players. The challenge to develop novel and safe anti-angiogenic compounds is thus an arduous task as the in vitro and in vivo angiogenesis assays are qualitative and not quantitative with no clue about the required safety profile in early drug discovery. The aim of the study was to evaluate zebrafish as an efficacy-safety model in tandem for drugs acting on the VEGF-VEGFR axis in early drug discovery. The optically transparent zebrafish, a fresh water teleost with conserved genetic pathways and protein structure with humans was evaluated as preclinical quantitative angiogenesis animal safety-efficacy model. Clinically approved and effective anti-angiogenic drugs (bevacizumab, sorafenib, sunitinib) were compared with anti-angiogenic drugs with known toxicity (SU5416, vatalanib). The lethal, sublethal effects were evaluated for compound toxicity while ability to inhibit proliferating sub intestinal vessels was evaluated for efficacy and its quantitative scoring. The zebrafish larvae could correctly predict the therapeutic index for anti-angiogenic drugs like sunitinib, sorafenib, SU5416, and vatalanib. The model could also correctly envisage cardiotoxicity associated with clinical usage of VEGF-VEGFR inhibitors. These results encourage the use of zebrafish model as a quick, economical intermediate between in vitro and in vivo studies to accelerate anti-angiogenic drug discovery and development.