re-80 and tamibarotene

The retinoic acid receptor (RAR) agonists, Re80 and Am80, partially inhibited the antigen-induced IL-4 production by rat mast cell line RBL-2H3 in a concentration-dependent manner (0.1 to 1000 nM). Both Re80 and Am80 also reduced the antigen-induced increase in IL-4 mRNA levels. The RAR antagonist LE540 at 4 microM reversed Re80 (100 nM)- and Am80 (100 nM)-induced inhibition of IL-4 production. The retinoid X receptor agonist HX600 (1 microM) by itself did not affect IL-4 production, but enhanced the inhibitory effect of Re80 (10 nM) and of Am80 (10 nM). Cyclosporin A suppressed the antigen-induced IL-4 production almost completely at 0.3 microM. These findings indicated that the antigen-induced IL-4 production by RBL-2H3 cells is partially inhibited by retinoids via RAR-dependent mechanisms.

Topics: Animals; Antigens; Benzoates; Cell Line; Cyclosporine; Dibenzazepines; Immunosuppressive Agents; Interleukin-4; Mast Cells; Rats; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Tetrahydronaphthalenes; Transcription Factors

RCJ C 5.18 (C 5.18) is a chondrogenic clonal cell line which, under standard culture conditions, develops chondroblastic features including the production of a cartilagenous matrix. Retinoic acid (RA) is known to inhibit the chondrogenic differentiation of C 5.18 cells and this may parallel the teratogenic effects of retinoids in vivo; however, the question as to which of the 3 retinoic acid receptors (RAR alpha, beta, gamma) or the 3 retinoid X receptors (RXR alpha, beta, gamma) mediate this RA-induced inhibition remains unanswered. We tested several retinoids with different receptor binding characteristics. Cartilage formation in C 5.18 cultures was evaluated by counting the number of cartilage nodules formed, and by quantitating the glycosaminoglycan content of the cultures using alcian blue staining. All of the retinoids prevented cartilage formation in a dose-dependent manner. Treatment with the retinoids did not affect cell number, thereby ruling out any toxic effects. RA, which binds to all 3 RARs with similar affinity, produced a 50% inhibition (IC50) of cartilage formation at 4 x 10(-10) M. We also tested Ch55, which also binds to all 3 RARs, but with higher affinity than RA. This compound was approximately 10 times more potent than RA (IC50 2 x 10(-11) M). 9-cis RA, which binds to the 3 RARs with affinities similar to RA and also binds to the 3 RXRs, was less active (IC50 8 x 10(-9) M), suggesting that RXR binding interferes with the inhibitory effect of ligand-activated RARs. 9-cis retinal, for which the binding characteristics are unknown, had the same effect as 9-cis RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzoates; Cartilage; Cell Differentiation; Cell Line; Chalcone; Chalcones; Dose-Response Relationship, Drug; Glycosaminoglycans; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Retinoids; Teratogens; Tetrahydronaphthalenes; Transcription Factors; Tretinoin

In a previous study, we demonstrated that retinoic acid or a synthetic retinoid, Ch 55 ((E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid), significantly affects in vivo angiogenesis, on the basis of our working hypothesis that a cell differentiation modulator could also exhibit anti-angiogenic activity. In the present study, three novel synthetic retinoids, Re 80 (4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl- 2- naphthalenyl)-1-propenyl]benzoic acid), Am 580 (4-[(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid) and Am 80 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl] benzoic acid), whose cell differentiation-modulating effects are roughly comparable to or more potent than that of Ch 55, which was the most effective angiostatic retinoid identified previously, were examined. Their anti-angiogenic effects were tested in an in vivo assay system involving chorioallantoic membranes of growing chick embryos. They were all found to exert dose-dependent anti-angiogenic effects in the picomolar range. Their rank order for inhibitory potency was Re 80 > Am 580 > Am 80, the ID50 values being 6.3, 23 and 28 pmol/egg, respectively. These results indicate that treatment involving these three novel synthetic retinoids might have potential therapeutic efficacy in various angiogenesis-dependent disorders, including solid tumors, psoriasis, rheumatoid arthritis and diabetic retinopathy.

Topics: Animals; Benzoates; Cell Differentiation; Chick Embryo; Dose-Response Relationship, Drug; Neovascularization, Pathologic; Tetrahydronaphthalenes