Zebrafish: A Predictive Model for Assessing Cancer Drug-Induced Organ Toxicity - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 139

11.3.4 Evaluation of Reversibility of Toxicity 48h
After Compound Removal

In order to evaluate if compound-induced acute toxicity was reversible, after
treatment for 24 h, zebrafish were washed in fresh fish water to remove compounds
and incubated for an additional 48 h. For 17-DMAG, although no lethality was
observed after treatment with any concentration for 24 h, at concentrations

M,
80-100% lethality was observed 48 h after compound removal. Organ morphology
and function were then reassessed visually in the surviving animals (Fig. 11.4).
Although pericardial edema was still present, degenerated brain tissue was not
observed. In addition, liver toxicity and defective kidney function were still present
48 h after compound removal. For HDAC inhibitor X, although no lethality was
observed after treatment with any concentration for 24 h, 48 h after removing 400

500 m

M
concentration, 30% lethality was observed. In addition, 48 h after removing HDAC
inhibitor X, pericardial edema and CNS, liver, and kidney toxicity were visible in
surviving animals, indicating delayed drug effects. Forty-eight h after removing
paclitaxel, no toxicity was detectable in any organ. Forty-eight h after removing
SMA-838, liver toxicity was still detectable. These results suggest that drug-induced
toxicity for 17-DMAG, HDAC inhibitor X, and SMA-838 was irreversible. In fact,
delayed lethality and toxicitywere observed, suggesting that for some drugs treatment
longer than 24 h may be required to induce toxicity. Organ toxicity results by
compound are summarized below.

m

11.3.4.1 17-DMAG Toxicity in all four organs, heart, CNS, liver, and kidney,
was observed both after 24 h treatment and 48 h after compound removal, indicating
irreversible toxicity. After 24 h treatment, cell death was observed in heart, CNS, and
liver, but not in kidney.

11.3.4.2 HDAC Inhibitor X Heart toxicity was observed after 24 h treatment

and 48 h after compound removal, indicating heart toxicity was irreversible. CNS,
liver, and kidney toxicity was not observed after 24 h treatment; however, toxicity in
these three organs was observed 48 h after compound removal, indicating delayed
toxicity. Cell death was observed in CNS, but not in heart, liver, or kidney after 24 h
treatment.

11.3.4.3 Paclitaxel Toxicity was not observed in any organ either after 24 h

treatment or 48 h after compound removal. However, low solubility (up to 2 M) in

fish water may have limited assessment of organ toxicity. Cell death was observed in
CNS, but not in heart, liver, or kidney after 24 h treatment.

m

11.3.4.4 SMA-838 Toxicity was not observed in heart, CNS, or kidney, either

after 24 h treatment or 48 h after compound removal. However, liver toxicity was
observed both after 24 h treatment and 48 h after compound removal, indicating