Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Retinoids”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 865 records · Page 48Linked to original sources
PubMed1997

Roles of retinoids and their nuclear receptors in the development and prevention of upper aerodigestive tract cancers.

Vitamin A analogs (retinoids) suppress oral and lung carcinogenesis in animal models and prevent the development of second primary tumors in head, neck, and lung cancer patients. These effects result from changes in the expression of genes that regulate cell growth and differentiation. Retinoic acid receptors (RARs; -alpha, -beta, and -gamma) and retinoid X receptors (RXRs; -alpha, -beta, and, -gamma) are retinoid-activated transcription factors, which mediate effects of retinoids on gene expression. Therefore, alterations in receptor expression or function could interfere with the retinoid signaling pathway and thereby enhance cancer development. We found that the expression of RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer and 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.

Head and Neck Neoplasms↗
PubMed1997

Retinoid-regulated gene expression in neural development.

The discovery and development of information surrounding the retinoic acid receptors (RAR and RXR) has ushered in a new era in understanding the molecular mechanism of action of vitamin A in embryonic development and cellular differentiation. The mechanisms involved in the regulation of gene expression by the retinoids is at least partially known and involves binding of the RAR and RXR to retinoic acid response elements. Additional factors, including coregulatory proteins, associated regulatory elements, and cell-specific factors, may also be involved in determining the specificity of retinoid-regulation of gene expression during development. During embryogenesis, retinoids are required for the development of the posterior hindbrain and its associated structures, as well as for the survival and differentiation of certain classes of neurons and neural crest cell derivatives. At least some of the effects of retinoid on hindbrain development are related to the regulation of Hox gene expression. Additional retinoid-regulated genes have been implicated in nervous system development, and the manner in which they lead to phenotypic changes during embryogenesis remains to be determined.

Animals↗
PubMed2006

Clinical trials with retinoids for breast cancer chemoprevention.

Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGF-binding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.

Antineoplastic Agents↗
PubMed1994

Modulation of collagen synthesis and degradation by retinoids and cytokines in 3T3 L1 preadipocytes.

We previously observed that a retinoid analog can protect against liver parenchymal damage and liver fibrosis, whereas it accelerates liver fibrosis which is not accompanied by any parenchymal damage. To elucidate these conflicting effects, we examined the effects of retinoid in 3T3 L1 preadipocytes as a model of liver stellate cells. Retinoids, including all-trans retinol, all-trans and 9-cis retinoic acids, enhanced the cell growth and the expression of the type I procollagen gene as well as its peptide synthesis, while reducing collagenase activities. Although no retinoid enhanced the transforming growth factor (TGF)-beta 1 mRNA, retinoids may stimulate collagen production through activating TGF-beta, as was recently reported. These results help explain the observation in the liver fibrosis model with no parenchymal damage. In contrast, we also found that interferon (IFN) alpha beta and gamma inhibited cell growth and down-regulated markedly type I procollagen as well as TGF-beta 1 mRNA, suggesting that they suppress by acting directly on extracellular matrix-producing cells.

3T3 Cells↗
PubMed2002

Discovery and design of retinoic acid receptor and retinoid X receptor class- and subtype-selective synthetic analogs of all-trans-retinoic acid and 9-cis-retinoic acid.

This review presents a historical overview of the discoveries of retinoic acid receptor (RAR) and retinoid X receptor (RXR) class- and subtype-selective synthetic retinoids. These synthetic retinoids are conformationally restricted by having aromatic rings in place of the tetraene bond systems of all-trans- and 9-cis-retinoic acids. Events leading to the design and synthesis of such retinoid transcriptional agonists as RAR subtype beta,gamma-selective 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naph-thalenecarboxylic acid (TTNN), the RARgamma-selective Z-oxime of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbonyl)-2-naphthalenecarboxylic acid (SR11254), RAR-selective 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid (TTAB), RXR-selective 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-cyclopropyl] benzoic acid (SR11246), RXR-selective 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-methylpropenyl]benzoic acid (SR11345), and RARgamma-selective retinoid transcriptional antagonist 2-(6-carboxy-2-naphthalenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dithiolane (SR11253) are described.

Alitretinoin↗
PubMed2001

The role of metabolism and toxicokinetics in retinoid teratogenesis.

Retinoids (vitamin A and its analogs) exert profound effects on a wide variety of life processes, including morphogenesis and embryonic development. Several retinoids are also effective drugs for therapy of skin diseases and some types of cancer. However, the applicability of this class of compounds is limited by their teratogenic activity. A major question in retinoid toxicology has been the marked interspecies differences in the lowest teratogenic doses of 13-cis-retinoic acid and retinol. In addition, great attention has been drawn to the risk assessment of embryotoxicity resulting from excessive intake of vitamin A by pregnant women. The present review first gives an overview of the biochemistry, metabolism and mode of action of retinoids as well as their role in embryonic development. It then summarizes the results of recent studies on retinoid metabolism, toxicokinetics, and embryonic exposure and discusses how the available information provides explanation of the aforementioned interspecies variations. Finally, it presents some approaches for risk assessment of high vitamin A intake by humans based on various animal models and epidemiological studies.

Abnormalities, Drug-Induced↗
PubMed2002

Retinoids in liver fibrosis and cancer.

Pathobiological functions and metabolism of retinoids (vitamin A and its derivatives) in liver fibrosis and hepatocellular carcinoma (HCC) are discussed in the present review. Retinoic acid (RA, active metabolite) exacerbates liver fibrosis that is not accompanied by hepatic necroinflammation, in which RA acts directly on hepatic stellate cells (HSCs); RA enhances plasminogen activator/plasmin levels and thereby induces proteolytic activation of latent transforming growth factor-beta (TGF-beta), a strong fibrogenic cytokine, resulting in enhanced collagen production. We have developed a protease inhibitor, camostat mesilate, that suppresses TGF-beta activation and thereby inhibits the transformation of HSCs, leading to reduced matrix production by the cells. The compound is effective not only in preventing but also in reducing hepatic fibrosis in rats when administered orally. HCC is refractory to RA due to its local depletion in the tumors and also due to malfunction of its nuclear receptor, retinoid X receptor-alpha (RXRalpha) Oral supplementation of a synthetic retinoid named acyclic retinoid led to the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently suppressed posttherapeutic recurrence of HCC in cirrhotic patients. These results suggest eradication of AFP-L3-producing latent malignant clones from the liver by the retinoid. We propose the concept of "clonal deletion" therapy for cancer chemoprevention, a new category of cancer chemotherapy.

Animals↗
PubMed1985

Intestinal absorption of nutrients in animals dosed orally with retinoids: considerations for chemopreventive studies.

Biochemical measurements demonstrate that, in some species, various retinoids administered in the diet, can reduce the tissue contents of several lipid-soluble compounds: vitamin K, alpha-tocopherol, cholesterol, and vitamin A itself. The effect is probably due to an interference with intestinal absorption, as indicated by use of radioactive compounds and administration of bile acids. In male rats, a vitamin K deficiency induced by retinoids in the diet can lead to fatal hemorrhaging. Although retinoids inhibit the uptake of dietary cholesterol, they do not change plasma and tissue concentrations of the endogenous compound. Conversely, cholesterol in the diet appears to interfere with the absorption of retinyl esters. alpha-Tocopherol deficiency caused by retinoids results in tissues with low antioxidant and high peroxide concentrations. Humans may be less susceptible to these effects of retinoids, which, however, still deserve consideration in the planning of clinical trials.

Administration, Oral↗
PubMed1999

Metabolism of retinaldehyde isomers in pregnant rats: 13-cis- and all-trans-retinaldehyde, but not 9-cis-retinaldehyde, yield very similar patterns of retinoid metabolites.

Retinaldehyde (RAL), a key intermediate in retinoid metabolism, acts as a retinoic acid (RA) precursor, but is also reduced to retinol (ROH), which can subsequently be esterified to retinyl esters, the storage form of vitamin A. Limited information is available on the metabolism of geometric isomers of RAL as well as on the transplacental distribution of their metabolites, including RA isomers. Such information would be very helpful for the assessment of the teratogenic potency of RAL isomers, as teratogenesis represents a major side effect of retinoid use in pharmacotherapy. In the present study we examined concentrations of retinoids in plasma, maternal tissues, and embryos of pregnant rats 2 h after a single oral dose (100 mg/kg body weight) of all-trans-, 13-cis-, or 9-cis-RAL on gestational day 13. The main findings of this study were the very similar patterns of retinoid metabolites (consisting of retinoids with mainly the all-trans-configuration) after administration of all-trans- and 13-cis-RAL, and the high concentrations of 9-cis-RA, 9,13-dicis-RA, and 9-cis-retinoyl-beta-D-glucuronide after dosing with 9-cis-RAL. In addition, all-trans-RA as a RAL metabolite reached the embryos to a much greater extent than any of its cis-isomers. The results are discussed in view of in vitro data on enzymes involved in the biotransformation of RAL isomers.

Animals↗
PubMed1999

Mannose 6-phosphate/insulin-like growth factor II receptor mediates the growth-inhibitory effects of retinoids.

Both retinoids and the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) have been shown to play an important role in controlling cell growth during embryonic development and oncogenesis. Our recent work (Kang et al., Proc. Natl. Acad. Sci. USA, 94: 13671-13676, 1997; Kang et al., Proc. Natl. Acad. Sci. USA, 95: 13687-13691, 1998) revealed a direct biochemical interaction between retinoic acid (RA) and the M6P/IGF2R, thereby leading us to hypothesize that the M6P/IGF2R may mediate a growth-inhibiting effect of RA. To test this hypothesis, cell growth and apoptosis in response to RA and various receptor-selective retinoids were examined in cells that lack or overexpress the M6P/IGF2R. RA and those retinoids capable of binding to the M6P/IGF2R induced a remarkable morphological change with characteristics of round shape and reduced spreading, apoptosis, and growth inhibition in stably transfected mouse P388D1 cells overexpressing the M6P/IGF2R but not in the M6P/IGF2R-deficient P388D1 cells. These effects of RA were neither blocked by a potent RA nuclear receptor (RAR) antagonist (AGN193109), nor mimicked by a selective RAR agonist (TTNPB), suggesting that the observed effects of RA are independent of RARs. Similar effects of the retinoids were observed in cultured neonatal rat cardiac myocytes that have high levels of the M6P/IGF2R. Furthermore, overexpression of the M6P/IGF2R in a RA-resistant cancer cell line (HL-60R) that lacked functional RARs gave the cells a susceptibility to RA-induced apoptosis. These data suggest that the M6P/ IGF2R may play an important role in mediating retinoid-induced apoptosis/growth-inhibition and provide insight into the similar biological effects of RA and the M6P/IGF2R on fetal development and carcinogenesis.

Actin Cytoskeleton↗
PubMedDate not supplied

Retinoids as regulators of gene transcription.

Our understanding on the molecular mechanisms that underlie complex biology of retinoids' action has increased tremendously in recent years. Retinoids can bind and activate heterodimeric receptors and can directly affect transcriptional regulation of certain genes. Alternatively, they can indirectly affect the transcriptional regulation by inhibiting certain transcription factors, such as AP-1 and STAT-3. Alterations in retinoid receptor and subsequent signaling during acute promyelocytic leukemia [APL, characterized by a specific chromosome translocation, t(15;17)], has provided invaluable tool for understanding the myeloid differentiation at molecular level. Studies with APL have highlighted the critical role that retinoids play in cancer and its treatment with retinoids.

Animals↗
PubMed1992

Ligand-dependent synergy of thyroid hormone and retinoid X receptors.

The binding of thyroid hormone receptors to DNA is enhanced by heterodimerization with nuclear proteins. One such heterodimerization partner has recently been characterized as the retinoid X receptor. 9-cis-Retinoic acid has been identified as a natural ligand for retinoid X receptors, suggesting a potential receptor-mediated interaction between thyroid hormone and 9-cis-retinoic acid in the regulation of thyroid hormone-responsive genes. A transient cotransfection assay was used to test for such an interaction. When a complex thyroid hormone response element composed of both direct and inverted repeat hexamers was tested, these two ligands activated gene expression synergistically. In contrast, when the response element consisted only of directly repeated hexamers, unliganded retinoid X receptors enhanced thyroid hormone responsiveness, but 9-cis-retinoic acid induced no additional activation. The results suggest a unique mechanism to achieve differential suggest a unique mechanism to achieve differential thyroid hormone sensitivity of thyroid hormone-responsive genes within a cell. Genes with appropriate response elements will show amplification of the thyroid hormone response by 9-cis-retinoic acid in the presence of retinoid X receptors; other thyroid hormone-responsive genes will be influenced by retinoid X receptors, but not 9-cis-retinoic acid.

Animals↗
PubMed2003

Responsiveness to the retinoic acid receptor-selective retinoid LGD1550 correlates with abrogation of transforming growth factor alpha/epidermal growth factor receptor autocrine signaling in head and neck squamous carcinoma cells.

PURPOSE: The use of retinoids to prevent and/or treat cancers, including head and neck squamous cell carcinoma (HNSCC), has been limited by the development of resistance and unwanted side effects. Receptor-selective retinoids are potentially less toxic than nonselective compounds. The present investigation was undertaken to determine the mechanism of responsiveness to an retinoic acid receptor-selective retinoid (LGD1550) that has shown antitumor efficacy in a xenograft model of HNSCC. EXPERIMENTAL DESIGN: A series of HNSCC cell lines were characterized with respect to proliferation and apoptosis after LGD1550 treatment. Relative responsiveness to LGD1550 was examined with respect to modulation of epidermal growth factor receptor (EGFR) signaling pathways. RESULTS: Cells were either growth inhibited and underwent apoptosis or were resistant to treatment with this compound. Retinoids have been shown to decrease the gene transcription rates of transforming growth factor (TGF)-alpha and EGFR in HNSCC. LGD1550 responsiveness was accompanied by decreased expression of TGF-alpha, EGFR, and modulation of EGFR signaling pathways, including signal transducers and activators of transcriptions and mitogen-activated protein kinase. In contrast, EGFR autocrine signaling pathways were not altered in HNSCC cells that were resistant to the growth inhibitory effects of LGD1550. CONCLUSIONS: These results suggest that there is a correlation between the efficacy of receptor-selective retinoids and modulation of TGF-alpha/EGFR signaling in HNSCC. Therefore, alterations of these signaling pathways may serve as a biomarker of clinical response.

Animals↗
PubMed2004

[The use of retinoids in dermatology].

Retinoids--new agents derived from vitamin A have initiated a new era in therapy of many skin diseases. They are highly effective medicines used in the treatment of severe forms of psoriasis. Also they are administered in many forms of acne, as alternative drugs do not exist. Moreover, retinoids show antineoplastic activity. They are also effective in the symptomatic treatment of the congenital keratinization disorder syndromes. The recent development of retinoids combined with the growth of expertise with regard to the biological function and mechanisms of retinoid receptors, are likely to improve the present therapeutic methods and to reveal new potentials regarding the use of retinoids in the therapy of many skin disorders.

Acne Vulgaris↗
PubMedDate not supplied

A review of the chemopreventive and chemotherapeutic effects of topical and oral retinoids for both cutaneous and internal neoplasms.

Retinoids, a group of compounds encompassing Vitamin A and its analogs, have been shown to inhibit tumor growth in laboratory studies. Based on these findings, a number of clinical trials have been conducted to investigate the chemoprotective and chemotherapeutic effects of retinoids. This paper reviews the current database regarding the use of oral and topical retinoids in the prevention and treatment of cutaneous and internal malignancies. Clinical studies have shown that retinoids have beneficial effects in the prevention and treatment of certain neoplasms. In view of the heightened concern of malignancy associated with the use of biologic agents in the treatment of psoriasis, retinoids may be an attractive option for combination therapy with the biologic agents. Future clinical investigations are needed to precisely define how this combination will fit into the treatment algorithm for moderate-to-severe psoriasis.

Administration, Oral↗
PubMed1992

Retinoids and the eye.

Systemic retinoids are being used more frequently to treat various disorders of the skin, particularly disorders of keratinization. They are promising agents for chemoprevention of cancer and as such may be widely used in the future. Both natural and synthetic retinoids may affect the eye, both on the surface epithelium and the visual metabolism. Three basic effects of pharmacologic doses of synthetic retinoids have been seen. Blepharoconjunctivitis has been particularly prominent with isotretinoin use. Pseudotumor cerebri has been reported sporadically. Recently, night blindness has been reported with both isotretinoin and fenretinide. The greater use of isotretinoin may be more important in explaining the increased incidence of these side effects than is the individual metabolism of the different available synthetic retinoids. These three major side effects of the eye will be carefully evaluated as newer synthetic retinoids are proposed for further trials. Fortunately, it seems that all of these ocular manifestations are dose dependent and reversible, giving the clinician several alternatives to adjust the treatment regimen.

Blepharitis↗
PubMed2005

Genotoxicity studies on benzimidazole retinoids.

Retinoids consist of a family of naturally occuring compounds including all-trans retinoic acid (ATRA), retinal, retinol (vitamin A), 9-cis retinoic acid, 13-cis retinoic acid as well as a large number of synthetic derivatives. Retinoids are known to elicit diverse pharmacological profiles such as controlling cell differentiation/proliferation and modulating specific premalignant lesions and reducing second primary tumors in patients. Clinical use of retinoids is limited due to their toxicity. Three benzimidazole retinoid derivatives (BITN, BITNm, BITNe) were synthesized and were examined in terms of genotoxicity towards human lymphocyte cultures by sister chromatid exchange (SCE) analysis. It has been found that BITN decreased the number of SCEs 20% at 10(-6) M, but had no effect at 10(-5) M. No significant effect on SCEs was observed for BITNm and BITNe at both concentrations. ATRA increased the SCEs (35%) at 10(-5) M but had no effect at 10(-6) M. The results have shown that benzimidazole retinoids did not induce SCE significantly. Besides this, BITN reduced the SCEs and had a protective effect at low concentration. Since the induction of glutathione S-transferase (GST) is associated with anticancer drug resistance, the effects of BITN, BITNm, BITNe and ATRA on human lymphocyte GSTs were also investigated using CDNB as substrate. BITN and BITNm induced GST activities 54% and 49% respectively at 10(-5) M, but had no effect at 10(-6) M. BITNe induced GST activity 62% at 10(-5) M and 35% at 10(-6) M. ATRA had no effect on GST activity at 10(-5) M.

Benzimidazoles↗
PubMed1991

Topical and oral retinoids protect Langerhans' cells and epidermal Thy-1+ dendritic cells from being depleted by ultraviolet radiation.

Murine epidermis contains two types of bone marrow-derived cells of the immune system, Langerhans' cells (LC), which are dendritic antigen-presenting cells, and Thy-1+ dendritic cells (Thy-1+ DEC), which express the gamma/delta T-cell receptor for antigen and hence are probably T cells whose function in the epidermis is unknown. Ultraviolet (UV) light greatly reduces the density of both of these cell types, and hence this may be one of the mechanisms by which UV light induces immunosuppression. It is important to develop strategies for protecting these cells from the effects of UV light. In this study we show that topical all-trans-retinoic acid (RA) and an orally administered retinoid, temarotene, protect both LC and Thy-1+ DEC from being depleted by UV light. However, neither retinoid inhibited the development of immunosuppression in response to application of a contact sensitizer. We also compared two congenic mouse strains, one albino, the other lightly pigmented and capable of tanning in response to UV light. There was no difference in the ability of UV light to deplete LC or Thy-1+ DEC in these two strains or of retinoids to inhibit their depletion. These studies demonstrate that retinoids but not melanin are able to inhibit UV light from depleting LC and Thy-1+ DEC; however, there are other immunosuppressive effects of UV light which are not protected by the retinoids.

Animals↗