Radiation-Induced Toxicity and Radiation Response Modifiers in Zebrafish - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 292

Table 21.1 Comparative Efficacy of Radiation Protectors in Zebrafish and Mammals

Effective
dose

Effective
dose

Target Compound Zebrafish Mammals

NF-kB Ethyl pyruvate þ 1mM þ 0.6mM

CDDO þ 1 mM þ 1 mM

IKK inhibitor 2 (wedelolactone) þ 0.1 mM

IKK inhibitor 3 (BMS-345541) þ 5 mM

IKK2 inhibitor 4 þ 0.25 mM

IKK2 inhibitor 5 (IMD-0354) þ 0.05 mM

GSK-3 LiCl þ 20mM þ 18.9mM

SB216763 þ 5 mM þ 1.6 mM

Azakenpaullone þ 0.3 mM

TDZD-8 þ 1 mM

Inhibitor VIII þ 10 mM

ROS Amifostine þ 4mM þ 1.9mM

DF-1 þ 100 mM þ 100 mM

Protection against IR-induced lethality is indicated by “þ”. Only a select number of drugs have been tested
in mice or rats to date. All compounds used in zebrafish were from Calbiochem/EMD. Note that protection
was achieved in zebrafish and mice at roughly equimolar concentrations, where data are available in both
model systems. Radioprotection of the gastrointestinal system in zebrafish was selectively tested and
observed for EP and CDDO as well as for LiCl, SB216763, and azakenpaullone. Animal testing data were
compiled using the following references: Daroczi et al. 2006, 2009, Meyer et al. (2006), Epperly et al.
(2007), Thotala et al. (2008), andWang et al. (2009). Testing in mammals was performed usingmice and, in
the case of CDDO, rats. Zebrafish GSK3 inhibitor data from Kari et al. (in preparation). Inhibition of the
molecular targets as indicated is described in the following references: ethyl pyruvate (Han et al., 2005),
CDDO (Ahmad et al., 2006), wedelolactone (Kobori et al., 2004), BMS-345541 (Burke et al., 2003), IKK2
inhibitor 4 (Podolin et al., 2005), IMD-0354 (Tanaka et al., 2005), LiCl (Zhang et al., 2003), SB216763
(Coghlan et al., 2000), azakenpaullone (Kunick et al., 2004), TDZD-8 (Martinez et al., 2002), Inhibitor VIII
(Bhat et al., 2003), amifostine (Andreassen et al., 2003), and DF-1 (Daroczi et al., 2006).

21.9 RADIATION PROTECTORS IN ZEBRAFISH

The results described above represent a cross section of reproducible “phenotypes”
and functional impairments of zebrafish embryos due to radiation exposure. These
results set the stage for testing the effects of modulators of the radiation response in
this system. Table 21.1 provides a summary of recent results from different studies
across molecular targets and species (zebrafish, mice, and rats) that aptly demonstrate
the utility of zebrafish for this purpose. The results in this table summarize beneficial
effects of the agents tested on overall survival and include analysis of GI protection. In
addition to ROS scavengers, agents that target nuclear factor (NF)- B and glycogen

synthase kinase 3 (GSK3) have been identified as promising radiation protectors. The
focus on NF-

k

B was due to earlier observations that irradiated normal epithelial
tissues are frequently characterized by excessive inflammation and that this inflam-
matory response limits the dose of radiation that can be safely administered. Since

k