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PubMed2001

From vitamin to Vesanoid: systemic retinoids for the new millennium.

Retinoids are a fascinating class of compounds that exert control over cellular function from the time of conception to death. They play a critical role in such vital processes as fetal morphogenesis, cellular differentiation and apoptosis. Over the years synthetic retinoids have provided dermatologists with a spectrum of medications that have profound therapeutic effects on a variety of recalcitrant skin disorders. Moreover, retinoids are an expanding component of the treatment arsenal against hematologic and solid malignancies. Retinoids are poised to offer exciting new therapeutic options in the field of endocrinology for the treatment of diabetes and lipid disorders. Researchers and clinicians are only beginning to unveil the therapeutic potential of this class of medications. The development of new retinoid compounds targeting specific receptors promises a wealth of new therapies for the new millennium.

Acne Vulgaris↗
PubMed2002

Prostatic intraepithelial neoplasia in mice with conditional disruption of the retinoid X receptor alpha allele in the prostate epithelium.

Retinoids, which are important regulators of cell growth, differentiation, and apoptosis, have been used in treatment or chemoprevention of multiple cancers including prostate cancer. To elucidate the mechanism of action of retinoids in the context of the prostate, we used the Cre-loxP system to disrupt the retinoid X receptor alpha (RXRalpha) gene specifically in the prostatic epithelium of the mouse. Evidence for tissue-specific gene inactivation was obtained at DNA, RNA, and protein levels. Phenotypic changes in the prostate in the homozygous animals of different age groups ranging from 1 to 15 months were investigated. Developmentally, prostatic ductal branching appeared to be increased from the loss of RXRalpha function. There was also a significant change in the profile of secretory proteins in the RXRalpha mutant prostate relative to littermate controls with intact RXRalpha allele. Histopathologically, homozygous RXRalpha-deficient prostates showed multifocal hyperplasia as early as 4 months of age. Lesions, which could be described as low-grade prostatic intraepithelial neoplasias, were detected after 5 months. Subsequently, beginning at approximately 10 months, high-grade prostatic intraepithelial neoplasias developed in some animals. The incidences of low-grade prostatic intraepithelial neoplasias and high-grade prostatic intraepithelial neoplasias among the animals 10-15 months of age were 62 and 17%, respectively. The heterozygous mutant mice also developed similar prostatic phenotypes but in a delayed manner, implying a role of haploinsufficiency. Together, these results indicated for the first time that a major component of retinoid action in the prostate is mediated by a retinoid receptor, RXRalpha, the inactivation of which in the prostatic epithelium leads to the development of preneoplastic lesions.

Alleles↗
PubMed1992

Effects of retinoids on tooth morphogenesis and cytodifferentiations, in vitro.

The first embryonic lower mouse molar was used as a model system to investigate the effects of two retinoids, retinoic acid (RA) and a synthetic analogue, Ch55, on morphogenesis and cytodifferentiations in vitro. Exogenous retinoids were indispensable for morphogenesis of bud, cap and bell-stage molars in serum-free, chemically-defined, culture media. Transferrin and RA or transferrin and Ch55 acted synergistically in promoting morphogenesis from bud and cap-stage explants. Transferrin, per se, had no morphogenetic effect. Epithelial histogenesis, odontoblast functional differentiation and ameloblast polarization always occurred in RA-depleted explants. Comparison of the distributions of bromodeoxyuridine (BrdU) incorporation between explants cultured in the absence or presence of RA revealed that RA could modify the patterns of cell proliferation in the inner dental epithelium and dental mesenchyme. Inner dental epithelium cell proliferation is regulated by the dental mesenchyme through basement membrane-mediated interactions, and tooth morphogenesis is controlled by the dental mesenchyme. Laminin is a target molecule of retinoid action. Using a monospecific antibody, we immunolocalized laminin and/or structurally-related molecules sharing the laminin B chain in the embryonic dental mesenchyme and in the dental basement membrane and showed that RA could promote the synthesis or secretion of these molecules. Based on previous in situ hybridization data, it was speculated that CRABPs might regulate the effects of RA on embryonic dental cell proliferation. The fact that Ch55, a retinoid which does not bind to CRABPs, is 100 times more potent than RA in promoting tooth morphogenesis in vitro seems to rule out this hypothesis. On the other hand, the stage-specific inhibition of tooth morphogenesis by excess RA is consistent with the hypothesis that CRABPs might protect embryonic tissues against potentially teratogenic concentrations of free retinoids.

Animals↗
PubMed1976

Effect of aromatic retinoids on rat chondrosarcoma glycosaminoglycan biosynthesis.

Synthetic aromatic analogs of retinoic acid were administered i.p. and p.o. to Fischer F344 rats bearing a transplantable chondrosarcoma. 35CO4 incorporation into glycosaminoglycans were compared for neoplastic and normal cartilage explants after removal from animals given various analogs. There was a direct relationship between [35S]glycosaminoglycan synthesis by chondrosarcoma chondrocytes and inhibition of tumor growth. The degree of inhibition of [35S]glycosaminoglycan synthesis in the neoplastic cartilage was dependent on the dose of the retinoid administered. At 20-mg/kg/day doses of retinoid for 4 weeks, 35SO4 incorporated into glycosaminoglycan by treated tumor explants was reduced as much as 95%. There was no reduction of [35S] glycosaminoglycan produced in normal costal cartilage of the same animals. Retinoid treatment of 20-mg/kg/day doses for 4 weeks resulted in a 75% reduction in glycosaminoglycan per mg of chondrosarcoma; there was no reduction in costal cartilage glycosaminoglycan. Retinoid (10- to 20-mg/kg/day doses) elevated collagen levels per mg of chondrosarcoma but had no effect on costal cartilage collagen. Combined in vitro and in vivo studies showed that retinoid administration modified neoplastic chondrocyte function but had no measurable effect on normal chondrocyte function.

Animals↗
PubMedDate not supplied

Histone deacetylase inhibitors enhance retinoid response in human breast cancer cell lines.

Solid tumors develop resistance to retinoids during carcinogenesis. One of the strategies to overcome this resistance may include the combination of these molecules with other differentiating, cytotoxic or chromatin-remodelling agents. We analysed the anti-proliferative activity of two histone-deacetylase inhibitors (HDACIs), Trichostatin A (TSA) and sodium phenylbutyrate (PB), alone or combined with retinoids, all-trans retinoic acid (ATRA) and Ro 41-5253, on two human breast cancer cell lines: the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231. These lines responded differently to retinoids: MCF-7 were sensitive, whilst MDA-MB-231 were rather resistant. When the retinoids were combined with HDACIs, these molecules potentiated the retinoid activity on growth inhibition, especially for the association Ro 41-5253 and TSA. By FACS analysis, we observed that the anti-proliferative effects were only partially due to pro-apopotic mechanisms, suggesting a cell-cycle block. The efficacy of the retinoids/HDACIs combinations could represent a new strategy in breast cancer chemotherapy, allowing inhibition of both ER + and ER- cell populations.

Acetylation↗
PubMed2007

The synergistic apoptotic effects of thiophenfurin, an inosine monophosphate dehydrogenase inhibitor, in combination with retinoids in HL60 cells.

New effective cytotoxic agents and combinations are urgently needed in cancer treatment. The enzyme inosine monophosphate dehydrogenase is a potentially useful target for drug development, since its activity has been shown to be amplified in malignant cells. Thiophenfurin, an inhibitor of the enzyme synthesized by us, is endowed with a significant apoptotic activity in promyelocytic leukaemia HL60 cells. Since retinoids were successfully employed in the treatment of patients with leukaemia, demonstrating significant differentiation-inducing and apoptotic effects, we carried out this study to evaluate the effects of the combination of thiophenfurin and several retinoid molecules, acting in different phases of the cell cycle in vitro. The results show that thiophenfurin is capable of eliciting significant S phase-specific antiproliferative effects in different sensitive and resistant cell lines with the IC50s ranging from 6.7 to 26 microM. When HL60 cells were treated with thiophenfurin in combination with retinoids, the effects on cell growth were additive or synergistic, depending on the kind of retinoid used and the sequence of treatment. In particular, we observed additive effects when the cells were exposed to thiophenfurin and all-transretinoic acid either simultaneously or sequentially. Instead, when the new heterocyclic retinoid isoxazole benzoic acid was used, synergism was obtained in the cells treated sequentially. The combination of thiophenfurin and isoxazole benzoic acid determined synergistic apoptotic effects through a mitochondrion-dependent mechanism, suggesting the possible usefulness of this combination in the treatment of leukaemia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Inhibitory effect of retinoids on the generation of procoagulant activity by blood mononuclear phagocytes.

Retinoids are known to modulate several functions of mononuclear phagocytes. We have studied the effect of retinyl acetate (RAc) and retinoic acid (RA) on the production of procoagulant activity (PCA) by human peripheral blood mononuclear cells stimulated with endotoxin (1 microgram/ml, 4 or 20 h at 37 degrees C). Both compounds caused a dose-dependent reduction in the expression of cell-associated PCA (from 86 to less than 10% of control in the range of concentration comprised between 0.1 and 100 microM). This effect was also observed when the cells were exposed to retinoids for 10 min and washed before challenge with endotoxin, indicating that it is rapid and irreversible. In contrast, incubation of RAc or RA for 3 h at 37 degrees C with cells that have been already stimulated with endotoxin (20 h at 37 degrees C) remained without influence on cell PCA. The inhibitory action of retinoids was also observed when monocyte-enriched (greater than 85%) preparations or highly purified monocyte-derived macrophages (greater than 99%) were used instead of whole mononuclear cells. BW755C, an inhibitor of cyclo-oxygenase and lipoxygenase, reversed the inhibitory effect of retinoids, whereas acetylsalycilic acid, an inhibitor of cyclo-oxygenase, was inactive, suggesting the involvement of a lipoxygenase product. The inhibition of monocyte/macrophage PCA production and the subsequent reduction of cell potential for fibrin deposition might represent one of the mechanisms whereby retinoids exert their antiinflammatory and immunomodulatory activities.

Blood Coagulation↗
PubMed1990

An in vitro cell model system to study the action of retinoids on Leydig cell steroidogenesis.

In this study we examined the effects of retinol and retinoic acid on steroid production in MA-10 mouse Leydig tumor cells. Results showed that both retinol and retinoic acid greatly increased progesterone production in this cloned cell line. The stimulatory effect of retinoids is not inhibited by cycloheximide suggesting that de novo protein synthesis is not required. The presence of the retinoid binding proteins CRBP and CRABP could not be detected in MA-10 Leydig cell cytosol indicating that the stimulatory action of retinoids on progesterone production is not mediated through these cellular binding proteins. Both previous and present findings suggest that retinoids play an important role in the regulation of Leydig cell steroidogenesis and that MA-10 Leydig tumor cells may represent an ideal in vitro cell system to study the mechanism of action of retinoids in Leydig cell steroidogenesis.

Animals↗
PubMedDate not supplied

Cytotoxic effect of TNF-alpha and abnormal regulation of cAMP in the retinoid resistant cell line U937/GTB.

We have studied the effect of retinoids, forskolin and TNF-alpha on two sublines of U937 cells, U937/clone 4 and U937/GTB. Retinoids induced differentiation of U937/clone 4, while the U937/GTB cells were resistant to induction of differentiation by retinoids. Retinoids effectively reduced the proliferation of both U937/clone 4 and U937/GTB, and decreased the steady state levels of c-myc mRNA in both sublines. Furthermore, the retinoid resistant U937/GTB cells were hypersensitive to the cytotoxic effect of TNF-alpha. Forskolin increased the cAMP level in the U937/clone 4 cells 14 times above basal level, but did not change the cAMP concentration in the U937/GTB cells.

Cell Differentiation↗
PubMed1989

Inhibition by retinoids of platelet growth factor-dependent stimulation of DNA synthesis and cell division in density-arrested C3H 10T1/2 fibroblasts.

The inhibition of neoplastic transformation by vitamin A and its natural and synthetic analogues, collectively called retinoids, is accomplished by an as yet unknown mechanism. In a recent report, the morphological transformation of carcinogen-treated C3H 10T1/2 fibroblasts to focus-forming transformed cells was shown to be a postconfluence event induced in density-arrested initiated cells by platelet growth factors in serum and was correlated with the mitogenic response of the preneoplastic cells to these polypeptides. The current study investigates the possibility that the inhibition of neoplastic transformation by retinoids is accomplished by blocking the mitogenic response of initiated cells to these growth factors. The results demonstrate that the stimulation by serum of DNA synthesis and cell division in normal and carcinogen-treated C3H 10T 1/2 fibroblasts after density-dependent growth arrest is inhibited in a dose-dependent manner by retinyl acetate, all-trans retinoic acid, and 4-hydroxyphenyl-retinamide over the same dose range and to the same extent that neoplastic transformation is inhibited by these retinoids. Cellular mitogenic processes sensitive to retinoid inhibition were shown to be induced specifically by platelet growth factors, rather than plasma growth factors, to occur within approximately 2 h of growth factor treatment, and to be common to cell division stimulated in density-arrested normal and initiated cells by highly purified platelet-derived or epidermal growth factor. These data suggest that the inhibition of neoplastic transformation by retinoids is accomplished by blocking the G0 to G1 transition in the mitotic response of initiated cells to platelet growth factors which act as endogenous promoters of transformation.

Animals↗
PubMed1986

Density of epidermal Langerhans cells in psoriasis patients treated with an aromatic retinoid (RO 10-9359). An immunoperoxidase study using anti-T6 and anti-Ia monoclonal antibodies.

Immunocytochemical techniques using antibodies to the specific T6 and Ia (Major Histocompatibility Complex, class II, human HLA-Dr) antigens were used to determine the densities of epidermal Langerhans cells (LC) in psoriasis patients treated with the aromatic retinoid RO 10-9359. Fourteen patients were treated with the aromatic retinoid and were skin biopsied before, during and after therapy. Two psoriasis patients receiving PUVA (systemic 8-methoxypsoralen + UVA irradiation) were included in the study. The results showed an increase in LC numbers during aromatic retinoid administration, which coincided with an improvement in the clinical severity of the lesions. At the end of retinoid administration the LC numbers were similar to those found in the initial psoriatic plaques. The density of Ia+ LC, in comparison with T6+ LC in the epidermis of psoriatic plaques were significantly different. Dendritic and non-dendritic Ia+ cells were also observed in the dermis of the plaques. Unlike aromatic retinoid treated patients, PUVA treated patients showed a decrease of both T6+ and Ia+ epidermal LC by the middle of therapy, a total absence of immunoreaction by the end of therapy, and a return to normal skin values a few weeks after treatment. This immunocytochemical study helps in distinguishing between dendritic and other possible Ia-expressing cells from the infiltrate that may penetrate the epithelium. These results do not conclusively demonstrate the role of LC in the pathogenesis of psoriasis. Other factors, such as the interrelationship with other immune response cell types and alterations in the lymphokine cascade may be important.

Adult↗
PubMed1986

Increased levels of several retinoid binding proteins resulting from retinoic acid-induced differentiation of F9 cells.

The embryonal carcinoma cell line F9 is known to differentiate when exposed to retinoic acid. We have examined the quantities of two intracellular retinoid-binding proteins in undifferentiated and differentiated F9 cells. The existence of a cell surface receptor that recognizes the plasma retinol-binding protein was also explored. It was shown that undifferentiated F9 cells contain low concentrations of the two retinoid-binding proteins. The cellular retinoic acid-binding protein was present in approximately 3-fold molar excess over the cellular retinol-binding protein. Upon culture in the presence of retinoic acid, F9 cells display elevated concentrations of both cellular retinol-binding protein and cellular retinoic acid-binding protein. Since the levels of beta 2-microglobulin, a marker of the differentiated state with no known involvement in the metabolism of vitamin A, increased in parallel with the retinoid-binding proteins, it seems unlikely that retinoic acid selectively increased the levels of the two retinoid-binding proteins. The differentiated, in contrast to the undifferentiated cells, can accumulate retinol from plasma retinol-binding protein and display a cell surface receptor for this protein. Despite the fact that retinoic acid-induced differentiation of F9 cells promotes increased levels of several proteins involved in the normal metabolism of vitamin A, no evidence was obtained to suggest that the cells were dependent on retinoids to maintain their differentiated state.

Animals↗
PubMed1979

N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat.

The synethesis of a new retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide, which has useful biological properties, is described. This retinoid was more potent than retinyl acetate in reversing keratinization caused by retinoid deficiency in tracheal organ culture. It was markedly less toxic than retinyl acetate when fed p.o. to rats over 2-week or 6-month periods. It was an effective agent for inhibition of the development of breast cancer induced in rats by N-nitroso-N-methylurea, although it was not as potent as retinyl acetate in this regard. However, the lesser toxicity of 4-hydroxyphenylretinamide makes it a superior agent for prevention of breast cancer. High-pressure liquid chromatographic analyses of liver and breast extracts from rats treated for 6 months with retinoids show the pharmacokinetic basis for the superiority of 4-hydroxyphenylretinamide; this retinoid and its metabolites were found in high concentrations in breast tissue, without any measurable accumulation in the liver or evident liver toxicity. In contrast, chronic feeding of retinyl acetate caused marked deposition of retinyl esters in the liver and severe hepatotoxicity. Whole mounts of rat mammary glands, made after chronic feeding of 4-hydroxyphenylretinamide, showed that it had a marked antiproliferative effect on mammary epithelium.

Animals↗
PubMed1982

Oral retinoid in combination with bleomycin, cyclophosphamide, prednisone and transfer factor in mycosis fungoides.

Oral retinoids seem to have been of great benefit in a non-randomized study on advanced mycosis fungoides using two different chemotherapy regimens, one with retinoid, the other without. Both groups also received a 3-drug chemotherapy with bleomycin, cyclophosphamide and prednisone. Complete remission including all signs of lymph-node involvement was found in 8 of 10 patients of the retinoid treated group, while none went into complete remission in the control group. All in the control group died between 3 and 12 months after therapy, whereas all but one in the retinoid treated group are alive. Other treatment differences between the groups were related to the use of transfer factor, topical treatment, and steroid administration. These differences make a final evaluation of the use of retinoids in mycosis fungoides difficult at the present stage. Further studies are needed.

Administration, Oral↗
PubMed1983

Evidence for anti-inflammatory activities of oral synthetic retinoids: experimental findings and clinical experience.

Oral retinoids obviously influence dermal components such as cutaneous capillaries and dermal inflammatory cells in addition to their well-known action on keratinizing epithelia. On this basis, they act as an anti-inflammatory drug. In particular, they reduce the elevated skin temperature, inhibit the motility of neutrophils and eosinophils and their migration into the epidermis, decrease DNA synthesis of human lymphocytes by blocking their response to lectins and stimulate Langerhans cells, monocytes and macrophages in various in vitro and in vivo models. These data indicate that oral retinoids may not only normalize disorders of keratinization but also exert distinct therapeutic effects on various skin diseases with dermal inflammatory involvement regardless of their particular aetiology. In some respects, retinoids resemble corticosteroids, acting as a modified hormone. Preliminary clinical experiences with oral retinoid treatment in skin diseases such as cutaneous disseminated LE, bullous pemphigoid, Duhring's disease, pemphigus, Behçet's disease and necrotizing vasculitis with eosinophilia support these data. Monotherapy or combined administration of oral retinoids with corticosteroids in low doses seems therapeutically beneficial in these disorders.

Acitretin↗
PubMed1983

Action of epidermal growth factor and retinoids on anchorage-dependent and -independent growth of nontransformed rat kidney cells.

Treatment of two nontransformed rat kidney cell lines with either retinoic acid or epidermal growth factor enhances anchorage-dependent cell growth and reduces cell substratum adhesiveness significantly, whereas the cell morphology is only moderately affected. Simultaneous treatment of these cells with these factors results in a dramatic change in cell morphology and increases cell growth and reduces cell substratum adhesiveness even further. Treatment of nontransformed rat kidney cells with certain retinoids enhances the binding of 125I-labeled mouse epidermal growth factor 2- to 3-fold. Addition of epidermal growth factor stimulates anchorage-independent growth of these cells. Retinoids enhance colony-forming ability in soft agar produced by epidermal growth factor, although retinoids by themselves do not affect anchorage-independent growth. Growth in soft agar induced by epidermal growth factor or epidermal growth factor plus retinoic acid treatments appears to be a reversible trait. Addition of epidermal growth factor stimulates secretion of plasminogen activator, whereas this production is not influenced by retinoids. A transformed rat kidney cell line, which exhibits very low epidermal growth factor binding and grows progressively in soft agar, is not significantly affected by retinoid treatment.

Agar↗
PubMedDate not supplied

Pharmacologic disposition of chemopreventive retinoids (review).

The disposition of natural and synthetic retinoids, some of which effectively prevent cancer in carcinogen-dosed animals, varies with the structure of the compound. Disappearance of retinoids from serum may be either linear or exponential, and there may be a prolonged terminal elimination phase. Metabolism of these compounds is extensive, with little or no absorbed retinoid being excreted unchanged. Compounds giving rise to retinol can be stored as retinyl esters in the liver. In contrast, retinoids with a terminal carboxyl group are not stored but are metabolized on the ring and/or on the sidechain prior to excretion, which occurs often after conjugation of the metabolites with glucuronic acid. Isomerization of the double bonds in the sidechain may also occur. The metabolites of natural retinoids do not appear to possess more biological activity than the parent compounds, leading to the conclusion that their metabolism is, in general, degradative.

Animals↗
PubMed1982

Variable effects of retinoids on two pigmenting human melanoma cell lines.

Two melanoma cell lines, each derived from a different patient with metastatic disease, were very similar in their appearance, their growth characteristics, and their tendency to differentiate and to pigment in culture as they become confluent. These lines, UCT-Mel 1 and UCT-Mel 2, were used to study the effects of retinoic acid and other derivatives of vitamin A. When added to UCT-Mel 1 cells, retinoids had only a modest effect on plasminogen activator release and were without measurable effect on morphology, growth, or tyrosinase synthesis. In contrast, when added to UCT-Mel 2 cells, retinoids appeared to induce a more differentiated state evident as an inhibition of cell proliferation and the assumption of a dendritic morphology. Paradoxically, however, retinoids caused a striking inhibition of the density-dependent intracellular accumulation of tyrosinase and melanin that was taken to represent spontaneous in vitro differentiation. Culture of UCT-Mel 2 cells in the presence of retinoic acid resulted in initial inhibition followed by marked stimulation of cellular plasminogen activator release. The data suggest that the manner in which retinoids exert their effects on cells in vitro does not depend on the histological origin of the tumor cells being studied but on the innate responsiveness of that particular cell line to the retinoid or compound in question.

Aged↗