AGN 193109 was recently identified as a potent
retinoic acid receptor (RAR) antagonist in vitro. The purpose of the present study was to determine if
AGN 193109 functions as an RAR antagonist in vivo and thus could prevent and/or treat
retinoid toxicity. Female hairless mice were treated topically for 5 consecutive days with the synthetic
retinoic acid receptor agonist (E)-4-[2-(5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propen-1-yl]
benzoic acid (
TTNPB) alone or in the presence of a 1-, 4-, or 16-fold molar excess of
AGN 193109.
TTNPB caused skin flaking, skin abrasions, and
splenomegaly, and these effects were blocked in a dose-dependent fashion by
AGN 193109 cotreatment. In the same model,
AGN 193109 also decreased topical irritation induced by the natural RAR agonist,
all-trans-retinoic acid. To determine if topical
AGN 193109 could block toxicity induced by an oral
retinoid, mice were treated by gavage with
TTNPB (0.75 mumol/kg/day) and topically with 0, 0.3, or 1.2 mumol/kg/day of
AGN 193109 for 4 days.
TTNPB treatment alone caused cutaneous irritation and
weight loss, and these effects were inhibited by
AGN 193109 cotreatment. To determine if
AGN 193109 could be used to treat preexisting
retinoid toxicity, mice were pretreated topically on Days 1-2 with
TTNPB (0.72 mumol/kg/day) and then treated topically on Days 3-5 with 0, 1.44, 7.2, or 36.0 mumol/kg of
AGN 193109.
TTNPB pretreatment caused precipitous
weight loss and, in the absence of
AGN 193109 intervention, 60% mortality.
AGN 193109 treatment at all dose levels significantly accelerated recovery of
body weight and prevented death in
TTNPB-intoxicated mice. These data demonstrate that
AGN 193109 is a potent RAR antagonist and a potential
antidote of
retinoid intoxication in vivo. In addition to potential clinical applications in the prevention and treatment of
retinoid toxicity,
AGN 193109 should provide a powerful experimental tool for the elucidation of
retinoid biology.