Discovery of Biologically Active Oncologic and Immunologic Small Molecule Therapies using Zebrafish: Overview and Example of Modulation of T Cell Activation

Nikolaus S. Trede1, William Heaton2, Suzanne Ridges2, Hossein Sofla2, Matthew Cusick3, David Bearss2, David Jones2, Robert S. Fujinami3

1 Department of Pediatrics, University of Utah, Salt Lake City, Utah, 2 Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, 3 Department of Pathology, University of Utah, Salt Lake City, Utah
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 14.24
DOI:  10.1002/0471141755.ph1424s60
Online Posting Date:  March, 2013
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Zebrafish models continue to gain popularity as in vivo models for drug discovery. Described in this overview are advantages and challenges of zebrafish drug screening, as well as a novel in vivo screen for immunomodulatory compounds using transgenic, T cell reporting zebrafish larvae designed for discovery of compounds targeting T cell leukemia. This assay system allows rapid screening of large numbers of compounds while avoiding the pitfalls of assays based on cell cultures, which lack biologic context and are afflicted by genomic instability. The rationale for this approach is based on similarities of immature normal T cells and developmentally arrested, malignant lymphoblasts in mammalian species. The screening algorithm has been used to identify a nontoxic compound with activity in both acute leukemia models and models of multiple sclerosis, demonstrating the utility of this screening procedure. Curr. Protoc. Pharmacol. 60:14.24.1‐14.24.13. © 2013 by John Wiley & Sons, Inc.

Keywords: zebrafish; leukemia; immunomodulatory agents; multiple sclerosis; melanoma; pancreatic carcinoma; liver cancer; rhabdomyosarcoma; testicular cancer; small molecule drug screening

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Table of Contents

  • Challenges in Drug Discovery Using In Vitro Cell‐Based Screening
  • Zebrafish as a Model for Human Disease and Drug Screening
  • Need for Targeted Therapies to Treat Immune‐Mediated Oncologic Diseases—Use of Zebrafish to Identify Immunomodulatory Agents
  • A Zebrafish Screen for Immunomodulatory Compounds
  • Summary
  • Acknowledgements
  • Literature Cited
  • Figures
  • Tables
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