Highlight article: Use of zebrafish to model chemotherapy and targeted therapy gastrointestinal toxicity

• Published in: Experimental biology and medicine (Maywood, N.J.) Vol. 244; no. 14; pp. 1178 - 1185
• Main Authors: Van Sebille, Ysabella ZA, Gibson, Rachel J, Wardill, Hannah R, Carney, Thomas J, Bowen, Joanne M
• Format: Journal Article
• Language: English
• Published: Sage UK: London, England SAGE Publications 01-10-2019
• Subjects: Original Research
• ISSN: 1535-3702; 1535-3699
• DOI: 10.1177/1535370219855334

Gastrointestinal toxicity arising from cancer treatment remains a key reason for
treatment discontinuation, significantly compromising remission. There are
drawbacks to the currently used
in vitro
and rodent models, and
a lack of translatability from
in vitro
to
in
vivo
work. A screening-amenable alternative
in
vivo
model such as zebrafish would, therefore, find immediate
application. This study utilized a transgenic reporter line of zebrafish,
Tg(cyp2k18:egfp), that shows eGFP induction as an indicator of drug-induced
pathology. Here, we investigate its utility as an alternative vertebrate model
to bridge the gap between simple
in vitro
cellular studies and
complex
in vivo
models for understanding gastrointestinal
toxicity induced by chemotherapy and targeted therapy. Transgenic zebrafish
larvae were administered afatinib or SN38, and assessed for viability and eGFP
induction. Adult zebrafish were administered afatinib via oral gavage, and SN38
via intraperitoneal injection. Fish were killed after 24 h, and had
gastrointestinal tracts removed and assessed for histopathological damage,
goblet cell changes, and apoptosis. While treatment with either compound did not
induce eGFP in the gastrointestinal tract of larvae, SN38 caused
histopathological damage to adult intestines. The lack of eGFP induction may be
due to poor solubility of the drugs. Chemotherapy agents with high solubility
and permeability would be more amenable to these models. Further progress in
this area would be greatly facilitated by the generation of robust and
reproducible genetic models of zebrafish intestinal toxicity that mimic the
known pathobiological pathways in rodents and humans, and can be readily induced
in a short time-frame.