Retinoids as therapeutic agents: today and tomorrow

Retinoids have shown beneficial therapeutic effects in pre-clinical and animal models for multiple pathologic indications, however severe adverse effects, restricting dosage and efficacy of oral formulations limit their use in patients. The focus of this review includes the actual medicinal use of retinoids and chemical efforts to generate highly selective and less toxic synthetic retinoids.     

Synergistic cytotoxicity exhibited by combination treatment of selective retinoid ligands with taxol (Paclitaxel).

The focus of this study was to develop retinoic acid receptor (RAR) RAR alpha/beta selective agonists with anticancer efficacy and reduced toxicity associated with RAR gamma activity. In these studies, we report the identification and characterization of high-affinity RAR alpha/beta selective agonists with limited RAR gamma activity. These compounds inhibited human tumor cell line proliferation with similar efficacy to that observed for a pan-RAR agonist. However, for most tumor cell lines, the efficacy of these compounds was restricted to the micromolar range. To determine whether the RAR alpha/beta selective agonists could be additive or synergistic with existing agents, we investigated the effects of combining RAR alpha/beta selective agonists with various cytotoxic agents. Our results showed that the alpha/beta selective retinoids dramatically lowered the effective dose of Taxol needed to induce cytotoxicity of a wide range of tumor cell lines. This synergy was specific to tubulin-modifying agents and could not be observed with a variety of other cytotoxic agents of diverse function. Examination of pathways common to Taxol and retinoid signaling revealed that this synergy was related in part to effects on Bcl-2 expression/phosphorylation as well as the activity of the c-Jun NH(2)-terminal kinase and activator protein-1. In contrast, the tubulin polymerization induced by Taxol was not further affected by cotreatment with a variety of retinoid receptor ligands. These observations indicate that potent RAR alpha/beta selective agonists may be of therapeutic benefit in combination with Taxol therapy.     

Cell-type and promoter-context dependent retinoic acid receptor (RAR) redundancies for RAR beta 2 and Hoxa-1 activation in F9 and P19 cells can be artefactually generated by gene knockouts.

By using RAR type (alpha, beta, or gamma)-specific synthetic retinoids and a pan-retinoic X receptor (RXR)-specific ligand, we have investigated the contribution of RARs and RXRs in the activation of RA target genes and the differentiation of embryonal carcinoma cells. We demonstrate cell-type- and promoter context-dependent functional redundancies that differ between the three RAR types for mediating the induction of RARbeta2 and Hoxa-1 in wild-type, RARgamma-/- and RARalpha-/- F9 cells and in P19 cells. The extent of redundancy between RARs is further modulated by the synergistic activation of RXRs with a pan-RXR agonist. We also demonstrate that the expression of RARbeta2 is auto-inducible in RARgamma-/- but not in wild-type F9 cells, indicating that the functional redundancies observed between RARs in gene disruption studies can be artefactually generated. Thus, even though all three RARs can functionally substitute each other for inducing the expression of RA target genes and cell differentiation, one RAR can cell-specifically override the activity of the other RARs. Interestingly, only RARgamma can mediate the retinoic acid-induced differentiation of wild-type F9 cells, whereas the differentiation of P19 cells can be mediated by either RARalpha or RARgamma.     

Evaluation of Retinoids as Therapeutic Agents in Dermatology

Evaluation of 13-cis-12-substituted analogues of retinoic acid in a series of dermatologic screens has revealed that structural modifications can lead to selectivity and specificity. An analogue, 11-cis,13-cis-12-hydroxymethylretinoic acid, -lactone, has been found to have good activity and to be devoid of topical and systemic toxicity.     

Frozen conformers of clotrimazole: reaction of imadazole with 1-Chloro-9-hydroxy-9-phenylxanthene

1-Chloro-9-hydroxy-9-phenylxanthene reacts with imidazole at 180 degrees to form a 5:1 mixture of the 9-(imidazo-1-yl)- and 9-(imidazo-2-yl)-1-chloro-9-phenylxanthenes. These products lack significant antifungal activity.     

Selective retinoids and rexinoids in cancer therapy and chemoprevention

Natural and synthetic retinoids are effective inhibitors of tumor cell growth in vitro and in vivo. However, the toxicity of natural derivatives of vitamin A limits their therapeutic use. Recently, synthetic compounds selective for the different retinoid receptor isotypes have been generated that circumvent pan-retinoid toxicity. The tumor-suppressive activity of selective retinoid and/or rexinoid ligands has been established preclinically, and emerging clinical trials are supportive of the chemotherapeutic and chemopreventive potential of these compounds in multiple oncology indications, with reduced toxicity. Moreover, the combination of retinoids and/or rexinoids with chemotherapeutic agents for the synergistic modulation of specific pathways could also be of benefit in cancer therapy.     

The Requirement for a Retinoic Acid Lactone of 11-cis, 13-cis-Stereochemistry for Topical Dermatologic Activity

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