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At least 487 records · Page 27Linked to original sources
PubMed1999

Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12 production by human peripheral blood mononuclear cells.

We have demonstrated previously that cells from both the skin and peripheral blood from patients with cutaneous T cell lymphoma (CTCL) have elevated levels of protein and mRNA for Th2 cytokines, interleukin-4 (IL-4) and IL-5, and depressed levels of Thl cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, IL-12 in vitro can restore IFN-gamma production by these patients' cells to near normal levels. Because retinoids exert therapeutic activity in CTCL and are potent modulators of growth and differentiation of hematopoietic cells, we investigated the role of retinoids in modulating Thl cytokine production. Peripheral blood mononuclear cells (PBMC) from normal donors and patients with CTCL were cultured with medium, IL-2, 13-cis-retinoic acid, all-trans-retinoic acid, acetretin or etretinate alone, or IL-2 plus the retinoids for 24 h, and levels of IFN-gamma were determined using ELISA. IL-2 or retinoids alone could induce low but significant levels of IFN-gamma. However, when IL-2 was cultured with each retinoid, a synergistic augmentation of IFN-gamma levels (4-fold to 90-fold) was observed except in the case of etretinate. All-trans-retinoic acid (ATRA) was the most potent IFN-y inducer. Similar studies performed using PBMC from CTCL patients indicated the IFN-gamma augmentation occurred but in a blunted manner. The IFN-y-inducing effect of ATRA and 13-cis-retinoic acid could be abrogated by addition of anti-IL-12 antibodies, suggesting that IL-12 plays a role in the synergistic upregulation of IFN-gamma. Using an IL-12 p40-specific radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plus retinoid-treated culture supernatants. Purified monocytes cultured with IL-2 plus ATRA did not secrete IL-12. Only when monocytes were cocultured with lymphocytes was there an increase in IL-12 production, suggesting the involvement of a paracrine feedback loop requiring both monocytes and lymphocytes. These data suggest that retinoids can induce Th1 cytokines from normal and CTCL PBMC and that this induction may be mediated through IL-12 production.

Antigen-Antibody Reactions↗
PubMed1995

Relation between beta-carotene intake and plasma and adipose tissue concentrations of carotenoids and retinoids.

We evaluated the relation between beta-carotene intake and plasma and adipose tissue concentrations of carotenoids and retinoids. In Study 1, beta-carotene intakes were significantly greater in vegetarians than in nonvegetarians. Plasma concentrations of beta-carotene were also significantly higher in vegetarians than in nonvegetarians but only after two nonvegetarians with excessive intake of carrots were omitted. Plasma retinoid (retinol, retinyl esters, and retinoic acid) concentrations were not different between the two groups. In Study 2, female subjects ingested a daily placebo or 90 mg beta-carotene for 3 wk. In the group fed beta-carotene, plasma beta-carotene concentrations were significantly increased from baseline at 1, 2, and 3 wk. No beta-carotene changes were observed in the placebo-fed group. Plasma retinoid concentrations did not change in either group. In Study 3, adipose tissue beta-carotene and retinoid concentrations were measured in men after an oral beta-carotene dose (120 mg, experimental subjects) or no beta-carotene (control subjects). In the experimental subjects, adipose beta-carotene concentrations increased from baseline at 5 and 10 d postdosing. The control group's adipose tissue beta-carotene concentration did not change over a 10-d period. Changes in retinoids in adipose tissue were not significant in either group. In conclusion, dietary and supplemental beta-carotene increased plasma beta-carotene concentrations but had no effect on plasma retinoid concentrations. There may be little tissue metabolism of beta-carotene to retinoids. Therefore, the anticarcinogenic effect of beta-carotene, if any, may be due to properties of the molecule itself.

Adipose Tissue↗
PubMed1999

Retinoids in lung cancer chemoprevention and treatment.

In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253.

Cell Transformation, Neoplastic↗
PubMed2002

Nuclear (receptor) power: retinoids in rat mesangioproliferative disease.

Cytokine-driven proliferation and inflammation play important roles in the response of the kidney to injury and precede the development of glomerulosclerosis. There is great interest in agents which may interfere with such proliferation and inflammation. Therefore, a rat model of mesangioproliferative glomerulonephritis was studied and the effects of all-trans retinoid acid (RA) and isotretinoin, powerful anti-proliferative and anti-inflammatory substances, on glomerular damage and cell proliferation were examined. The use of retinoids was also warranted because of their known (suppressive) effects on genes involved in the pathogenesis of renal damage. RA prevented the blood pressure increase evoked by anti-Thy1.1 nephritis. Treatment with either RA or isotretinoin reduced the albumin excretion rate by 70%. Periodic acid-Schiff (PAS) stains revealed significantly fewer glomerular cells in nephritic rats treated with retinoids. Similarly, the number of mitoses and of cells which stained positively for proliferating cell nuclear antigen was significantly less in nephritic glomeruli treated with retinoids compared with the vehicle-treated group. Glomerular expression of platelet-derived growth factor B-chain was significantly reduced in the presence of retinoids. It was concluded that retinoids limit glomerular proliferation, glomerular lesions and albuminuria in an established model of renal damage. These findings point to retinoids as potential novel modulators of glomerular injury.

Animals↗
PubMed2000

TCDD suppression of tissue transglutaminase stimulation by retinoids in malignant human keratinocytes.

The human keratinocyte line SCC-4 is a model system in which to explore the mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interferes with the action of hormones in the steroid receptor superfamily. In present work, retinoid induction of tissue transglutaminase mRNA was suppressed 60-70% by 10 nM TCDD in the human squamous carcinoma cell line SCC-4. This effect occurred without enhanced degradation of the mRNA and thus appeared to result from altered transcription. The actions of all-trans-retinoic acid and the synthetic retinoid TTNPB ((E)4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthylenyl)-1propenyl] benzoic acid), which resists metabolic degradation, were suppressed to the same extent without obvious changes in their EC(50)s. In addition, TCDD suppression of reporter transcription, driven by a retinoic acid response element, was not evident in transient or stable transfections of SCC-4 cells. Sodium butyrate (3 mM) alone induced tissue transglutaminase and augmented retinoid induction. In the presence of butyrate, TCDD acted as an inducer and did not reduce retinoid stimulation. Retinoic acid induction of tissue transglutaminase displayed a lag phase of >24 h, indicating that the induction has an indirect component. Rather than depleting active retinoid in the culture medium or generally inactivating retinoid receptor function, TCDD may suppress retinoid action in this case by interfering with the late phase of induction.

Benzoates↗
PubMed1992

Developmental changes in endogenous retinoids during pregnancy and embryogenesis in the mouse.

Vitamin A and its analogs (retinoids) have acquired particular significance in embryonic development since the discovery that retinoic acid (RA) possesses properties of an endogenous morphogen and that embryonic tissues contain specific nuclear receptors for RA. Since the mammalian embryo does not synthesize RA de novo but rather must acquire it directly or in a precursor form from the maternal circulation, we sought to establish the relationship between levels of RA, retinol, and retinyl esters in the maternal system and their acquisition by the embryo, particularly during organogenesis in the mouse. Results indicate profound changes in maternal vitamin A levels during pregnancy in the mouse. These changes were characterized by a large, transient decrease in plasma retinol levels coincident with the period of organogenesis (e.g. gestational Days 9-14), and an apparent increase in mobilization from hepatic stores to the conceptus. During organogenesis, the embryo exhibited a steady increase in retinol levels with little increase in retinyl esters and virtually no change in RA. Analysis of retinoid accumulation patterns in the embryonic liver indicate that functional onset of vitamin A storage occurs by mid-organogenesis. In contrast, placental levels of these retinoids remained unchanged throughout organogenesis. Analysis of the conceptus as a developmental unit revealed that during early organogenesis the majority of retinoids are contained in the placenta (8-fold more than in the embryo). However, by mid-organogenesis the retinoid content of the embryo exceeds that of the placenta. Together, these results provide evidence that pregnancy in the mouse is accompanied by pronounced alterations in maternal retinoid homeostasis that occur coincident with the period of high embryonic sensitivity to exogenous retinoids.

Animals↗
PubMed1985

Pharmacokinetics of topically applied radiolabeled retinoids in hairless mouse epidermis and dermis after single applications.

The retention of tritium-labeled all-trans-retinoic acid (RA), 13-cis-retinoic acid (13-cis-RA), aromatic retinoid, and arotinoid ethyl ester in the epidermis and dermis of hairless mice was measured up to 24 h following a single topical application in an acetone vehicle. The radioactivity in the tissues was extractable with chloroform:methanol, and the identities of the radioactive species extracted were confirmed as retinoids using thin-layer chromatography. All the retinoids were absorbed into the skin rapidly. After an initial period of distribution and penetration (lasting for about 1 h) the amount of the applied retinoid remaining in the epidermis and dermis decreased more slowly, obeying first order (exponential) decay kinetics. Both the arotinoid and the aromatic retinoid persisted for longer in the epidermis than equivalent doses of RA or 13-cis-RA. The half-lives of the retinoids in the dermis tended to be longer than in the epidermis, except for the arotinoid. Aromatic retinoid persisted for longest in the dermis with a half-life of 11 h.

Administration, Topical↗
PubMed1996

Oral retinoids--efficacy and toxicity in psoriasis.

Psoriasis is a disease of unknown aetiology, affecting approximately 1-3% of the population. In most cases involving relatively localized disease, patients are best managed with either topical therapy alone or topical therapy in combination with UV-phototherapy. However, approximately 35% of patients do not respond well to these conventional treatments or have moderate-to-severe disease requiring more aggressive forms of therapy. The second-generation retinoids, etretinate and its metabolite acitretin, are important additions to the armamentarium of agents used to treat these recalcitrant or severe forms of the disease. Generalized pustular psoriasis generally responds well to high-dose (0.7-1 mg/kg/day) oral retinoid monotherapy. In contrast, increasing small doses of the retinoid are recommended initially in erythrodermic psoriasis in order not to provoke the disease. Long-term clinical experience favours a combination treatment of the retinoid with either topical and/or UV irradiation in chronic plaque-like psoriasis. Both oral retinoids have comparable efficacy and tolerability profiles, and the relapse rates for both drugs are similar. The toxicities associated with both short- and long-term treatment with oral retinoids are significant and include mucocutaneous effects, adverse modulation of serum lipid chemistries, elevation of liver enzymes, and after long-term chronic dosing, skeletal and ligamentous calcification, and hyperostosis. Both etretinate and acitretin, like all retinoids, are known teratogens in animal models, and documented evidence exists for teratogenic activity in humans as well. Consequently, women of childbearing age are strongly advised to avoid pregnancy during treatment and up to 5 years following cessation of therapy with both etretinate and the carboxylic acid metabolite acitretin.

Administration, Oral↗
PubMed2003

Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma.

Retinoids, natural and synthetic derivatives of vitamin A, are biological regulators of differentiation, proliferation, apoptosis, and immune response. Retinoic-acid-receptor-selective retinoids (all-trans retinoic acid, 13-cis-retinoic acid, and the synthetic analogs isotretinoin, etretinate and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphoma (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid-X-receptor retinoid to be approved by the FDA for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Bexarotene treatment induces apoptosis of CTCL cells with down-regulation of its receptors and of survivin, an inhibitor of apoptosis. Identification of new receptor subtype-selective retinoids, combination of various receptor-selective retinoids or other agents, and a new drug delivery system may improve the clinical efficacy of retinoids in the future.

Administration, Topical↗
PubMed2004

Systemic and topical retinoids in the management of skin cancer in organ transplant recipients.

BACKGROUND: Nonmelanoma skin cancers are the most frequent malignancies in organ transplant patients. Patients who develop multiple new skin cancers may benefit from retinoid chemoprevention. OBJECTIVE: The objective of this study was to advise on the use of retinoids in organ transplant recipients. METHODS: A summary was performed of the existing literature regarding experience with retinoid chemoprevention for skin cancer in organ transplant patients. RESULTS: Systemic retinoids, specifically acitretin, are effective in inhibiting tumor development in organ transplant patients. This effect is only present during therapy, however. Topical retinoids have some effect in the treatment of actinic keratoses. CONCLUSIONS AND RECOMMENDATIONS: Systemic retinoids can be used for chemoprevention of skin cancer. For a good result, long-term treatment with acitretin is necessary. Side effects, however, limit the use of retinoid chemoprevention. It is advised that treatment be started at a low dose, and patients should be monitored regularly for triglyceride and cholesterol levels and transaminases.

Acitretin↗
PubMed2006

Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects.

BACKGROUND: In patients with nonmelanoma skin cancer that is high risk or characterized by numerous tumors, chemoprevention with systemic retinoids may effectively decrease the number of new tumors whereas the chemosuppressive effects may reduce the risk of recurrence or disease progression. A patient's intolerance of the mucocutaneous effects of retinoid therapy or abnormal laboratory findings may hamper continuous therapy. OBJECTIVE: To present a method for optimizing tolerance of systemic retinoids for chemoprevention and for monitoring and managing adverse events. METHODS: After reviewing the data on the use of systemic retinoids for chemoprevention, we developed a simplified approach for administering oral retinoids for chemoprevention of nonmelanoma skin cancer as well as basic guidelines for the prevention and management of adverse effects and appropriate laboratory monitoring. RESULTS: Chemoprevention with systemic retinoids in patients with a history of numerous tumors or high-risk skin cancer can be optimized with graduated dose escalation and preventive strategies for the most common adverse effects. Routine laboratory monitoring may assist in detecting adverse effects, which can be managed in most cases. CONCLUSION: In our experience, the effective use of systemic retinoids for chemoprevention of nonmelanoma skin cancer in high-risk patients can be optimized through a standardized, proactive approach.

Acitretin↗
PubMed2006

Retinoids and wound healing.

BACKGROUND: Retinoids are widely used in dermatology and may play a role in wound healing. The exact role of retinoids in wounds is confusing and controversial, however. Systemic retinoids are presumed to be detrimental to wound healing; however, this standard is based on isolated reports. OBJECTIVE: The objective was to provide a critical review of the available literature regarding the role of both topical and systemic retinoids in various aspects of wound healing. CONCLUSIONS: Pretreatment with retinoids likely promotes wound healing after facial resurfacing procedures and full- or partial-thickness wounds. While the evidence is mixed regarding the effects of retinoids applied to fresh and healing wounds, the majority of the evidence available shows favorable wound-healing properties in this setting. The medical-legal standard regarding the avoidance of facial resurfacing and surgical procedures in patients on or recently completing a course of systemic retinoids was likely prematurely established.

Humans↗
PubMedDate not supplied

Treatment of cutaneous T-cell lymphoma with retinoids.

Retinoids are biologic regulators of differentiation, proliferation, apoptosis, and immune response. Retinoids (all-trans retinoic acid, 13-cis-retinoic acid, and the synthetic analogs isotretinoin, etretinate, and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphomas (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid X receptor retinoid to be approved by the Food and Drug Administration for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Use of retinoids in future long-term clinical trials and their eventual application in CTCL regiments will require strategies to decrease the side effects of existing retinoids, identify novel receptor subtype-selective retinoids with better therapeutic index, and explore biologically based synergistic combination therapies with other active agents.

Humans↗
PubMed1999

Teratology of retinoids.

Either an excess or a deficiency of vitamin A and related compounds (retinoids) causes abnormal morphological development (teratogenesis). Potential retinoid sources come from dietary intake, nutritional supplements, and some therapeutic drugs. Therefore, understanding the mechanisms of retinoid teratogenesis is important. This review first gives an overview of the principles of teratology as they apply to retinoid-induced malformations. It then describes relevant aspects of the biochemical pathway and signal transduction of retinoids. The teratogenic activity of various retinoid compounds, the role of the retinoid receptors, and important toxicokinetic parameters in teratogenesis are reviewed.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Retinoids and renal development.

Although it has long been appreciated that retinoids play an essential role in kidney organogenesis, it has only recently been recognized that even mild fetal vitamin A deficiency syndromes can result in a reduction in nephron number. Recent studies have also begun to define the cellular and molecular events associated with retinoid actions in the fetal kidney and have demonstrated the essential function of retinoids in branching growth of the ureteric bud. Importantly, characterization of the renal developmental effects of RAR alpha/beta 2 double homozygous mice combined with metanephric organ culture studies have together shown that one essential function of retinoid action in the developing kidney is the maintenance of c-ret expression in the tips of the ureteric bud. However, many other potential retinoid target genes including midkine, sonic hedgehog, Hox d-11, matrix metalloproteinases, and tissue inhibitors of metalloproteinases appear to play important roles in renal development and might be important downstream mediators of retinoid effects in the developing kidney. It can, therefore, be anticipated that important new insights into fetal kidney development will be forthcoming in the near future, as the essential target genes affected by retinoid signal transduction are progressively elucidated.

Animals↗
PubMed1997

Effects of vitamin D3 on keratinocyte proliferation and differentiation in vitro: modulation by ligands for retinoic acid and retinoid X receptors.

Keratinocytes express receptors for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], all-trans-retinoic acid (all-trans-RA), 9-cis-retinoic acid (9-cis-RA) and triiodothyronine (T3). The vitamin-D receptor (VDR) can act as a transcription factor by forming homodimers or heterodimers with the retinoic-acid receptor (RAR), the retinoid X receptor (RXR) or the triiodothyronine receptor (TR). This study investigated whether the antiproliferative and prodifferentiating effects of 1,25(OH)2D3 on normal human keratinocyte cultures is modified by all-trans-RA, a ligand for RAR, by CD2809, a ligand for RXR, by 9-cis-RA, a ligand for the RAR and RXR, and T3, a ligand for the TR. Submerged, second-passage normal human keratinocytes were grown to approximately 30% confluency before incubation for 4 days with ligands in keratinocyte growth medium supplemented with 3% charcoal-stripped fetal calf serum and 0.3 mM Ca2+. Proliferation was measured by the dimethylthiazolyl-diphenyl-tetrazolium-bromide assay. Then differentiation was determined in the same culture, performing a cell ELISA for transglutaminase type 1. All-trans-RA, 9-cis-RA and CD2809 had a slight stimulatory effect on proliferation. In combination with 1,25(OH)2D3, all retinoids partially counteracted the antiproliferative effect of 1,25(OH)2D3. The differentiation was dose-dependently inhibited by all-trans-RA, 9-cis-RA and CD2809 alone. In combination with 1,25(OH)2D3, all retinoids reversed the prodifferentiating effect of 1,25(OH)2D3, resulting in a net inhibition of differentiation. T3 had no effect on proliferation of differentiation, either alone or in combination with 1,25(OH)2D3. In conclusion, retinoids with different receptor selectivities had similar effects on keratinocyte proliferation and differentiation. The effects of 1,25(OH)2D3 on proliferation and differentiation were reversed by all retinoids. Therefore ligand-dependent heterodimer formation between the VDR and retinoid receptors may not be important for the combined effects of 1,25(OH)2D3 and retinoids on keratinocyte proliferation and differentiation in vitro.

Alitretinoin↗
PubMed1992

Retinoids and contraception.

The main side effect of the retinoids is teratogenicity. Every dermatologist has a moral obligation to ensure that this effect is avoided, and the present publication is aimed at helping prescribe these drugs. After a review of the key properties of each of the retinoids on the market, the different forms of contraception available and their indication in young patients undergoing retinoid treatment are discussed. Unless otherwise contraindicated, oral contraception with an estrogen-progestogen formulation is the contraceptive method of choice for women undergoing retinoid treatment. The intrauterine device (IUD) is of little or almost no relevance for young women undergoing treatment with a retinoid. IUDs are indicated in older multiparae who have practised this form of contraception before starting retinoid treatment and who refuse to take the pill. Natural and local methods of contraception are totally unsuitable for women undergoing treatment with retinoids. However, they may be used as an additional precautionary measure by IUD users.

Abnormalities, Drug-Induced↗
PubMed1996

Retinoid receptor expression and all-trans retinoic acid-mediated growth inhibition in vascular smooth muscle cells.

BACKGROUND: Retinoids have been used in the successful treatment of a variety of human hyperproliferative diseases. Their role in smooth muscle cell (SMC) growth control, however, has not been clearly established. The present study was designed to assess the retinoid receptor mRNA expression profile in SMCs and to determine whether retinoids exert a growth-inhibitory effect in these cells. METHODS AND RESULTS: Five of the six retinoid receptors were expressed in both cultured SMCs and aorta as determined by Northern blotting or reverse transcriptase-polymerase chain reaction. Receptor activity was demonstrated in SMCs with the use of a reporter assay with a retinoid receptor DNA binding sequence linked to a chloramphenicol acetyltransferase reporter gene. DNA synthesis and cell proliferation assays were performed to show that all-trans retinoic acid (atRA) antagonized platelet-derived growth factor-BB and serum-stimulated SMC growth. Growth inhibition was distal to early growth-signaling events because induction of c-fos, c-jun, and egr-1 mRNA was unaffected by atRA. However, with an activated protein-1-linked chloramphenicol acetyltransferase reporter, atRA was shown to inhibit the activity of activated protein-1-dependent transcription in a transient transfection assay. CONCLUSIONS: These results establish the presence of functional retinoid receptors in SMCs and document the growth-inhibitory action of atRA on these cells. Retinoid compounds, already in clinical use as antiproliferative agents for nonvascular indications, should be assessed further in in vivo models of intimal disease.

Animals↗