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PubMed1986

Retinoids. Structure-function relationship in normal and leukemic hematopoiesis in vitro.

Retinoids were studied both to identify what skeletal components are important in the modulation of normal and leukemic human myeloid clonal proliferation and differentiation in vitro and to elucidate the mechanism by which retinoids modulate proliferation of hematopoietic cells. Retinoids with a derivatized terminal carboxyl group were significantly less active than all-trans-retinoic acid, and those with the addition of two methyl groups to the cyclohexenyl ring of retinoic acid or substitution of its beta-cyclogeranylidene group with a 1,1,3,3-5-indanyl ring system were markedly more active than all-trans-retinoic acid. Five of the retinoids strongly inhibited clonal growth of the HL-60 and KG-1 human leukemic cell lines (50% inhibition in the range of 3 X 10(-10)-1 X 10(-8) M) and markedly stimulated normal human myeloid colony formation (granulocyte-macrophage colony-forming cells [GM-CFC] 150% stimulation in the range of 3 X 10(-9)-3 X 10(-8) M). Further studies suggested that: Common structural requirements of the retinoids were important in the modulation of both normal and leukemic hematopoiesis. The retinoids were able to inhibit leukemic proliferation without induction of differentiation of the neoplastic cells. Studies on normal human GM-CFC suggested that the retinoids did not act by themselves as a colony-stimulating factor (CSF), or by stimulating accessory cells to produce CSF, but either required earlier progenitor cells to become GM-CFC or enhanced the sensitivity of GM-CFC to the action of CSF.

Bone Marrow Cells↗
PubMed2006

MEK blockade converts AML differentiating response to retinoids into extensive apoptosis.

The aberrant function of transcription factors and/or kinase-based signaling pathways that regulate the ability of hematopoietic cells to proliferate, differentiate, and escape apoptosis accounts for the leukemic transformation of myeloid progenitors. Here, we demonstrate that simultaneous retinoid receptor ligation and blockade of the MEK/ERK signaling module, using the small-molecule inhibitor CI-1040, result in a strikingly synergistic induction of apoptosis in both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells with constitutive ERK activation. This proapoptotic synergism requires functional RAR and RXR retinoid receptors, as demonstrated using RAR- and RXR-selective ligands and RAR-defective cells. In the presence of MEK inhibitors, however, retinoid-induced chromatin remodeling, target-gene transcription, and granulocytic differentiation are strikingly inhibited and apoptosis induction becomes independent of death-inducing ligand/receptor pairs; this suggests that apoptosis induction by combined retinoids and MEK inhibitors is entirely distinct from the classical "postmaturation" apoptosis induced by retinoids alone. Finally, we identify disruption of Bcl-2-dependent mitochondrial homeostasis as a possible point of convergence for the proapoptotic synergism observed with retinoids and MEK inhibitors. Taken together, these results indicate that combined retinoid treatment and MEK blockade exert powerful antileukemic effects and could be developed into a novel therapeutic strategy for both AML and APL.

Acute Disease↗
PubMed1994

Constitutively active retinoid receptors exhibit interfamily and intrafamily promoter specificity.

Retinoid receptors are ligand activated transcription factors that regulate gene transcription through a complex network of interactions with members of the nuclear hormone receptor superfamily. Although ligand is required for trans-activation, addition of ligand to mammalian cells in vitro complicates the study of individual activated retinoid receptors. In order to circumvent this problem we have constructed a series of retinoid receptors which do not require ligand for trans-activation. This was accomplished by fusing the acidic activation domain of the herpes simplex viral protein VP16 to the carboxyl terminus of individual retinoid receptors. All of the chimeric receptors were found to exhibit constitutive trans-activation activity in CV-1 and P19 cells when cotransfected with a reporter that contained a trimerized retinoic acid receptor-beta 2 (RAR beta 2) retinoic acid response element. Further analysis conducted on reporters containing either the RAR beta 2 promoter or the rat cellular retinol binding protein II (rCRBPII) promoter showed that promoter specificity was well conserved between the chimeric receptors in the absence of exogenous retinoid and their ligand-induced native counterparts. Moreover, on the RAR beta 2 promoter reporter construct, the chimeric retinoid receptors displayed both cell type and inter- and intrafamily differences in trans-activation, whereas, trans-activation of the rCRBPII in the absence of exogenous ligand in CV-1 and P19 cells was found to be stimulated only by chimeric retinoid X receptor-alpha (RXR alpha). In P19 cells trans-activation of the rCRBPII promoter by RXR alpha v in the absence of exogenous ligand was inhibited by RAR alpha and the constitutive forms of RAR alpha, RAR beta, RAR gamma, RXR beta, and to a lesser extent RXR gamma.

Animals↗
PubMed1988

Characterization of retinoid metabolism in the developing chick limb bud.

Retinoids (vitamin A derivatives) have been shown to have striking effects on developing and regenerating vertebrate limbs. In the developing chick limb, retinoic acid is a candidate morphogen that may coordinate the pattern of cellular differentiation along the anteroposterior limb axis. We describe a series of investigations of the metabolic pathway of retinoids in the chick limb bud system. To study retinoid metabolism in the bud, all-trans-[3H]retinol, all-trans-[3H]retinal and all-trans-[3H]retinoic acid were released into the posterior region of the limb anlage, the area that contains the zone of polarizing activity, a tissue possibly involved in limb pattern formation. We found that the locally applied [3H]retinol is primarily converted to [3H]retinal, [3H]retinoic acid and a yet unidentified metabolite. When [3H]retinal is locally applied, it is either oxidized to [3H]retinoic acid or reduced to [3H]retinol. In contrast, local delivery of retinoic acid to the bud yields neither retinal nor retinol nor the unknown metabolite. This flow of metabolites agrees with the biochemical pathway of retinoids that has previously been elucidated in a number of other animal systems. To find out whether metabolism takes place directly in the treated limb bud, we have compared the amount of [3H]retinoid present in each of the four limb anlagen following local treatment of the right wing bud. The data suggest that retinoid metabolism takes place mostly in the treated limb bud. This local metabolism could provide a simple mechanism to generate in a controlled fashion the biologically active all-trans-retinoic acid from its abundant biosynthetic precursor retinol. In addition, local metabolism supports the hypothesis that retinoids are local chemical mediators involved in pattern formation.

Animals↗
PubMed1990

Localization of specific retinoid-binding sites and expression of cellular retinoic-acid-binding protein (CRABP) in the early mouse embryo.

Retinoids (vitamin A derivatives) are important for normal embryogenesis and retinoic acid, an acidic derivative of vitamin A, was recently proposed to be an endogenous morphogen. Several retinoids are also potent teratogens. Using an autoradiographic technique, we have identified tissues and cells in early mouse embryos that are able to specifically accumulate a radiolabelled synthetic derivative of retinoic acid. Strong accumulation of radioactivity was seen in several neural crest derivatives and in specific areas of the CNS. Gel filtration analyses of cytosols from embryos that received the radiolabelled retinoid in utero suggested that cellular retinoic acid-binding protein (CRABP) was involved in the accumulation mechanism. Immunohistochemical localization confirmed that cells accumulating retinoids also expressed CRABP. Strong CRABP immunoreactivity was found in neural crest-derived mesenchyme of the craniofacial area, in visceral arches, in dorsal root ganglia and in cells along the gut and the major vessels of the trunk region. In CNS, CRABP expression and retinoid binding was largely restricted to the hindbrain, to a single layer of cells in the roof of the midbrain and to cells in the mantle layer of the neural tube. Our data suggest that cells in the embryo expressing CRABP are target cells for exogenous retinoids as well as endogenous retinoic acid. Retinoic acid may thus play an essential role in normal development of the CNS and of tissues derived from the neural crest. We propose that the teratogenic effects of exogenous retinoids are due to an interference with mechanisms by which endogenous retinoic acid regulates differentiation and pattern formation in these tissues.

Animals↗
PubMed1989

Effect of substratum and retinoids upon the mucosecretory differentiation of airway epithelial cells in vitro.

The lining of the trachea consists of a pseudostratified, mucociliary epithelium that under a variety of conditions, such as vitamin A deficiency, toxic and mechanical injury, becomes a stratified squamous epithelium. Several in vitro cell culture models have been established to study the regulation of the mucosecretory phenotype. Such studies have indicated that the mucosecretory phenotype in tracheal epithelial cells can be modulated by substratum and the presence of retinoids. Cells grown on a collagen type I gel matrix in the absence of retinoids undergo stratification and squamous cell differentiation. Cells grown on a collagen gel matrix in the presence of retinoids express a mucosecretory phenotype. As in the normal tracheal epithelium, these cultures contain columnar, polarized cells that exhibit apical tight junctions and secretory granules. Biochemical analysis of radiolabeled glycoconjugates released into the medium indicate the synthesis of mucinlike glycoproteins. Retinoids appear to determine whether tracheal epithelial cells become committed to a pathway of squamous differentiation or to a mucosecretory pathway of differentiation. The collagen gel matrix appears not to determine the commitment of the pathway of differentiation but allows the expression of the secretory phenotype in retinoic acid-treated cultures. The mechanisms by which retinoids and substratum modulate differentiation in tracheal epithelial cells is still poorly understood. It is clear that differentiation into squamous or mucous cells requires the activation and suppression of different genes. In the case of retinoids, the alterations in gene activity may be mediated by the nuclear retinoic acid receptor. In summary, in tracheal epithelial cells the substratum and extracellular matrix in conjunction with hormonal factors such as retinoids determine the ultimate function of these cells.

Animals↗
PubMed2004

Retinoid signaling regulates CTGF expression in hypertrophic chondrocytes with differential involvement of MAP kinases.

UNLABELLED: Retinoids are important for growth plate chondrocyte maturation, but their downstream effectors remain unclear. Recently, CTGF (CCN2) was found to regulate chondrocyte function, particularly in the hypertrophic zone. The goal of the study was to determine whether CTGF is a retinoid signaling effector molecule, how it is regulated, and how it acts. INTRODUCTION: Using a combination of in vivo and in vitro approaches, we carried out a series of studies at the cellular, biochemical, and molecular level to determine whether and how retinoid signaling is related to expression and function of connective tissue growth factor (CTGF) in chondrocyte maturation and endochondral ossification. MATERIALS AND METHODS: Limbs of chick embryos in ovo were implanted with retinoic pan-antagonist RO 41-5253-filled beads, and phenotypic changes were assessed by in situ hybridization. CTGF gene expression and roles were tested in primary cultures of immature and hypertrophic chondrocytes. Cross-talk between retinoid signaling and other pathways was tested by determining endogenous levels of active ERK1/2 and p38 MAP kinases and phenotypic modulations exerted by specific antagonists of mitogen-activated protein (MAP) kinases and BMP signaling (Noggin). RESULTS: Interference with retinoid signaling blocked expression of CTGF and other posthypertrophic markers in long bone anlagen in vivo and hypertrophic chondrocyte cultures, whereas all-trans-retinoic acid (RA) boosted CTGF expression and even induced it in immature proliferating cultures. Exogenous recombinant CTGF stimulated chondrocyte maturation, but failed to do so in presence of retinoid antagonists. Immunoblots showed that hypertrophic chondrocytes contained sizable levels of phosphorylated ERK1/2 and p38 MAP kinases that were dose- and time-dependently increased by RA treatment. Experimental ERK1/2 inhibition led to a severe drop in baseline and RA-stimulated CTGF expression, whereas p38 inhibition increased it markedly. These responses were gene-specific, because the opposite was seen with other hypertrophic chondrocyte genes such as collagen X and RA receptor gamma (RARgamma). Tests with Noggin showed that RA induction of CTGF expression was negatively influenced by BMP signaling, whereas induction of collagen X expression was BMP-dependent. CONCLUSIONS: Retinoids appear to have a preeminent role in controlling expression and function of CTGF in hypertrophic and posthypertrophic chondrocytes and do so with differential cooperation and intervention of MAP kinases and BMP signaling.

Animals↗
PubMed1995

Regulation and regulatory role of the retinoids.

Retinoids regulate differentiation and cellular growth, exerting their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Although RAR/RXR heterodimers form preferentially in vitro and in vivo, it does not exclude the possibility that RXR/RXR homodimers may regulate a distinct signaling pathway. Synthetic retinoids that selectively activate or antagonize retinoic acid receptor isoforms promises to be useful tools for the elucidation of specific retinoid response pathways. Considerable progress has been made in understanding the molecular basis underlying limb bud formation, particularly the manner in which retinoic acid interacts with other signaling molecules to determine pattern formation. The phenotypic abnormalities observed in compound null mutants of retinoid receptors, recapitulating those described in the vitamin A deficiency syndrome, confirm the crucial function of endogenous retinoids in fetal development. However, the absence of phenotypic abnormalities in null mutants of individual RAR isoforms raises the possibility of functional redundancy among RAR subtypes and at the same time challenging the concept that the diverse effects of retinoids are related to the multiplicity of fnctionally distinct receptors.

Animals↗
PubMed2001

Retinoids, apoptosis and cancer.

Retinoids are a class of natural and synthetic vitamin A analogs structurally related to all-trans-retinoic acid (ATRA). Natural retinoids are involved in the physiology of vision and as morphogenic agents during embryonic development; they are also known to play a major role in regulating growth and differentiation of a wide variety of normal and malignant cell types, and, indeed, they can in various ways inhibit cell proliferation, induce differentiation and cell death by apoptosis. The development of new active retinoids and the identification of two distinct families of retinoid receptors has led to an increased understanding of the cellular effects of activation of these receptors and of mechanisms involved in the retinoid-induced apoptosis. In this review a brief summary of cellular pathways relevant to programmed cell death is given together with therapeutic potentialities of retinoids having apoptotic activity. Structure-activity relationship studies concerning the importance of different stereochemistry at the C9 double bond of retinoids in conferring apoptotic activity will be described. It will be also described the preparation and the potent cytotoxic and apoptotic activity of a novel class of heterocycle-bridged arotinoids.

Animals↗
PubMed2006

Natural and synthetic retinoids in prostate cancer.

Prostate cancer (PCa) is the most common cancer for men in Europe, North America, and some parts of Africa. Initially, growth of prostate cancer is usually androgen-dependent, but often it becomes androgen-independent after androgen-deprivation therapy. Managing hormone-refractory prostate carcinoma remains a difficult challenge for clinicians. Retinoids, vitamin A and its synthetic analogs are one of the most studied class of chemopreventive drugs for PCa. Retinoids play a key role in several vital functions as vision and development, and also exert anti-proliferative actions. Anti-proliferative effects of retinoids rely on the regulation of many biological processes, including differentiation, cell proliferation, and apoptosis. Retinoid actions are mediated by two classes of nuclear proteins called retinoic acid (RARalpha,beta and gamma and retinoic alpha,beta and gamma receptors, which are ligand-regulated transcription factors. Effects of both all-trans-retinoic acid (RA), the natural active derivative of vitamin A, and its synthetic derivatives, on prostate gland or prostate cell lines implicate retinoids in the regulation of prostate growth and suppression of PCa development. Deficient retinoid availability and action at the cellular level because of either decreased content or altered metabolism in PCa cells can play a key role in abnormal cellular differentiation pathways, and the loss of anti-proliferative effects. Here we review the in vitro and in vivo effects of retinoids in PCa.

Animals↗
PubMed1998

Anticoagulant effects of synthetic retinoids.

We have recently found that retinoic acids (RAs) evoke anticoagulant effect by upregulating thrombomodulin (TM) and downregulating tissue factor (TF) expression in acute promyelocytic leukemia (APL) and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have been identified. Each receptor class consists of three subtypes. We have used several synthetic retinoids to find which receptor subtypes are involved in the regulation of TM and TF expression in APL cells NB4, monoblastic leukemia cells U937 and human umbilical vein endothelial cells (HUVECs). Am80, which does not have a binding affinity to RARgamma, Ch55, which does not bind to cytoplasmic retinoic acid binding protein (CRABP), and a specific RARalpha agonist Ro40-6055, have shown to upregulate TM and downregulate TF in NB4 and U937 cells similar to all-trans RA (ATRA). A specific RARalpha antagonist Ro41-5253 efficiently suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells and HUVECs. In contrast, only when both RARalpha and RARbeta antagonists were preincubated, downregulation of TF by the retinoids was suppressed in NB4 cells. These results indicate the mechanically distinct transactivation and transrepression functions of RARs, the major role of RARalpha in TM upregulation by retinoids in leukemic cells and HUVECs and the cooperative role of RARalpha and RARbeta in TF downregulation by retinoids. This implies that synthetic retinoids will provide a very useful means to control distinct targets, TM and TF genes, at the level of transcription. Synthetic retinoids may develop as new type of antithrombotic agents which may change the character of cells as well as act as malignant cell differentiation inducers.

Anticoagulants↗
PubMed2000

Retinoids in chemoprevention and differentiation therapy.

Retinoids are essential for the maintenance of epithelial differentiation. As such, they play a fundamental role in chemoprevention of epithelial carcinogenesis and in differentiation therapy. Physiological retinoic acid is obtained through two oxidation steps from dietary retinol, i.e. retinol-->retinal-->retinoic acid. The latter retinal-->retinoic acid step is irreversible and eventually marks disposal of this essential nutrient, through cytochrome P450-dependent oxidative steps. Mutant mice deficient in aryl hydrocarbon receptor (AHR) accumulate retinyl palmitate, retinol and retinoic acid. This suggests a direct connection between the AHR and retinoid homeostasis. Retinoids control gene expression through the nuclear retinoic acid receptors (RARs) alpha, beta and gamma and 9-cis-retinoic acid receptors alpha, beta and gamma, which bind with high affinity the natural ligands all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Retinoids are effective chemopreventive agents against skin, head and neck, breast, liver and other forms of cancer. Differentiation therapy of acute promyelocytic leukemia (APL) is based on the ability of retinoic acid to induce differentiation of leukemic promyelocytes. Patients with relapsed, retinoid-resistant APL are now being treated with arsenic oxide, which results in apoptosis of the leukemic cells. Interestingly, induction of differentiation in promyelocytes and consequent remission of APL following retinoid therapy depends on expression of a chimeric PML-RAR alpha fusion protein resulting from a t(15;17) chromosomal translocation. This protein functions as a dominant negative against the function of both PML and RARs and its overexpression is able to recreate the phenotypes of the disease in transgenic mice. The development of new, more effective and less toxic retinoids, alone or in combination with other drugs, may provide additional avenues for cancer chemoprevention and differentiation therapy.

Animals↗
PubMed1998

[Study on effects of new retinoids in combination with IFN-gamma on proliferation and differentiation of U937 cell and its mechanism].

OBJECTIVE: To illustrate the effects of new retinoids in combination with IFN-gamma on the proliferation and differentiation of U937 cell and its mechanism. METHOD: Effects of new retinoids R9158, YS904012 in combination with IFN-gamma on the proliferation and differentiation of U937 cells were studied by detecting NBT, expression of CD14, CD68 and c-myc, and cell cycle shift. RESULT: When the U937 cells had been first treated with new retinoid for 24 hours, and then with IFN-gamma, the differentiation activity could be enhanced, the reverse of the use of two agent in chronology displayed much lower synergistical effect. Retinoids could down regulate c-myc expression and shift the cell population from S phase to G0/G1 phase within 24 hours, and the activity of YS904012 was greater than that of other retinoids. CONCLUSION: New retinoids in combination with IFN-gamma synergistically induced U937 differentiation. Retinoids may play an important role in triggering the differentiation.

Cell Division↗
PubMed2001

Effects of receptor-selective retinoids on CYP26 gene expression and metabolism of all-trans-retinoic acid in intestinal cells.

Retinoids mediate most of their function via interaction with retinoid receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)], which act as ligand-activated transcription factors controlling the expression of a number of target genes. The complex mechanistic pattern of retinoid-induced effects on gene expression of CYP26 and intestinal metabolism of all-trans-retinoic acid (RA) was investigated here by studying the effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoid acid receptors, RARs and RXRs, in human intestinal Caco-2 cells. We show here that CYP26 is expressed in human duodenum and colon. In Caco-2 cells not only all-trans-RA but also synthetic agonists of the RAR induced intestinal CYP26 gene expression and all-trans-RA metabolism as well. The RARalpha ligand Am580 induced the CYP26 gene expression more than the RARbeta ligand CD2019 or the RARgamma ligand CD437 suggesting the highest specificity for RARalpha on intestinal CYP26 gene regulation. RXR ligands alone did not induce CYP26 gene expression or RA metabolism in Caco-2 cells at all. But together with the RARalpha ligand, Am580, there were enhanced effects on the induction of CYP26 gene expression and on the induction of the metabolism of all-trans-RA. We conclude that gene regulation of CYP26 and the metabolism of all-trans-RA in intestinal cells is regulated through RXR and RAR heterodimerization. When coadministered, RAR agonists showed the highest potency for CYP26 gene regulation. Receptor-selective retinoids showed enhanced effects on induction of CYP26 gene expression and all-trans-retinoic acid metabolism.

Caco-2 Cells↗
PubMed2001

Quantitative assessment of retinoid signaling pathways in the developing eye and retina of the chicken embryo.

Retinoid signaling has been implicated as an important regulator of retinal development and differentiation. We have used state of the art high-pressure liquid chromatography to identify and quantitate biologically active retinoids, immunohistochemistry to localize the retinoic acid synthetic enzyme retinaldehyde dehydrogenase 2 (RALDH2), and nucleic acid assays to quantitate and localize retinoid receptor gene transcripts in the developing eye and retina of the chicken. Our results demonstrate spatial distinctions in retinoid synthesis and signaling that may be related to laminar differentiation in the developing retina. Retinoic acids (RAs) and their precursor retinols (ROHs) are the predominant retinoids in the developing eye. All-trans-RA and all-trans-3,4-didehydro-RA are present in the neuroepithelium in approximately equal amounts from early stages of neurogenesis until shortly before hatching. The retinoid X receptor (RXR) ligand 9-cis-RA is undetectable at all stages; if present, it cannot exceed a small percentage of the total RA content. RAs are not detected in the pigment epithelium. All-trans-ROH is present in the neuroepithelium and pigment epithelium, whereas all-trans-3,4-didehydro-ROH is detected only in the pigment epithelium and/or the choroid and sclera. RALDH2 immunoreactivity is intense in the choroid, low or absent in the pigment epithelium, and moderate in the neuroepithelium, where it is highest in the outer layers. Transcripts of all five chicken retinoid receptor genes are present in the neural retina and eye throughout development. During the period of neurogenesis, at least three of the receptors (RAR gamma, RXR gamma, RXRalpha), exhibit dynamic patterns of differential localization within the depths of the neural retina.

Aldehyde Oxidoreductases↗
PubMed2001

Retinoids for the treatment of psoriasis: outlook for the future.

Despite the demonstrated clinical success of retinoid therapy in psoriasis, its mechanism of action has not been fully elucidated, and investigators are confronted with two paradoxes. Firstly, the binding of retinoids to nuclear retinoic acid receptors (RARs) does not match their therapeutic efficacy. Secondly, formation of retinoic acid is probably increased in the psoriatic lesions. Answering these questions should result in: (i) the better use of acitretin, an oral synthetic retinoid, and tazarotene, the first compound for topical use; (ii) the development of new retinoids with specific pharmacological profile such as subtype-selective retinoids including molecules with an 'antiretinoid' activity and dissociating antiproliferative retinoids; and (iii) the better characterization of non-genomic effects of retinoids.

Animals↗
PubMedDate not supplied

Retinoids and malignant melanoma: a pathway of proliferation inhibition on SK MEL28 cell line.

BACKGROUND: It has been observed, in preclinical and clinical studies, that retinoids may interfere with the carcinogenic process in different ways such as the control of proliferation, differentiation and apoptosis. MATERIALS AND METHODS: We evaluated the in vitro efficacy of some synthetic retinoids (RAR-alpha, beta and gamma; RXR-alpha agonists and RAR-alpha antagonist) and compared these to the panagonist all-trans retinoic acid in inhibiting growth of the human melanoma cell line, SK MEL 28. We estimated, in parallel, apoptosis as a function of the treatment and, by RT-PCR, we analysed the effects of retinoids on the transcriptional profile of relevant genes, such as retinoid receptors and regulatory proteins. RESULTS: We observed a marked antiproliferative rate with the RAR-gamma selective agonist RO 44-4753 and the RAR-alpha selective antagonist RO 41-5253; on the contrary, the other synthetic retinoids exhibited a rather low efficacy. All the tested retinoids appeared to activate the RAR-beta gene and major expression was evidenced following RO 44-4753 and RO 41-5253 treatment. CONCLUSION: Among the tested retinoids, RO 41-5253 exhibited marked effects on proliferation and RARs mRNA expression and its action appeared mainly related to a cell-cycle arrest rather than an apoptotic mechanism.

Antineoplastic Agents↗
PubMedDate not supplied

Systemic pharmacokinetics of acitretin, etretinate, isotretinoin, and acetylenic retinoids in guinea pigs and obese rats.

Etretinate, a highly lipophilic retinoid, is known to accumulate in the human body with a slow systemic elimination (half-life approximately 100 days) after long-term treatment. Retinoids with high lipophilicity and slow body elimination have the propensity of eliciting teratogenic effects. Therefore, synthetic retinoids with reduced systemic retention are desired. In this study, we evaluated the systemic pharmacokinetics of acitretin, etretinate, isotretinoin, synthetic acetylenic retinoic acids (AGN 190121, AGN 190186, and AGN 190299), and acetylenic retinoates (AGN 190073, AGN 190089, and AGN 190168) in guinea pigs following iv doses. Their pharmacokinetics were also measured in obese rats to probe the effect of body fat on the drug disposition of retinoids. The acetylenic retinoates were hydrolyzed to their corresponding free acids at a much faster rate than etretinate in both animal species. All retinoates showed faster body clearance and larger volume of distribution than their free acids. In the obese rats, longer elimination half-lives and slower body clearance of the retinoids, except isotretinoin, were observed as compared to those in the normal rats. These results suggest that body fat has a significant effect on drug disposition and slows down the systemic clearance of retinoids. Since the synthetic acetylenic retinoates rapidly converted to their less lipophilic free acids after systemic absorption, the potential accumulation of these retinoids, as reported for lipophilic etretinate, were unlikely to occur in humans and animals.

Acitretin↗