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At least 613 records · Page 34Linked to original sources
PubMed1990

Effects of retinoids on DNA synthesis of pig epidermis: its relation to epidermal beta-adrenergic adenylate cyclase response and to epidermal superoxide dismutase activity.

It has been suggested that the epidermal beta-adrenergic adenylate cyclase response and the epidermal superoxide dismutase (SOD) activity is inversely associated with keratinocyte cell proliferation. Effects of various retinoids on the thymidine incorporation of pig epidermis were compared with their effects on the beta-adrenergic response and the SOD activity. Following 24 h incubation with synthetic retinoids (etretin and E-5166 (3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid)), thymidine incorporation of epidermis was significantly decreased. The effect of etretin was more potent than that of E-5166; the former revealed the inhibitory effect at lower concentrations than the latter. The effect of etretinate was not statistically significant. Following the 24 h incubation with the synthetic retinoids, the epidermal beta-adrenergic adenylate cyclase responses were increased. Etretin was again more potent than E-5166, while etretinate showed also little effect on the beta-adrenergic response of epidermis. Thus the inhibitory effect on the thymidine incorporation was inversely correlated with the beta-adrenergic augmentation effect among these synthetic retinoids. On the other hand, physiologic retinoids (retinol and retinoic acid) revealed no correlation between these two parameters; whereas both compounds decreased the thymidine incorporation to a similar extent, only retinoic acid revealed a marked beta-adrenergic augmentation effect. Decreased SOD activity has been observed in various hyperproliferative epidermis. The SOD activity, however, was totally unaffected by the retinoid-treatments.

Acitretin↗
PubMed2004

Retinoids suppress premalignant MCF10AT but not malignant MCF10CA1a breast epithelial cells in vivo. Role of retinoic acid receptor beta2 expression.

Recently we found that retinoic acid receptors (alpha, beta, gamma) and retinoid X receptors (alpha, beta, gamma) are variably expressed in MCF10A model of breast cancer development and progression. Here we employed this model to assess both in vitro and in vivo sensitivity of cells to retinoids and the role of RARbeta2 in mediating the antitumor potential of retinoids. In vitro, we found that transformation of the benign MCF10A cells into premalignant MCF10AT and malignant MCF10CA1a cells increased their sensitivity to 4-(Hydroxyphenyl)retinamide (4-HPR) and all-trans-retinoic acid (atRA) but not to 9-cis-retinoic acid (9cRA) and LGD1069 and this was associated with loss of induction of RARbeta2 by retinoids. RARbeta2 expression in premalignant MCF10AT cells decreased their proliferating activity and increased their sensitivity to atRA. In vivo, when transplanted into the mammary fat pads of nude mice, MCF10A cells did not grow, MCF10AT cells formed slow-growing tumor nodules, and MCF10CA1a cells were highly malignant, grew quickly and infiltrated the surrounding tissues. Of the retinoids used, only 4-HPR suppressed the growth of slow-growing hyperplastic and premalignant MCF10AT but not of the malignant MCF10CA1a tumor nodules. These data may have clinical implication in selecting women with hyperplastic and premalignant breast lesions that may benefit the most from clinical trials with retinoids.

Breast Neoplasms↗
PubMed2004

Retinoid and lipid patterns in the blubber of common dolphins (Delphinus delphis): implications for monitoring vitamin A status.

We determined retinoid concentrations in various body positions of the blubber of 25 common dolphins (Delphinus delphis) to study topographical variation in concentrations. Specimens were obtained from incidental catches and were apparently healthy. We found concentrations to be high and therefore conclude that blubber represents a significant contribution to total retinoid body load. Consequently, blubber is proposed as a tissue of choice for monitoring retinoid status in this species. Anterior-ventral blubber had the highest vitamin A concentration and posterior-dorsal the lowest. Therefore, when assessing retinoid status, topographical variation should be taken into account to ensure consistent sampling. This pattern appeared to be explained by a parallel variation in lipid content. Thus, the dynamics and body distribution of retinoids appear to be basically governed by the lipophilicity of the molecules. The highest lipid richness found in the anterior-ventral region might indicate that this region is comparatively more important for insulation and lipid storage than the dorsal posterior region. Retinoid levels did not appear to vary according to sex, but they did vary with lipid content. This should be taken into account when designing sampling protocols; for monitoring purposes, biopsies from healthy, free-ranging individuals should be preferred to samples from stranded animals.

Adipose Tissue↗
PubMedDate not supplied

Comparison of topical retinoids in the treatment of acne.

Topical retinoids are been used to successfully treat acne for almost 3 decades. At the beginning, a retinoid was a compound of similar structure and action to retinol (vitamin A).(1) Changes at the carboxylic end group, the polyene chain, and the aromatic ring can result in the modification of the original molecule. To date, three generations of retinoids have been developed: the nonaromatics (retinol, tretinoin, and isotretinoin), the monoaromatics (etretinate and acitretin), and the polyaromatics (arotinoid, adapalene, and tazarotene). The new synthetic retinoid molecules have little resemblance with retinol but nonetheless are included in this family because they have the ability to bind with or activate retinoid receptors. Therefore, retinoids are vitamins and also hormones.(3)

Administration, Cutaneous↗
PubMed2005

Organochlorine contaminant and retinoid levels in blubber of common dolphins (Delphinus delphis) off northwestern Spain.

The effect of age, sex, nutritive condition and organochlorine concentration on blubber retinoid concentrations was examined in 74 common dolphins incidentally caught off northwestern Spain. Age and blubber lipid content were strong determinants of the retinoid concentrations in males, while these variables did not account for the variation found in females. Retinoids were positively correlated with organochlorines in males and negatively in females. However, pollution levels were moderate and likely to be below threshold levels above that a toxicological response is to be expected. Thus, a cause-effect relationship between organochlorine and retinoid concentrations could not be properly established, and the observed correlation may be the result of an independent association of the two variables with age. Further research on the influence of the best predictor variables on retinoid dynamics is required to implement the use of retinoids as biomarkers of pollutant exposure in cetaceans.

Age Factors↗
PubMed2006

Oral retinoids for chemoprevention of skin cancers in organ transplant recipients: results of a survey.

Systemic retinoid therapy is thought to be beneficial for chemosuppression of skin cancers in solid organ transplant recipients. We present the results of a survey of 28 dermatologists with experience managing transplant recipients to clarify when and how systemic retinoids are used in this population. Almost 80% of respondents use retinoids in some transplant recipients. Factors influencing the use of retinoids include the incidence and aggressiveness of cutaneous squamous cell carcinomas and the extent of concomitant actinic keratoses. Patients are monitored more closely during periods of dose adjustment than during the maintenance phase of therapy. Adverse effects are variably managed symptomatically, with dose adjustment, by discontinuation of retinoids, or by referral to another specialist for further evaluation. In the absence of large randomized controlled trials, the practice habits of experienced physicians serve as a useful guide for the use of oral retinoids in transplant recipients.

Administration, Oral↗
PubMed2003

Combined RAR alpha- and RXR-specific ligands overcome N-myc-associated retinoid resistance in neuroblastoma cells.

Retinoids induce human neuroblastoma cells to undergo growth inhibition and neuritic differentiation in vitro, through interactions with nuclear retinoid receptor proteins. In this study, we found that three different neuroblastoma cell lines exhibited wide variation in their responsiveness to the growth inhibitory effects of the retinoic acid receptor (RAR) agonist, all-trans-retinoic acid (aRA). Resistance to the growth inhibitory effect of aRA correlated with the presence of N-myc gene amplification and not aRA-induced RAR beta levels. Over-expression of N-myc in a neuroblastoma cell line with no endogenous N-myc expression caused a marked reduction in retinoid-induced growth inhibition. Combination of receptor-specific retinoid agonists for RXR and RAR alpha significantly enhanced the sensitivity of N-myc-amplified neuroblastoma cells to the growth inhibitory effects of aRA. Our results indicate that combination receptor-specific retinoid therapy can overcome N-myc-mediated retinoid resistance and may be a more effective chemo-preventive strategy in the disease.

Blotting, Western↗
PubMed1986

Mechanism of action of retinoids.

In several recent reviews, we have suggested that the mechanism of action of retinoids in controlling cell differentiation is related to their effects on the expression of oncogenes and peptide growth factors. It is currently believed that oncogenes control metabolic pathways that involve peptide growth factors and their receptors, as well as postreceptor signaling mechanisms. Retinoids, therefore, have been valuable probes to study the function of oncogenes and peptide growth factors. In several tumor cells, including human promyelocytic leukemia, human and murine neuroblastoma, and murine teratocarcinoma, retinoic acid induces terminal differentiation, accompanied by suppression of the expression of either the c-myc or the N-myc gene. Many studies have indicated that retinoic acid can markedly increase the number of cellular receptors for epidermal growth factor, which is partially encoded by another oncogene, erb-B. We have shown that retinoic acid greatly inhibits the anchorage-independent growth of a rat fibroblast cell line that has been transfected with the c-myc gene, particularly when these cells are stimulated by the combination of platelet-derived growth factor and transforming growth factor-beta. At present, the mechanisms by which retinoids control oncogene and growth factor expression are unknown. A wide range of new compounds, including the retinoidal benzoic acid derivatives, are now available to study these mechanisms, and will necessitate the identification of a high-affinity receptor for retinoids and the elucidation of the interaction of this receptor with the genome of the cell. The recent synthesis of new terephthalic acid anilides and chalcone carboxylic acid derivatives, which have retinoid-like activity, offers a particularly useful approach to this problem.

Animals↗
PubMed1986

Epidermal effects of retinoids: in vitro studies.

Cell culture provides controlled conditions in which to investigate the effects of retinoids on the molecular and cell biology of epidermal differentiation. In general, retinoids enhance proliferation and desquamation of cultured epidermal cells and suppress differentiation. In the presence of 10(-6) mol/L retinoic acid, cultured human epidermal cells stratify, but they do not form the granular layer and anucleate, stratum corneum-like superficial layer typical of normal epidermis. Retinoic acid in the growth medium alters keratin synthesis and inhibits the formation of cross-linked envelopes. Expression of other keratinocyte proteins, including filaggrin and components of desmosomes, may also be affected by retinoids. The molecular mechanisms of retinoid action on epidermal cells are still unclear. Cells cultured from normal and pathologic epidermis appear to differ significantly in their responsiveness to retinoids. Recent data suggest that retinoids may modulate gene transcription, stabilize cell membranes, and alter posttranslational processing of several keratinocyte proteins.

Cell Differentiation↗
PubMed1986

Epidermal effects of retinoids: supramolecular observations and clinical implications.

Retinoids, synthetic vitamin A analogs, stimulate mucous metaplasia and gap-junction proliferation in embryonic and neoplastic epidermis. Such effects demonstrate that vitamin A has potent effects on epidermal differentiation. Oddly, however, retinoid action in normal postnatal tissues, where these drugs are used clinically, appears to be quite different. In animals and humans, both topical and systemic retinoids produce acanthosis, hypergranulosis, and a relative (but not absolute) decrease in the thickness of the stratum corneum. These changes reflect the distinct boost in cell turnover that results from retinoid treatment. On the ultrastructural level, desmosomes are actively shed by cells of the spinous layer, resulting in many fewer attachment points along the cell membranes of the outer epidermis. Loss of desmosomes, coupled with decreased tonofilaments, enhanced keratinocyte autolysis, and intercellular deposition of glycoconjugates (not mucin), cause loosening and fragility of the stratum corneum (so-called anti-keratinizing effects). The biochemical basis of retinoid activity, in addition to stimulating increased cell turnover, appears to be a global enhancement of glycoconjugate synthesis and the generation of less mature keratins. The epidermal effects of retinoids can be exploited therapeutically: to cause loosening of thickened stratum corneum, for example in psoriasis or ichthyosis; to enhance penetration of pharmacologic agents such as 5-fluorouracil across hypertrophic actinic keratoses; and to normalize differentiation in neoplastic epidermis involving mucous metaplasia and gap-junction proliferation.

Animals↗
PubMed1997

The treatment of acne with topical retinoids: one man's opinions.

Acne is a family of disorders that vary greatly in pathogenesis and clinical manifestation. Accordingly, no simple recipe for treatment can be given, and treatment options vary with the stage and intensity of the disease. Topical retinoids are the mainstay for treating common varieties of acne vulgaris. They also prevent development of comedones, halting progression to inflammatory lesions. Tretinoin was the first retinoid used in the topical treatment of acne more than 25 years ago. Isotretinoin, which has recently become available, is less irritating, but is probably somewhat less effective. Adapalene is a recently introduced topical retinoid used to treat acne. It enjoys therapeutic equivalence to tretinoin but is less irritating. Except for very mild acne cases, topical retinoids should be used concommitantly with other drugs. The operating principle is to choose drugs whose modes of action are different from topical retinoids, that is, antibiotics or benzoyl peroxide. Topical retinoids, however, constitute the core of nearly all therapeutic programs for acne.

Acne Vulgaris↗
PubMed1997

Lack of involvement of retinoic acid receptor alpha in retinoid-induced skin irritation in hairless mice.

It has been proposed that RAR gamma, the major retinoic acid receptor (RAR) subtype in skin, mediates retinoid-induced skin irritation. However, RAR alpha is also found in skin, and its role in retinoid-induced skin irritation has not been tested. In this study, RAR subtype-specific agonists and antagonists were used to test the possible contribution of RAR alpha to retinoid-induced skin irritation. Female hairless mice were treated topically on the dorsal skin for 5 days with various retinoids over a 2-log dose range, and cutaneous toxicity was scored by semiquantitative visual observations of skin flaking and abrasions daily up to 3 days post-treatment. Three RAR alpha-selective agonists were > or = 100-fold less potent as skin irritants than the structurally-related RAR pan-agonist, TTNPB. Skin irritation potency decreased in the following order: TTNPB > > Am580 > AGN 193835 > > 193836 and correlated with RAR beta and/or RAR gamma binding affinity rather than RAR alpha binding affinity. TTNPB-induced skin irritation was blocked in a dose-dependent fashion by co-treatment with the RAR pan-antagonist AGN 193109 but was not blocked by co-treatment with the RAR alpha-specific antagonist AGN 194301. In contrast, skin irritation induced by the RAR alpha-selective agonist AGN 193835 was almost completely blocked by co-treatment with AGN 193644, an RAR beta/gamma-selective antagonist. These data demonstrate that RAR alpha is not significantly involved in mediating retinoid-induced skin irritation in mice and suggest that RAR alpha-selective agonists may have reduced mucocutaneous side effects relative to other retinoids.

Animals↗
PubMed1990

Chromatography of retinoids.

This article reviews the determination of retinoic acids and their metabolites (first-generation retinoids), aromatic retinoids (second generation) and arotinoids (third generation) in biological samples. Because of the sensitivity of the retinoids to isomerization and oxidation, special care has to be taken from sample collection and storage, throughout extraction, till the final chromatographic separation. High and strong protein binding, and insolubility in aqueous solutions hamper the extraction from biological samples. Various extraction procedures are discussed, mainly involving liquid-liquid extraction of biological fluids or lyophilized tissue samples. The new technique involving direct injection of biological fluids or tissue homogenates, using high-performance liquid chromatography (HPLC) with automated column switching, provides full protection from light and simplifies sample work-up. HPLC with ultraviolet detection is the method of choice for the determination of retinoids, because it is rapid, sensitive and allows separation of geometric isomers and metabolites within a wide polarity range. Gas chromatography-mass spectrometry is not appropriate for first- and second-generation retinoids because of isomerization, but allows very sensitive determination of third-generation retinoids, although very extensive sample clean-up and derivatization are necessary. However, direct injection of large volumes of biological fluids into HPLC systems, using on-line solid-phase extraction and automated column-switching, results in very sensitive methods even with simple ultraviolet detection and may become the method of choice for routine analyses.

Body Fluids↗
PubMed1999

A new class of RAR subtype selective retinoids: correlation of pharmacological effects with receptor activity.

The synthesis and biological activity of a series of structurally related retinoids with different RAR subtype selectivities are described. These retinoids bind to all three RAR subtypes but in functional transactivation assays, they show RARbeta or RARbeta,gamma selectivity with weak RARalpha activity. The subtype selectivity of these retinoids was found to correlate with their efficacy (ODC inhibition) and toxicity (topical irritation and teratogenicity) profiles. The degree of RARgamma transactivation activity correlates with their topical toxicity and teratogenicity as measured by the inhibition of chondrogenesis. Of the RARbeta selective retinoids reported here, retinoid 12 is the most promising, as it is completely devoid of two common retinoid related toxicities, namely topical irritation and teratogenesis.

Animals↗
PubMedDate not supplied

Retinoids in combination therapies for the treatment of cancer: mechanisms and perspectives.

Retinoid derivatives have been of special interest in cancer research because of their antiproliferative and differentiation-inducing activities in premalignant and malignant cells. Some retinoids are clinically effective in cancer therapy and prevention, and all-trans-retinoic acid is being used for the treatment of acute promyelocytic leukemia. Unfortunately, classical retinoids are not effective against most advanced solid tumors and cause undesirable side effects, which have limited the full development of retinoids as chemopreventive and chemotherapeutic drugs. The recent identification of selective retinoid derivatives capable of inducing apoptosis and their combination with other anticancer therapies promises a more effective and less toxic manner to the successful use of retinoids in cancer therapy.

Animals↗
PubMed2004

Retinoids: potential in cancer prevention and therapy.

Retinoids (derivatives of vitamin A) are signalling molecules that play important roles in cell growth, differentiation and death. Retinoids act through two types of receptors - retinoic acid receptors (RAR alpha, RAR beta and RAR gamma) and retinoid X receptors (RXR alpha, RXR beta and RXR gamma) - which themselves act as ligand-dependent transcription factors. Retinoids are of special interest in cancer research owing to their antiproliferative and cancer-preventative properties. They have been used successfully to cure acute promyelocytic leukaemia (APL) and can suppress carcinogenesis in a variety of tissue types (e.g. skin, lung, breast and oral cancers). Extensive research efforts have been dedicated to elucidating the molecular and cellular networks that are induced by retinoids, and this has recently yielded novel insights into how retinoids can both prevent and combat cancer.

Drug Design↗
PubMed1986

In vivo isomerization of all-trans- to 11-cis-retinoids in the eye occurs at the alcohol oxidation state.

The vertebrate biochemical pathway for regeneration of visual pigments in the living eye after bleaching is largely uncharacterized. Since isomerization of an all-trans-retinoid to an 11-cis-retinoid could conceivably occur via the aldehyde, alcohol, or ester forms of vitamin A, it is important to determine the oxidation state of the retinoid that is isomerized in vivo. To address this problem, light-adapted rats and frogs were injected intraperitoneally with a mixture of [15-3H]-all-trans-retinol and [15-14C]-all-trans-retinol. After 4 or 24 h of dark adaptation, labeled retinoids in the animal's eyes were analyzed. All rats had the expected 50% loss of 3H label (relative to 14C) in 11-cis-retinal, a loss of 3H that must occur when [15-3H]retinol is oxidized to retinal. 11-cis-Retinyl esters in the rats' eyes at 4 h retained 67% of the 3H label, and this could be increased to 81% when the rats were pretreated with 4-methylpyrazole, an alcohol dehydrogenase inhibitor known to inhibit dark adaptation. This result demonstrates that retinoid isomerization occurs at the alcohol oxidation state in the rat eye. Had it occurred at the aldehyde oxidation state, at least 50% of the 3H in the 11-cis-retinyl esters would have been lost. The importance of this isomerization pathway is emphasized by the observation that dark-adapting rats whose alcohol dehydrogenase(s) had been inhibited by 4-methylpyrazole had increased amounts of 11-cis-retinyl ester in their eyes relative to control rat eyes, a result that is understandable only if retinoids are isomerized in vivo at the alcohol oxidation state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Retinoids and chemoprevention of aerodigestive tract cancers.

Natural and synthetic vitamin A metabolites and analogs (retinoids) were found to suppress head and neck and lung carcinogenesis in animal models and inhibit carcinogenesis in individuals with premalignant lesions and a high risk to develop cancer of the aerodigestive tract. Likewise, retinoids prevent the development of second primary cancers in head and neck and lung cancer patients who had been treated for the first primary. These effects are thought to result from changes in the expression of genes that regulate cell growth and differentiation. Most of the effects of retinoids on gene expression are mediated by nuclear retinoic acid receptors RARs (alpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma), which function as retinoid-activated transcription factors. Like vitamin A deficiency, alterations in receptor expression or function could interfere with the retinoid signaling pathway and thereby enhance cancer development even in vitamin A sufficient individuals. We found that the expression of RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer (e.g., oral leukoplakia and squamous metaplasia), in dysplastic lesions adjacent to cancer, and in malignant oral and lung carcinomas. The expression of the other receptors was not different among normal, dysplastic, and malignant oral tissues. However, the expression of RAR gamma and RXR beta was somewhat decreased in lung cancers. These results show that RAR beta expression is lost at early stages of carcinogenesis in the aerodigestive tract and support the hypothesis that the loss of RAR beta expression may facilitate the development of some of these cancers.

Anticarcinogenic Agents↗