ro-15-1570 and 4-(2-(5-6-7-8-tetrahydro-5-5-8-8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic-acid

Three retinoids of the arotinoid series, namely the free carboxylic acid Ro 13-7410, its ethyl ester Ro 13-6298, and the new arotinoid ethyl sulfone Ro 15-1570, were tested for their embryotoxic and teratogenic activity in rats. The retinoids were administered orally on either day 9 or 13 of gestation. Treatment on day 9 of gestation resulted mainly in malformations of the head and the trunk; whereas, on day 13 limb malformations were prominent. Ro 13-7410 and Ro 13-6298 were about 1000 times more embryotoxic and teratogenic than retinoic acid but induced a similar malformation pattern to retinoic acid. In contrast, the sulfur-containing arotinoid Ro 15-1570 was active at similar dose levels to retinoic acid but caused a peculiar malformation pattern on day 13 of gestation. This finding supports the hypothesis that the arotinoid ethyl sulfone Ro 15-1570 has unique biological properties, inducing no bone toxicity in adult rats and distinctly affecting limb development.

Topics: Abnormalities, Drug-Induced; Animals; Benzoates; Embryo, Mammalian; Female; Gestational Age; Pregnancy; Rats; Retinoids; Time Factors

Arotinoids, third generation retinoids, inhibited significantly 12-lipoxygenase in platelets and 5-lipoxygenase in human neutrophils. The doses required for inhibition of 12-lipoxygenase in platelets were as low as 1 pM and of 5-lipoxygenase in neutrophils as low as 100 pM. No cytotoxicity was observed in neutrophils at concentrations used, as assayed by exclusion of trypan blue dye. In contrast to various studies reported in the literature, arotinoids used inhibited ionophore-induced arachidonic acid (AA) release in platelets and neutrophils of humans. The doses required for 50% inhibition of AA release were between 10 pM and 75 nM for platelets and between 1 and 50 nM for neutrophils. The data suggest that arotinoids are excellent dual inhibitors of cyclooxygenase and lipoxygenase pathways of AA metabolism. The mechanism for inhibition of eicosanoids lies apparently in the inhibition of AA deacylation from phospholipid membrane. It cannot, however, be ruled out that the accumulation of AA results from arotinoid-induced stimulation of reacylation of AA into the phospholipid membrane.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Benzoates; Blood Platelets; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Neutrophils; Retinoids