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PubMed2003

Retinoid cycle in the vertebrate retina: experimental approaches and mechanisms of isomerization.

Retinoid cycle describes a set of chemical transformations that occur in the photoreceptor and retinal pigment epithelial cells. The hydrophobic and labile nature of the retinoid substrates and the two-cell chromophore utilization-regeneration system imposes significant constraints on the experimental biochemical approaches employed to understand this process. A brief description of the recent developments in the investigation of the retinoid cycle is the current topic, which includes a review of novel results and techniques pertaining to the retinoid cycle. The chemistry of the all-trans-retinol to 11-cis-retinol isomerization is also discussed.

Animals↗
PubMed2003

Basaloid follicular hamartomas associated with autoimmune disease: a possible role for retinoids in therapy.

A basaloid follicular hamartoma (BFH) may be localized or diffuse. It may also be congenital or acquired. Development of diffuse BFHs has been associated with autoimmune disease and with the development of diffuse alopecia. Two women with autoimmune diseases had diffuse alopecia develop. We present the histologic features of BFH seen in these 2 women using vertical and transverse sections, and the response of 1 patient to retinoid therapy. Histologic sections showed a hamartomatous proliferation of hair follicles involving the majority of their hairs. The hamartomatous follicles showed variable degrees of hair differentiation. One patient, treated with oral and then topical retinoids, showed a partial regrowth of scalp hair and some regression of the cutaneous nodules. Increased sonic hedgehog signaling pathways with increased Gli-1 transcription has been shown to be present in the spectrum of follicular hamartomatous changes seen in BFHs. This may explain the response of one patient to retinoid therapy, because retinoids decrease Gli-1 transcriptional activity.

Adult↗
PubMed1986

Topical retinoids: in vivo predictive assays.

Vitamin A is important for epithelial cell proliferation and differentiation and therefore has been used as a therapy for a variety of skin diseases. Synthetic vitamin A derivatives, called retinoids, have been used to treat a number of clinical skin conditions, including cystic acne and various forms of ichthyosis, Darier's disease, and psoriasis. Because of the toxicity of existing retinoids, newer vitamin A derivatives have been synthesized and must be evaluated in preclinical assays. Retinoids have profoundly differing biologic properties that can be evaluated selectively by studying their efficacy in different in vivo animal assays. This review will discuss some of the assays that may be useful predictors of retinoid efficacy.

Acne Vulgaris↗
PubMed1988

Liver toxicity of retinoid therapy.

Vitamin A metabolism involves storage in the liver. Hypervitaminosis A results in liver abnormalities, including fibrosis and cirrhosis. Ito cells are increased and promote fibrogenesis, which results in cirrhosis. Retinoids (Accutane and Tegison) are used clinically for the treatment of a variety of skin diseases. Since retinoids are analogs of vitamin A, their potential to produce liver disease is reviewed. Animal and human studies of liver function tests suggest some abnormalities in the liver in about 25% of patients treated. Liver biopsy studies have included isolated case reports and two retrospective and one prospective liver biopsy study of retinoids in humans. Although some increase in histologic liver changes have been noted, most liver biopsy specimens showed no change or improvement. Retinoids do not appear to produce consistent toxic liver abnormalities.

Animals↗
PubMed1998

Rational design of receptor-selective retinoids.

Orally administered retinoids can be associated with significant adverse effects because of high systemic exposure and a lack of receptor selectivity. Targeting the diseased tissue and improving the selectivity of the retinoid-receptor interaction to activate only those discrete pathways required for efficacy may minimize adverse effects. First- and second-generation retinoids contain several alternating single and double bonds that confer great conformational flexibility, allowing the molecules to adopt a variety of shapes and creating the potential to interact with multiple receptors. We hypothesized that, by designing a more rigid conformational structure, the receptor selectivity of retinoids could be improved and their therapeutic index enhanced. This strategy has resulted in the development of tazarotene. The receptor selectivity of tazarotene, together with its topical delivery, ensures a targeted action on psoriatic keratinocytes.

Administration, Cutaneous↗
PubMedDate not supplied

Effect of retinoids on the growth of squamous cell carcinoma of the palate in rats.

The in vivo effects of retinoids on head and neck tumors were studied using Fisher 344 rats with squamous cell carcinoma implanted in the palate. Retinoids were given orally to rats, starting 2 weeks after tumor implantation. The animals were killed at 4 weeks, and the tumor volumes and body weights were measured. The animals had a greater response to all-trans-retinoic acid (58 per cent) and 13-cis-retinoic acid (60 per cent) than to all-trans-retinol (20 per cent) and 13-cis-retinal (30 per cent). Comparison of both tumor volumes and body weights among the retinoid-treated groups revealed that the body weights increased while the tumor volumes decreased. Retinoids seem to inhibit local tumor growth through their effects on host cellular and humoral immunity and through the inhibition of tumor cell keratinization.

Animals↗
PubMed1996

Inhibitory effects of retinoids on development of squamous metaplasia in rat mammary epithelial organoids cultured in Matrigel.

Squamous metaplasia (SQM) developed in cultures of rat mammary organoids in reconstituted basement membrane, Matrigel, under either a complete hormone medium (CHM) or a serum-free mammary epithelium growth medium (MEGM). Organoids cultured in CHM gave rise to fewer such SQM (approximately 5%) than those in MEGM (approximately 16%). Formation of SQM was completely suppressed when retinoids were added to CHM. However, a few SQM were still observed in cultures in MEGM with added retinoids. Addition of 5% fetal bovine serum suppressed development of SQM cultured in MEGM. Delayed addition of retinoids also inhibited further development of SQM. Development of SQM from mammary epithelial cells is not common, and regulatory molecules other than retinoids apparently are involved in their formation and prevention.

Animals↗
PubMed1999

Differential expression of retinoid receptors in the adult mouse central nervous system.

The immunocytochemical distribution of retinoid receptors has been analysed in the mouse adult central nervous system. All retinoic acid receptors (alpha, beta and gamma) and retinoid X receptors (alpha, beta and gamma) were detected and found to exhibit specific patterns of expression in various areas of the telencephalon, diencephalon and rhombencephalon. The protein localization of several retinoic acid receptors and retinoid X receptors did not correlate with the distribution of the corresponding RNA transcripts, as studied by in situ hybridization and RNase protection assays. This suggests that the expression of retinoid receptors could be post-transcriptionally regulated, which may contribute to their specific localization in the adult nervous system.

Animals↗
PubMed1998

Reversed-phase gradient high-performance liquid chromatographic procedure for simultaneous analysis of very polar to nonpolar retinoids, carotenoids and tocopherols in animal and plant samples.

A reversed-phase gradient high-performance liquid chromatographic (HPLC) procedure, which utilizes gradient elution and detection by a photodiode-array detector, has been developed to analyze simultaneously very polar retinoids, such as 4-oxo-retinoyl-beta-glucuronide, retinoyl beta-glucuronide and 4-oxo-retinoic acid; polar retinoids, such as retinoic acid and retinol; nonpolar retinoids, such as retinyl esters; along with xanthophylls, monohydroxy carotenoids, hydrocarbon carotenoids, and tocopherols. The procedure has been applied to the simultaneous analysis of retinoids, carotenoids, and tocopherols present in human serum and liver, rat serum and tissues, and for carotenoids in a number of fruits and vegetables. Bilirubin present in human serum can also be simultaneously analyzed. By this gradient HPLC procedure, 3.4-didehydroretinyl ester (vitamin A2 ester) has been identified as a minor constituent in a human liver sample. Lycopene was identified as a major carotenoid in one specimen of papaya fruit, and 5,6,5',6'-diepoxy-beta-carotene was characterized as a major carotenoid in one specimen of mango fruit.

Animals↗
PubMed2004

Retinoid therapy for psoriasis.

This article focuses on the treatment of psoriasis with acitretin, the only systemic retinoid approved for psoriasis, and also briefly discusses its predecessor, etretinate, which was replaced by acitretin in 1997 and is no longer available. The use of topical tazarotene is also discussed in detail. Combination therapy of retinoids, both topical and systemic,with phototherapy and other therapeutic agents is described. In addition, new retinoid analogues that are undergoing clinical investigation are mentioned. Finally, potential toxicities and adverse effects associated with retinoids are discussed.

Administration, Oral↗
PubMed1996

Retinoid actions and implications for prevention and therapy of oral cancer.

Squamous cell carcinomas of the oral cavity can be preceded by clinically obvious premalignant changes, and they have a high rate of incidence of development of second primary tumors. Recent studies suggest retinoids not only for the treatment of oral eukoplakia, but also for the prevention of second primaries. Although retinoids are promising therapeutic agents, their therapeutic potential has been limited by their undesirable side-effects. A complete network of nuclear receptors has now been identified that mediate the action of retinoids and can interfere directly with cell proliferation signals by interacting with transcription factors. It has recently been shown that retinoids with receptor-selective activities can be obtained that are likely to have fewer side-effects because of their restricted biologic activities.

Antineoplastic Agents↗
PubMed1999

Abnormal anteroposterior and dorsoventral patterning of the limb bud in the absence of retinoids.

We describe here how the early limb bud of the quail embryo develops in the absence of retinoids, including retinoic acid. Retinoid-deficient embryos develop to about stage 20/21, thus allowing patterns of early gene activity in the limb bud to be readily examined. Genes representing different aspects of limb polarity were analysed. Concerning the anteroposterior axis, Hoxb-8 was up-regulated and its border was shifted anteriorly whereas shh and the mesodermal expression of bmp-2 were down-regulated in the absence of retinoids. Concerning the apical ectodermal genes, fgf-4 was down-regulated whereas fgf-8 and the ectodermal domain of bmp-2 were unaffected. Genes involved in dorsoventral polarity were all disrupted. Wnt-7a, normally confined to the dorsal ectoderm, was ectopically expressed in the ventral ectoderm and the corresponding dorsal mesodermal gene Lmx-1 spread into the ventral mesoderm. En-1 was partially or completely absent from the ventral ectoderm. These dorsoventral patterns of expression resemble those seen in En-1 knockout mouse limb buds. Overall, the patterns of gene expression are also similar to the Japanese limbless mutant. These experiments demonstrate that the retinoid-deficient embryo is a valuable tool for dissecting pathways of gene activity in the limb bud and reveal for the first time a role for retinoic acid in the organisation of the dorsoventral axis.

Animals↗
PubMed1991

Rheumatological symptoms due to retinoids.

Isotretinoin and etretinate are synthetic derivatives of vitamin A widely used in the treatment of dermatological diseases, mainly those affecting keratinization. They have numerous side-effects, among which the rheumatic symptoms are not the most common or the most severe. The main skeletal adverse reaction of retinoids is hyperostosis. It mainly occurs with protracted treatments and high dosages, and its incidence may exceed 80% after a few years of administration. Hyperostosis is axial, located in the cervical and thoracic spine, and may be responsible for limitation of movement; in the appendicular bone, enthesopathies occur at the foot, pelvis, hip, and less commonly the shoulder and elbow. They are usually mild and asymptomatic. The radiological appearance is very similar to diffuse idiopathic skeletal hyperostosis. Isotretinoin tends to be responsible for axial involvement, etretinate for peripheral locations. The other skeletal side-effects are uncommon and include periosteal proliferation, calcification of the interosseous membrane of the forearm and diffuse radiological bone hyperlucency. In children, premature epiphyseal closure is very rare. About 20% of patients complain of musculoskeletal pain and arthralgias. A few cases of true arthritis have been reported. Retinoids may be responsible for muscular damage and an abnormality of muscular tone resembling the stiff-man syndrome. Some cases of necrotizing vasculitis and three cases of Wegener's granulomatosis have been observed in patients treated with retinoids. Except for these latter arguable cases, rheumatoid syndromes due to retinoids are rather benign, and should not be an obstacle to the future development of their therapeutic utilization.

Bone Diseases↗
PubMed1999

Cross-regulation of beta-catenin-LEF/TCF and retinoid signaling pathways.

Vitamin A derivatives (retinoids) are potent regulators of embryogenesis, cell proliferation, epithelial cell differentiation and carcinogenesis [1]. In breast cancer cells, the effects of retinoids are associated with changes in the cadherin-beta-catenin adhesion and signaling system [2] [3]. beta-catenin is a component of the Wnt signaling pathway, which regulates several developmental pathways [4]. Increases in cytoplasmic beta-catenin and beta-catenin signaling are also associated with numerous cancers, and are particularly important in colon cancer [5]. The oncogenic and developmental effects of beta-catenin are mediated by its interaction with and activation of members of the LEF/TCF family of transcription factors [6] [7] [8]. Here, we shown that retinoic acid (RA) decreases the activity of the beta-catenin-LEF/TCF signaling pathway. This activity of RA was independent of the adenomatous polyposis coli (APC) tumor suppressor and ubiquitination-dependent degradation of cytoplasmic beta-catenin. Consistent with this finding, beta-catenin interacted directly with the RA receptor (RAR) in a retinoid-dependent manner, but not with the retinoid X receptor (RXR), and RAR competed with TCF for beta-catenin binding. The activity of RA on RAR-responsive promoters was also potentiated by beta-catenin. The data suggest that direct regulation of beta-catenin-LEF/TCF signaling is one mechanism whereby RA influences development, cell differentiation and cancer.

Caco-2 Cells↗
PubMed2001

Differential effects of retinoids on proliferation of bovine mammary epithelial cells in collagen gel culture.

The effects of increasing concentrations of retinol, retinal and retinoic acid on proliferation of bovine mammary epithelial cells were investigated in collagen gel cultures. All retinoids significantly inhibited proliferation of mammary epithelial cells. The relative inhibitory potency of the retinoids was: retinoic acid > retinal > retinol. Maximal inhibition at 10 microg/ml corresponded to a 75-95% inhibition of proliferation obtained in basal medium. Retinol, retinal and retinoic acid also inhibited proliferation of cells growth-stimulated with insulin-like growth factor-I (IGF-I). Retinoids in highest concentrations (10 microg/ml) inhibited 68-85% of proliferation of cells obtained in culture medium containing 25 ng IGF-I/ml. Retinol and retinoic acid also inhibited proliferation of cells growth-stimulated by insulin and other growth factors from the IGF growth factor family (des(1-3)IGF-I and IGF-II), as well as growth factors from the epidermal growth factor family (EGF and TGF-alpha), with retinoic acid being more effective than retinol. At a concentration of 100 ng/ml retinol and retinoic acid inhibited respectively 24-38 and 44-52% of mammary cell proliferation stimulated by growth factors of the IGF family, and at 10,000 ng/ml, 61-71% of cell proliferation was inhibited. The growth-stimulating effect of insulin, EGF and TGF-alpha was inhibited 42-64% by retinol and retinoic acid at 100 ng/ml, and 64-84% at 10,000 ng/ml. The present results show that retinol, retinal and retinoic acid are potent inhibitors of bovine mammary epithelial cell proliferation. It is suggested that retinoids may have concentration-dependent roles in regulation of pubertal mammary growth and development, indicating that the milk yield potential of heifers may be affected by vitamin A status.

Animals↗
PubMed1988

Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity.

Two types of aromatic amides, terephthalic monoanilides and (arylcarboxamido)benzoic acids, have been shown to possess potent retinoidal activities and can be classified as retinoids. The structure-activity relationships of these amides are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. In generic formula 4 (X = NHCO or CONH), the necessary factors to elicit the retinoidal activities are a medium-sized alkyl group (isopropyl, tert-butyl, etc.) at the meta position and a carboxyl group at the para position of the other benzene ring. The bonding of the amide structure can be reversed, this moiety apparently having the role of locating the two benzene rings at suitable positions with respect to each other. Substitution at the ring position ortho to the amide group or N-methylation of the amide group caused loss of activity, presumably owing to the resultant change of conformation. It is clear that the mutual orientation of the benzylic methyl group(s) and the carboxyl group and their distance apart are essential factors determining the retinoidal activity. Among the synthesized compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (Am80) and 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido] benzoic acid (Am580) were several times more active than retinoic acid in the assay. They are structurally related to retinoic acid, as is clear from the biological activity of the hybrid compounds (M2 and R2).

Amides↗
PubMed1996

Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.

Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription. There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR alpha, beta, gamma and RXR alpha, beta, gamma. Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.

Animals↗
PubMed2002

Decryption of the retinoid death code in leukemia.

The recent elucidation of several molecular paradigms by which retinoids regulate growth, differentiation, and apoptosis highlights their promise as drugs for cancer therapy and prevention. Several novel signaling pathways by which retinoids induce cell death have been identified recently. They comprise (a) the induction by RARalpha-selective retinoids of the tumor-selective death ligand TRAIL that kills acute promyelocytic leukemia (APL) cells in a paracrine mode of action, which is the cause of retinoic acid-induced apoptosis after maturation: (b) a novel RARalpha-independent rexinoid-PKA cross-talk that induces maturation of both ATRA-sensitive and ATRA-resistant APL cells and does not invoke ligand-induced alteration of PML-RARalpha signaling, stability, or compartmentalization; and (c) a novel rexinoid signaling pathway that triggers apoptosis of immature APL cells and may correspond to a default death pathway that is operative in the absence of "survival" factors. This rexinoid apoptosis is inhibited by RXR but not RAR antagonists and is distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis. Here we discuss the promise of retinoids for cancer treatment and prevention with an emphasis on the recently identified mechanisms by which they control (cancer) cell proliferation.

Apoptosis↗