tretinoin and Hyperplasia

Presenile diffuse familial sebaceous hyperplasia (PDFSH) presents as extensive yellowish papules with central umbilication on the face without involvement of periorificial regions and occurs in adolescents or young adults with a positive family history. Thirteen cases of PDFSH have been reported in the English-language published work, 10 of which responded to oral isotretinoin from 0.5 to 1 mg/kg per day but recurrences were often observed. Herein, we report two cases of PDFSH, which were successfully managed without recurrence with prolonged low-dose isotretinoin (0.2 mg/kg per day, a cumulative dose of 41 and 64 mg/kg, respectively). Treatment protocols among different published works were reviewed to verify the efficacy of isotretinoin.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Anti-Bacterial Agents; Biopsy; Cheek; Clinical Protocols; Dermatologic Agents; Facial Dermatoses; Female; Fluticasone; Humans; Hyperplasia; Isotretinoin; Maintenance Chemotherapy; Male; Recurrence; Sebaceous Glands; Treatment Outcome; Tretinoin

Hyperplasia and squamous differentiation in epidermal and tracheobronchial epithelial cells is a multistage process. In stage I, quiescent progenitor cells are recruited to reenter the cell cycle. Protein kinase C activators, retinoids, cytokines, and polypeptide growth factors have been identified to control this stage of hyperproliferation. In stage II, cells become committed to irreversible growth arrest, which in normal cells appears to be a prerequisite for the expression of the differentiated phenotype (stage III). Confluence or treatment with interferon gamma or phorbol esters are conditions that induce irreversible growth arrest and differentiation. Retinoids do not block stage II but specifically suppress the expression of stage III. The action of retinoids appears to be mediated by nuclear retinoic acid receptors. Studies understanding the mechanisms that regulate hyperplasia and squamous metaplasia may provide insight into the processes that lead to squamous cell carcinomas. Such studies may also provide new strategies for chemotherapy and chemoprevention.

Topics: Bronchi; Carrier Proteins; Cell Differentiation; Cell Division; Gene Expression Regulation; Humans; Hyperplasia; Lung Neoplasms; Receptors, Retinoic Acid; Retinoids; Skin; Trachea; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

Adult kidneys, which are principally composed of tubulointerstitium, do not normally regenerate or expand their working pool of functional cells at a very high rate. Loss of kidney tissue, however, can lead to some compensatory renal enlargement. The catalytic forces initiating such exchanges have not been fully articulated by current experimental endeavors. Increasing evidence, nevertheless, does suggest that factors other than simple changes in renal hemodynamics may be involved in this process. Different cellular elements in the tubulointerstitial microenvironment probably modulate changes in tubular enlargement or size through a complex cytokine network. Autocrine and paracrine stimulation of enlargement by different local growth factors also seem to play a pivotal role. After binding to cellular receptors, these factors activate signal transduction pathways resulting in expression of immediate early genes, which by themselves can synchronize the expression of subsequent genes through the medium of transacting factors. The renal enlargement response can also be modified by endocrine hormones that can activate such genes directly and/or stimulate other adjunctive processes, like receptor expression for the regional binding of growth factors. Furthermore, renal enlargement is under negative feedback of inhibitory factors like TGF beta. It is possible, for example, that special genes exist which are only expressed to arrest enlargement. It has been further suggested that activation of the Na+/H+ antiporter is a common denominator in renal enlargement. Recent findings, however, indicate that the activation of this antiporter is not always necessary, and might rather be a parallel event rather than a key phenomena in tubular enlargement. G0/G1 transition of tubular cells seems to involve similar factors in tubular hypertrophy and hyperplasia. The factors which are responsible for the final determination of the enlargement pattern (hypertrophy vs. proliferation) are unknown. The separation between hypertrophy and hyperplasia, although suggested by striking differences in cellular regulation, may be somewhat artificial, since responses leading to tubular enlargement also exist in circumstances where hyperplasia and hypertrophy are combined events. Recently it has been proposed that growth factors stimulate gluconeogenesis in proximal tubular cells producing hyperplasia, whereas factors inhibiting gluconeogenesis might induce hypertrophy. Whether the common p

Topics: Animals; Carrier Proteins; Cell Cycle; Gene Expression; Growth Substances; Humans; Hydrogen-Ion Concentration; Hyperplasia; Hypertrophy; Kidney; Kidney Tubules; Proto-Oncogenes; Signal Transduction; Sodium-Hydrogen Exchangers; Steroids; Tretinoin

Topics: Alkynes; Animals; Cell Differentiation; Cytoplasmic Granules; Epidermis; Hair; Hyperplasia; Keratins; Phorbol Esters; Phorbols; Protein Biosynthesis; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

Topics: Animals; Carcinogens; Cocarcinogenesis; Cyclamates; Cyclophosphamide; Humans; Hyperplasia; Mice; Neoplasms, Experimental; Rats; Saccharin; Schistosomiasis; Time Factors; Tretinoin; Tryptophan; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Calculi; Vitamin A Deficiency

Topics: Animals; Cell Division; Cyclic AMP; Cyclic GMP; DNA; Fibroblasts; Humans; Hyperplasia; Lymphocytes; Phorbol Esters; Prostaglandins E; Psoriasis; Salivary Glands; Skin; Tretinoin; Ultraviolet Rays

Topical formulations of tretinoin precursors (retinol and its ester derivatives) are widely available over the counter and may offer similar clinical benefits to those of tretinoin for treatment of photoaging. However, which of the many purported molecular effects of retinoids most strongly drives clinical improvements in tretinoin-treated skin remains unclear.. To evaluate the clinical efficacy of topical tretinoin precursors (TTP) vs tretinoin (RA) in treating moderate to severe facial photodamage and to identify potential biomarkers that correlate with clinical efficacy.. This randomized, double-blind, single-center, parallel-arm study of 24 patients with moderate to severe facial photodamage was conducted at an academic referral center from November 2010 to December 2011, with data analysis performed from January 2012 to December 2021.. Daily topical application of 0.02% RA or 1.1% TTP formulation containing retinol, retinyl acetate, and retinyl palmitate for 24 weeks.. Photoaging and tolerability were assessed by dermatologist evaluations and patient-reported outcomes. Target gene expression was assessed by real-time quantitative polymerase chain reaction of biopsied tissue from treated areas.. A total of 20 White women were ultimately analyzed (9 randomized to TTP, 11 randomized to RA). At week 24, there was no significant difference in Griffiths photoaging scores among patients receiving TTP vs RA (median, 4 vs 5) (TTP - RA difference: -1; 95% CI, -2 to 1; P = .27). Treatment with TTP was associated with erythema 6 times less frequently than RA (11% vs 64%) (TTP - RA difference: -0.53; 95% CI, -0.88 to -0.17; P = .01). Target gene analysis showed significant CRABP2 messenger RNA (mRNA) induction (confirming retinoic acid receptor signaling) but no significant changes in procollagen I or MMP1/3/9 mRNA in TTP-treated samples. Instead, MMP2 mRNA, which encodes a type IV collagenase, was significantly reduced in TTP-treated samples (week 24 - baseline mRNA difference: -5; 96% CI, -33 to 1.6; P = .02), and changes in MMP2 were strongly correlated with changes in fine wrinkles (r = 0.54; 95% CI, 0.12 to 0.80; P = .01). Interestingly, patients with severe baseline wrinkles exhibited greater improvements (r = -0.74; 95% CI, -0.89 to -0.43; P < .001). This trend was mirrored in MMP2 mRNA, with initial expression strongly predicting subsequent changes (r = -0.78; 95% CI, -0.89 to -0.43; P < .001).. In this randomized clinical trial, there was no significant difference in efficacy between this particular formulation of TTP and tretinoin 0.02%. However, the results of these mechanistic studies highlight MMP2 as a possible mediator of retinoid efficacy in photoaging.. ClinicalTrials.gov Identifier: NCT01283464.

Topics: Biomarkers; Double-Blind Method; Female; Humans; Hyperplasia; Matrix Metalloproteinase 2; Retinoids; RNA, Messenger; Skin; Skin Aging; Treatment Outcome; Tretinoin; Vitamin A

Seborrheic keratosis is one of the most common skin benign tumors in humans with a high occurrence rate of 80%-100% in people > 50 years of age; however, its pathogenesis is still unclear. The standard treatment includes cryotherapy and laser surgery for physically removing lesions. Drug therapy for this condition has not been well established. We aimed to evaluate the use of all-trans retinoic acid (ATRA)-loaded microneedle (MN) patches as a simple, alternative therapeutic option to traditional surgical treatments. This therapeutic strategy was designed to induce the proliferation of basal keratinocytes and accelerate stratum corneum turnover, leading to the lesion falling off the surface of the skin. The MN patch induced epidermal hyperplasia and marked expression of heparin-binding epidermal growth factor-like growth factor mRNA and protein corresponding to ATRA activity in the skin of HR-1 hairless mice. The acceleration of stratum corneum turnover was also observed by the dansyl chloride method. The skin irritation study in mice and safety study in humans support the safety findings of our study. Overall, MN patches can offer an effective and safe means of ATRA delivery into the skin, and the ATRA-loaded MN patch appears to be an effective pharmaceutical product providing a novel therapeutic option for seborrheic keratosis.

Topics: Adult; Animals; Collagen; Cytokines; Dermatologic Agents; Drug Delivery Systems; Female; Heparin-binding EGF-like Growth Factor; Humans; Hyperplasia; Intercellular Signaling Peptides and Proteins; Keratosis, Seborrheic; Male; Mice; Mice, Hairless; Microinjections; Middle Aged; Needles; Receptors, Retinoic Acid; RNA, Messenger; Skin; Skin Irritancy Tests; Transdermal Patch; Tretinoin

We investigated the clinical, histologic, and molecular responses of normal human skin to all-trans-retinol (ROL) application, compared to those induced by topical all-trans-retinoic acid (RA), and measured ROL-derived metabolites. Up to 1.6% ROL, 0.025% RA in vehicle (70% ethanol/30% propylene glycol), or vehicle alone were applied in a double-blind fashion to normal buttock skin and occluded for 4 d. ROL produced from none to only trace erythema, which was clinically and statistically insignificant, whereas RA induced a significant 3.7-fold increase in erythema score compared to vehicle (n = 10, p < 0.01). However, ROL induced significant epidermal thickening (1.5-fold at 1.6% ROL, p < 0.01), similar to RA (1.6-fold at 0.025% RA, p < 0.01), relative to the vehicle. ROL, compared with vehicle, also increased mRNA levels of cellular retinoic acid binding protein (CRABP-II) and cellular retinol binding protein (CRBP) genes as determined by Northern analysis (5-6-fold and 6-7-fold, respectively) and riboprobe in situ hybridization. CRABP-II and CRBP protein levels were also higher following ROL than vehicle treatment, as measured by ligand binding (3.2-fold, p < 0.001; n = 7) and Western analysis (3.6-fold, p < 0.003; n = 6), respectively. Epidermal retinyl ester (RE) content, measured after removal of stratum corneum, rose 240-fold (p < 0.005, n = 5) by 24 h of ROL occlusion. RA content, however, was undetectable or detectable only at trace amounts in all samples obtained at 0, 6, 24, and 96 h after ROL occlusion. Detectability of RA was not correlated with ROL treatment (compared to untreated normal skin, p = 0.86) or baseline skin ROL levels (average r = -0.1, p > 0.3). These data demonstrate that ROL application 1) produces trace erythema not significantly different from vehicle, whereas RA causes erythema; 2) induces epidermal thickening and enhances expression of CRABP-II and CRBP mRNAs and proteins as does RA; 3) causes marked accumulation of retinyl ester; and 4) does not significantly increase RA levels. Taken together, the data are compatible with the idea that ROL may be a prohormone of RA, because it produces changes in skin similar to those produced by RA but without measurable RA or irritation.

Topics: Administration, Cutaneous; Adult; Dose-Response Relationship, Drug; Drug Eruptions; Epidermis; Erythema; Esters; Gene Expression Regulation; Humans; Hyperplasia; In Situ Hybridization; Occlusive Dressings; Receptors, Retinoic Acid; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Safety; Tretinoin; Vitamin A

In 1983, intervention of precancerous lesion of esophagus was undertaken in the high risk area of esophageal cancer, Heshun Village, Linxian County. It had been expected that cancerous degeneration rate of esophageal dysplasia should be reduced by 50% so as the prevention of esophageal cancer could become possible. 6758 subjects of the general population aging from 40 to 65 were examined by esophageal exfoliative cytology, 1729 had marked dysplasia and 2411 had mild dysplasia of esophageal epithelium. Those with marked dysplasia were randomized into 3 groups to take their respective medication: antitumor B (Chinese herbs); retinamide (4-Ethoxycarbophenylretinamide) and placebo. The subjects with mild dysplasia were divided randomly into 2 groups for treatment by riboflavin and placebo. 95% of the subjects had taken 90% or more of the total medication for 3 years, at the end of which they were reexamined by esophageal exfoliative cytology. The reexamination rate was 94.1%. The incidence of esophageal cancer in the antitumor B group (3.9%) was reduced by 53% as compared with that of the placebo group (8.3%). This difference had statistical significant (means 2 = 7.672, P less than 0.05). The incidence of esophageal cancer in retinamide and riboflavin groups were reduced by 33.7% and 19% as compared with those of the control groups. The regression rate of dysplasia in the treatment groups were increased than that of the control groups. The above results showed that our hypothesis about the secondary prevention of esophageal cancer is correct. The intervention of precancerous lesion of the esophagus is effective in the prevention of esophageal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Drugs, Chinese Herbal; Esophageal Neoplasms; Female; Humans; Hyperplasia; Male; Middle Aged; Precancerous Conditions; Riboflavin; Tretinoin

Skin development and patterning is dependent on factors that regulate the stepwise differentiation of dermal fibroblasts concomitant with dermal-epidermal reciprocal signaling, two processes that are poorly understood. Here we show that dermal EZH2, the methyltransferase enzyme of the epigenetic Polycomb Repressive Complex 2 (PRC2), is a new coordinator of both these processes. Dermal EZH2 activity is present during dermal fibroblast differentiation and is required for spatially restricting Wnt/β-catenin signaling to reinforce dermal fibroblast cell fate. Later in development, dermal EZH2 regulates the expression of reticular dermal markers and initiation of secondary hair follicles. Embryos lacking dermal Ezh2 have elevated epidermal proliferation and differentiation that can be rescued by small molecule inhibition of retinoic acid (RA) signaling. Together, our study reveals that dermal EZH2 is acting like a rheostat to control the levels of Wnt/β-catenin and RA signaling to impact fibroblast differentiation cell autonomously and epidermal keratinocyte development non-cell autonomously, respectively.

Topics: Animals; beta Catenin; Cell Differentiation; Cell Proliferation; Dermis; Enhancer of Zeste Homolog 2 Protein; Epidermis; Fibroblasts; Hyperplasia; Keratinocytes; Mice; Organogenesis; Polycomb Repressive Complex 2; Retinoids; Signal Transduction; Stem Cells; Tretinoin; Wnt Signaling Pathway

Peripheral arterial disease is a leading cause of morbidity and mortality. The most commonly utilized prosthetic material for peripheral bypass grafting is expanded polytetrafluoroethylene (ePTFE) yet it continues to exhibit poor performance from restenosis due to neointimal hyperplasia, especially in femoral distal bypass procedures. Recently, we demonstrated that periadventitial delivery of all-trans retinoic acid (atRA) immobilized throughout porous poly(1,8 octamethylene citrate) (POC) membranes inhibited neointimal formation in a rat arterial injury model. Thus, the objective of this study was to investigate whether atRA immobilized throughout the lumen of ePTFE vascular grafts would inhibit intimal formation following arterial bypass grafting. Utilizing standard ePTFE, two types of atRA-containing ePTFE vascular grafts were fabricated and evaluated: grafts whereby all-trans retinoic acid was directly immobilized on ePTFE (atRA-ePTFE) and grafts where all-trans retinoic acid was immobilized onto ePTFE grafts coated with POC (atRA-POC-ePTFE). All grafts were characterized by SEM, HPLC, and FTIR and physical characteristics were evaluated in vitro. Modification of these grafts, did not significantly alter their physical characteristics or biocompatibility, and resulted in inhibition of intimal formation in a rat aortic bypass model, with atRA-POC-ePTFE inhibiting intimal formation at both the proximal and distal graft sections. In addition, treatment with atRA-POC-ePTFE resulted in increased graft endothelialization and decreased inflammation when compared to the other treatment groups. This work further confirms the biocompatibility and efficacy of locally delivered atRA to inhibit intimal formation in a bypass setting. Thus, atRA-POC-ePTFE grafts have the potential to improve patency rates in small diameter bypass grafts and warrant further investigation.

Topics: Animals; Blood Vessel Prosthesis; Humans; Hyperplasia; Male; Neointima; Polytetrafluoroethylene; Rats, Sprague-Dawley; Tretinoin; Tunica Intima

Rheumatoid arthritis (RA) is a systemic autoimmune disease including synovitis and synovial hyperplasia that contribute to joint destruction. Pivotal pathogenic mechanisms in this process are the dysregulated proliferation and apoptosis of fibroblast-like synoviocytes (FLS). Unfortunately, the mechanisms of FLS dysregulation are not completely elucidated. Here, we explored a new hypothesis based in the potent anti-proliferative and pro-apoptotic activity of retinoids in some types of cancer. Specifically, we investigated the role of retinoids and of the retinoic acid binding proteins, CRABP2 and FABP5, on the proliferation and apoptosis of FLS from RA by adding all-trans retinoic acid (ATRA) or silencing CRABP2 and FABP5. We showed an unconventional behaviour of RA FLS, which were relatively insensitive to ATRA. In effect, ATRA increased the resistance to apoptosis despite the high CRABP2/FABP5 ratio of RA FLS; and CRABP2 suppression sensitized RA FLS to Fas-induced apoptosis. This latter effect was associated with changes in expression of kinases, ASK1 up-regulation and ERK down-regulation, and increased phosphorylation of JNK. In addition, the potentiation of FLS apoptosis by CRABP2 silencing persisted in the presence of pro-inflammatory mediators, TNF e IL1β. Therefore, the results point to CRABP2 as a potential target to decrease synovial hyperplasia in RA.

Topics: Apoptosis; Arthritis, Rheumatoid; Drug Delivery Systems; Extracellular Signal-Regulated MAP Kinases; fas Receptor; Fatty Acid-Binding Proteins; Female; Humans; Hyperplasia; Male; Receptors, Retinoic Acid; Synovial Membrane; Synoviocytes; Tretinoin

Recently a mouse skin carcinogenesis study reported that a β-blocker carvedilol displayed antitumor-properties via antihyperplastic effects. However, the antihyperplastic mechanism is unclear as the β-blocker is characterized with multiple pleiotropic effects including stimulation of endothelial NO release and verapamil-like calcium channel blocking activity. To investigate the nature and the origin of the antihyperplastic effects, we tested topical pretreatment with pindolol, heptaminol, ATRA or verapamil against Balb/c mouse ear skin hyperplasia that was induced by TPA. We found that pindolol, heptaminol or ATRA, but not verapamil, inhibited the TPA-induced immunoinflammatory skin changes in an NO-dependent manner, which included epidermal hyperplasia, skin edema and fibrosis. Furthermore, we also observed NO-dependent alleviation of the TPA-induced NK cell depletion in the ear tissues by heptaminol pretreatment. Together our results suggest that stimulation of NO generation from constitutive synthases may be primarily responsible for the reported antihyperplastic and NK cell-preserving effects of the β-blockers, and that similar effects may be observed in other immunity normalizing compounds that also promote endothelial NO synthesis.

Topics: Animals; Female; Fibrosis; Heptaminol; Hyperplasia; Killer Cells, Natural; Mice; Mice, Inbred BALB C; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pindolol; Skin; Tetradecanoylphorbol Acetate; Tretinoin; Verapamil

Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 μg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 μmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.

Topics: Adventitia; Animals; Apoptosis; Carotid Artery Injuries; Carotid Artery, Common; Carotid Stenosis; Cell Proliferation; Cells, Cultured; Citrates; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Fibroblasts; Hyperplasia; Macrophages; Male; Membranes, Artificial; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Polymers; Rats, Sprague-Dawley; Recurrence; Time Factors; Tretinoin; Vascular Cell Adhesion Molecule-1

Lung hypoplasia can be prevented in vitro by retinoic acid (RA). Recent evidence suggests that amniotic fluid stem (AFS) cells may integrate injured lungs and influence their recovery. We tested the hypothesis that AFS cells might improve lung growth and motility by paracrine mechanisms. Pregnant rats received either nitrofen or vehicle on E9.5. In vitro E13 embryonic lungs were cultured in the presence of culture medium alone or with RA, basophils, or AFS cells. In vivo green fluorescent protein-expressing (GFP(+)) rat AFS cells were transplanted in nitrofen-exposed rats on E10.5. E13 lung explants were cultured before analysis. The surface, the number of terminal buds, and the frequency of bronchial contractions were assessed. Protein gene product 9.5 (PGP 9.5) and α-actin protein levels were measured. The lung explants transplanted with AFS cells were stained for α-actin, PGP 9.5, and TTF-1. The levels of FGF-10, VEGFα, and TGF-β1 secreted by the AFS cells in the culture medium were measured. Comparison between groups was made by ANOVA. In vitro, the surface, the number of terminal buds, and the bronchial peristalsis were increased in nitrofen+AFS cell explants in comparison with nitrofen-exposed lungs. While nitrofen+RA lungs were similar to nitrofen+AFS ones, basophils did not normalize these measurements. PGP 9.5 protein was decreased in nitrofen lungs, but after adding AFS cells, the value was similar to controls. No differences were found in the expression of α-actin. In vivo, the surface, number of terminal buds, and peristalsis were similar to control after injection of AFS cells in nitrofen-exposed rats. Colocalization with TTF-1-positive cells was found. The levels of FGF-10 and VEGFα were increased in nitrofen+AFS cell explants, while the levels of TGF-β1 were similar to controls. Lung growth, bronchial motility, and innervation were decreased in nitrofen explants and rescued by AFS cells both in vitro and in vivo, similarly to that observed before with RA. The AFS cell beneficial effect was probably related to paracrine action of growth factor secretion.

Topics: Amniotic Fluid; Animals; Cell Movement; Female; Hyperplasia; Lung; Microscopy, Confocal; Pesticides; Phenyl Ethers; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation; Tretinoin

Infants born with intrauterine growth retardation (IUGR) are at increased risk of adverse pulmonary outcomes at birth, including meconium aspiration and persistent pulmonary hypertension. Preterm infants with IUGR are at especially high risk of developing bronchopulmonary dysplasia (BPD), a disease hallmarked by alveolar hypoplasia. Although vitamin A supplementation has been shown to decrease the incidence of BPD or death in preterm very low birth weight infants, its potential to reduce BPD or death in preterm infants with IUGR remains unknown. We used a well-characterized rat model of caloric restriction to mimic IUGR and determine the impact of IUGR on lung development. We hypothesized that retinoic acid treatment would preserve alveolar formation through increases in key signaling molecules of the retinoic acid signaling pathway. Our results showed that alveolar hypoplasia caused by caloric restriction can be reversed with refeeding, and that retinoic acid prevents the alveolar hypoplasia coincident with the increased expression of elastin and retinoic acid receptor-α and decreased transforming growth factor-β activity in developing rat lungs. These findings suggest that alveolar hypoplasia attributable to caloric restriction is reversible, and raises the possibility that retinoic acid therapy may prove a useful strategy to prevent adverse pulmonary sequelae such as BPD in preterm infants with IUGR.

Topics: Animals; Caloric Restriction; Elastin; Female; Hyperplasia; Lung; Maternal Exposure; Pregnancy; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Signal Transduction; Transforming Growth Factor beta; Tretinoin

We previously reported that mice with skin-specific deletion of stearoyl-CoA desaturase-1 (Scd1) recapitulated the skin phenotype and hypermetabolism observed in mice with a whole-body deletion of Scd1. In this study, we first performed a diet-induced obesity experiment at thermoneutral temperature (33°C) and found that skin-specific Scd1 knockout (SKO) mice still remain resistant to obesity. To elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin phenotype, we performed microarray analysis of skin gene expression in male SKO and control mice fed a standard rodent diet. We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebaceous gland hypoplasia, inflammation and epidermal hyperplasia in SKO mice. Additionally, transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis, elongation and desaturation, which may be attributed to decreased abundance of key transcription factors including SREBP1c, ChREBP and LXRα. Conversely, genes involved in cholesterol synthesis were increased, suggesting an imbalance between skin fatty acid and cholesterol synthesis. Unexpectedly, we observed a robust elevation in skin retinol, retinoic acid and retinoic acid-induced genes in SKO mice. Furthermore, SEB-1 sebocytes treated with retinol and SCD inhibitor also display an elevation in retinoic acid-induced genes. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin phenotype.

Topics: Acute-Phase Proteins; Animals; Epidermis; Fatty Acids; Gene Expression Profiling; Hair; Hyperplasia; Inflammation; Lipocalin-2; Lipocalins; Male; Mice; Mice, Knockout; Obesity; Oligonucleotide Array Sequence Analysis; Oncogene Proteins; PPAR delta; Receptors, Retinoic Acid; Sebaceous Glands; Skin; Stearoyl-CoA Desaturase; Sterols; Temperature; Transcription Factors; Transcriptional Activation; Tretinoin; Vitamin A

Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice.. We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced.. Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds could have not only physiological but also therapeutic implications.

Topics: Alitretinoin; Animals; Blotting, Western; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Epidermis; Female; Hyperplasia; Hypothyroidism; Interleukin-6; Keratins; Lymphocytes; Macrophages; Male; Mice; Mice, Knockout; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tetradecanoylphorbol Acetate; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Tretinoin; Tumor Necrosis Factor-alpha

All-trans retinoic acid (RA) compromises epidermal differentiation and causes keratinocyte hyperproliferation through mechanisms not completely understood, but may involve the regulatory matrix molecule hyaluronan. In this work, the influences of all-trans RA on epidermal morphology and hyaluronan metabolism were examined in organotypic and monolayer cultures of rat epidermal keratinocytes (REKs). All-trans RA treatment of organotypic REK cultures (10 days) increased the synthesis of hyaluronan, the expression of hyaluronan synthases Has2 and Has3, and the CD44 receptor, with hyperplasia of the epidermis. The hyperplasia and hyaluronan production induced by all-trans RA were blocked with (1) AG1478, an inhibitor of the EGFR; (2) UO126, an inhibitor of the MAPK/ERK kinase, and (3) GM6001, an inhibitor of the matrix metalloproteinases. These effects were consistent with the findings that all-trans RA upregulated heparin-binding epidermal growth factor-like growth factor mRNA expression and increased the phosphorylation of EGFR and extracellular signal-regulated kinase 1/2 (ERK1/2). Interestingly, the activation of EGFR and ERK1/2 was seen already 30 minutes after all-trans RA treatment, suggesting that the activation of this signaling pathway is a primary response to all-trans RA. These results indicate that the effects of all-trans RA on keratinocyte proliferation and hyaluronan synthesis are partly mediated through EGFR signaling.

Topics: Animals; Cell Line; Enzyme Inhibitors; Epidermis; ErbB Receptors; Glucuronosyltransferase; Hyaluronan Receptors; Hyaluronan Synthases; Hyaluronic Acid; Hyperplasia; Keratinocytes; MAP Kinase Kinase Kinases; Metalloproteases; Rats; Signal Transduction; Tretinoin

The TAF4 subunit of transcription factor TFIID was inactivated in the basal keratinocytes of foetal and adult mouse epidermis. Loss of TAF4 in the foetal epidermis results in reduced expression of the genes required for skin barrier function, leading to early neonatal death. By contrast, TAF4 inactivation in adult epidermis leads to extensive fur loss and an aberrant hair cycle characterised by a defective anagen phase. Although the mutant epidermis contains few normal anagen-phase hair follicles, many genes expressed at this stage are strongly upregulated indicating desynchronized and inappropriate gene expression. The TAF4 mutant adult epidermis also displays interfollicular hyperplasia associated with a potent upregulation of several members of the EGF family of mitogens. Moreover, loss of TAF4 leads to malignant transformation of chemically induced papillomas and the appearance of invasive melanocytic tumours. Together, our results show that TAF4 is an important regulator of keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity.

Topics: Animals; Cell Differentiation; Cell Proliferation; Epidermis; Female; Genetic Predisposition to Disease; Hair; Hyperplasia; Keratinocytes; Male; Mice; Mice, Knockout; Nevus, Pigmented; Protein Subunits; Skin Neoplasms; TATA-Binding Protein Associated Factors; Transcription Factor TFIID; Tretinoin; Tumor Suppressor Proteins

Retinoids are widely used in the treatment of photoaging to stimulate dermal repair. However, retinoids also induce epidermal hyperplasia, which can lead to excessive scaling. Scaling is the major deterrent to topical retinoid therapy. Keratinocyte growth is strongly stimulated via ligand activation of EGFR. We examined regulation of EGFR ligands by retinoids and the role of EGFR in retinoid-induced hyperplasia in human skin in vivo. Topical treatment of human skin with all-trans retinoic acid (tRA) induces EGFR ligands heparin-binding (HB)-EGF and amphiregulin (AR), and reduces betacellulin mRNA levels. Laser capture microdissection-coupled real-time reverse transcription-PCR reveals that tRA increases HB-EGF mRNA throughout the epidermis, whereas AR induction is limited to basal keratinocytes. Topical tRA activates extracellular signal-regulated kinase 1/2 (Erk1/2) downstream EGFR effectors in human skin in vivo. tRA increases the soluble forms of AR and HB-EGF proteins, and induces epidermal hyperplasia, in human skin organ culture. Neutralization of HB-EGF or AR with specific antibodies strongly reduces tRA-induced epidermal hyperplasia. Finally, inhibition of EGFR activation by genistein reduces epidermal hyperplasia caused by topical retinoid treatment. These data demonstrate the central role of EGFR activation in retinoid-induced epidermal hyperplasia, and suggest that EGFR inhibitors can mitigate retinoid-induced scaling.

Topics: Amphiregulin; Antibodies; Cells, Cultured; EGF Family of Proteins; Epidermal Growth Factor; Epidermis; ErbB Receptors; Glycoproteins; Heparin-binding EGF-like Growth Factor; Humans; Hyperplasia; Intercellular Signaling Peptides and Proteins; Ligands; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Retinoids; RNA, Messenger; Skin Diseases; Tretinoin

Vascular smooth muscle cell (VSMC) differentiation and phenotypic modulation are characterized by changes in gene expression for smooth muscle (SM) marker contractile proteins such as SM alpha-actin and SM22alpha. Hyperplasia suppressor gene (HSG) is a potent VSMC proliferation-inhibiting factor; however, it is not known if HSG is involved in the redifferentiation of VSMCs. Here, the redifferentiation of the dedifferentiated VSMCs was induced by serum withdrawal or all-trans retinoic acid (atRA), HSG gene expression and its role in VSMC phenotypic modulation were studied by reverse transcription - polymerase chain reaction, Western blotting, and cell migration assay. The results indicated that HSG gene expression increased significantly during VSMC redifferentiation induced by serum deprivation or atRA and peaked at 24 h, then was maintained at higher levels. Meanwhile, SM marker contractile proteins SM alpha-actin and SM22alpha were increased by more than 2-fold. Coimmunoprecipitation and immunofluorescent experiments revealed that anti-HSG antibody could precipitate SM alpha-actin, and HSG and SM alpha-actin colocalized within the cytoplasm of differentiated VSMCs. Migration activity of VSMCs was dramatically suppressed after cells were transfected with HSG expression plasmids. These findings suggested that HSG is associated with SM alpha-actin in VSMC cytoplasm, and is involved in VSMC differentiation and migration.

Topics: Actins; Animals; Cell Differentiation; Gene Expression; Hyperplasia; Keratolytic Agents; Male; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Tretinoin

Heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF-family, is thought to be important for keratinocyte functions. HB-EGF is first synthesized as a membrane-anchored form, and its soluble form is released by ectodomain shedding. Here we investigate the role of HB-EGF in epidermal hyperplasia induced by all-trans retinoic acid (tRA) treatment. HB-EGF is normally expressed in epidermis of normal adult mice at very low levels, but topical tRA treatment results in epidermal hyperplasia, concomitant with the strong induction of HB-EGF expression in the suprabasal layer. tRA-induced epidermal hyperplasia was reduced both in the keratinocyte-specific HB-EGF null mice (K5-HB(del/del)) and knock-in mice expressing the uncleavable mutant form of HB-EGF (HB(uc/uc)), as compared with wild-type HB-EGF knock-in mice (HB(lox/lox)). Among ErbB tyrosine kinase receptors, EGF receptor (EGFR) and ErbB2 were selectively activated by tRA treatment in skin from wild-type mice, while the activation of these ErbB receptors was significantly reduced in the skin of HB-EGF null mice. These results indicate that expression of HB-EGF and generation of its soluble form, followed by activation of EGFR and ErbB2, are pivotal processes in tRA-induced epidermal hyperplasia.

Topics: Animals; Cell Proliferation; Epidermal Growth Factor; Epidermis; ErbB Receptors; Female; Heparin-binding EGF-like Growth Factor; Hyperplasia; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Keratinocytes; Mice; Mice, Inbred Strains; Mice, Transgenic; Receptor, ErbB-2; RNA, Messenger; Time Factors; Tretinoin

Organ cultures of human skin were incubated for 8 days with 1 microg/ml 14-all trans retinoic acid (14-all trans RA) and concomitantly treated with varying concentrations of soy extract. The epidermis of organ cultures treated with 14-all trans RA alone underwent a hyperplastic response. In cultures treated with a combination of 14-all trans RA and soy extract (4-40 microg/ml), hyperplasia was reduced by 16-41%. The same concentrations of soy extract that reduced epidermal hyperplasia in organ culture also suppressed proliferation of rapidly growing keratinocytes in monolayer culture (approximately 25% reduction at 20 and 40 microg/ml). On the other hand, soy extract did not further inhibit proliferation of quiescent keratinocytes; rather, it stimulated growth (50-52% increase relative to control). When dermal fibroblasts were examined for a response to soy extract (i.e., proliferation and synthesis of type I procollagen), both responses were stimulated (proliferation: 75% increase and collagen production 114% increase relative to control). Genistein, the major isoflavone in extracts of soy also inhibited epidermal hyperplasia in organ culture (34-40% reduction relative to control). The same concentrations that reduced epidermal hyperplasia (0.5-1.0 microg/ml) also inhibited keratinocyte proliferation in monolayer culture but had little effect on fibroblast growth. Two other isoflavones (daidzein and glycetein) were also inhibitory, but were less effective than genistein. Taken together, these data suggest that use of soy extract or its constituent isoflavones in conjunction with 14-all trans RA may provide a way to mitigate unwanted epidermal effects of topical retinoid therapy without compromising beneficial retinoid effects in the dermis.

Topics: Cell Proliferation; Cells, Cultured; Collagen Type I; Culture Media, Conditioned; Dose-Response Relationship, Drug; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Epidermis; Fibroblasts; Glycine max; Humans; Hyperplasia; Isoflavones; Keratinocytes; Organ Culture Techniques; Plant Extracts; Tretinoin

We used cultured neonatal rat cardiac myocytes to test the hypothesis that all-trans retinoic acid (atRA) may act to modulate ANG II actions in inducing myocyte hypertrophy. Our observations were as follows. 1) atRA (10(-7) to approximately 10(-5) M ) inhibited ANG II-induced hyperplasia of fibroblasts in a dose-dependent manner. 2) Treatment of atRA attenuated the ANG II-induced increase in total cell protein content. 3) Treated with ANG II (10(-7) M) for 5 days, the cultured neonatal rat cardiac myocytes demonstrated an apparent accumulation of sarcomeric fiber proteins and Golgi's complex, as well as reorganization of the sarcomeric unit within individual myocytes. atRA (10(-6) M) treatment reduced the accumulation of contractile proteins and Golgi's complex without affecting the ANG II-induced reorganization of the sarcomeric unit. 4) atRA attenuated the ANG II-induced increase in intracellular Ca2+. Our results show that atRA inhibits some effects of ANG II on neonatal rat cardiac myocytes and suggest that atRA may be a therapeutic candidate for the prevention and therapy of cardiac hypertrophy and remodeling.

Topics: Angiotensin II; Animals; Animals, Newborn; Calcium; Cardiomegaly; Cell Count; Cell Division; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblasts; Golgi Apparatus; Hyperplasia; Intracellular Fluid; Myocardium; Proteins; Rats; Rats, Wistar; Sarcomeres; Tretinoin

To investigate the roles of retinoic acid (RA) receptors (RARs) in the physiology of epidermis that does not express RAR beta, conditional spatio-temporally controlled somatic mutagenesis was used to selectively ablate RAR alpha in keratinocytes of RAR gamma-null mice. Keratinocyte proliferation was maintained in adult mouse epidermis lacking both RAR alpha and RAR gamma, as well as in RAR beta-null mice. All RAR-mediated signalling pathways are therefore dispensable in epidermis for homeostatic keratinocyte renewal. However, topical treatment of mouse skin with selective retinoids indicated that RXR/RAR gamma heterodimers, in which RXR transcriptional activity was subordinated to that of its RAR gamma partner, were required for retinoid-induced epidermal hyperplasia, whereas RXR homodimers and RXR/RAR alpha heterodimers were not involved. RA-induced keratinocyte proliferation was studied in mutant mice in which RXR alpha, RXR alpha and RAR alpha, RAR gamma, or RXR alpha and RAR gamma genes were specifically disrupted in either basal or suprabasal keratinocytes. We demonstrate that the topical retinoid signal is transduced by RXR alpha/RAR gamma heterodimers in suprabasal keratinocytes, which, in turn, stimulate proliferation of basal keratinocytes via a paracrine signal that may be heparin-binding EGF-like growth factor.

Topics: Alleles; Animals; Cell Division; Crosses, Genetic; Dimerization; Epidermal Cells; Epidermal Growth Factor; Epidermis; Gene Targeting; Heparin-binding EGF-like Growth Factor; Homeostasis; Hyperplasia; Intercellular Signaling Peptides and Proteins; Keratinocytes; Mice; Mice, Knockout; Mice, Transgenic; Mutagenesis; Paracrine Communication; Protein Multimerization; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Retinoids; Tamoxifen; Transcription Factors; Transcription, Genetic; Tretinoin

Thymic hyperplasia can occur after cytotoxic therapy for various malignancies. The possible cause could be rebound enlargement after initial atrophy caused by these drugs. During the treatment of hematological malignancies this could be a cause of great concern. We report here a case of thymic hyperplasia after chemotherapy for acute myeloid leukemia. Awareness of this unusual side-effect may prevent needless investigation and therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Female; Humans; Hyperplasia; Leukemia, Promyelocytic, Acute; Pseudotumor Cerebri; Radiography; Sweet Syndrome; Thymus Gland; Tretinoin

Sun-protected human skin was maintained in organ culture and treated with all-trans retinoic acid in the presence or absence of reversible or irreversible pharmacologic antagonists of c-erbB receptor tyrosine kinase activity. In the absence of these inhibitors, all-trans retinoic acid induced epidermal hyperplasia comparable to that induced in intact skin by all-trans retinol or all-trans retinoic acid itself. There was a strong correlation between inhibition of epidermal hyperplasia in organ culture and inhibition of epidermal-growth-factor-dependent keratinocyte growth in monolayer culture. In additional studies it was shown that all-trans retinoic acid could overcome the known inhibitory effects of calcium on expression of HB-EGF-like growth factor mRNA in organ-cultured skin. Further, it was shown that an antibody to HB-EGF-like growth factor inhibited retinoid-stimulated epidermal hyperplasia in organ culture and reduced proliferation in cultured keratinocytes. In contrast, the c-erbB receptor tyrosine kinase antagonists and the neutralizing HB-EGF-like growth factor antibody were ineffective in inhibiting all-trans-retinoic-acid-dependent survival and proliferation of human dermal fibroblasts. Taken together, these data indicate (i) that retinoid-induced epidermal hyperplasia in human skin proceeds through c-erbB, and (ii) that HB-EGF-like growth factor is one of the c-erbB ligands mediating this effect.

Topics: Adult; Antibodies; Calcium; Cell Division; Cell Survival; Epidermal Growth Factor; Epidermis; ErbB Receptors; Fibroblasts; Gene Expression; Heparin-binding EGF-like Growth Factor; Humans; Hyperplasia; Intercellular Signaling Peptides and Proteins; Keratinocytes; Keratolytic Agents; Organ Culture Techniques; Receptors, Cell Surface; RNA, Messenger; Tretinoin

All-trans-retinoic acid (RA) regulates epithelial differentiation and growth through activation of specific nuclear RA receptors (RARs). Because high-rate metabolism largely impairs the biological efficacy of RA, we have sought for compounds capable of inhibiting the metabolic breakdown of the retinoid. This study identifies R115866 as a novel inhibitor of the cytochrome P450 (CYP)-mediated metabolism of RA. In vitro, nanomolar concentrations of R115866 inhibited the conversion of RA by CYP26, a RA-inducible RA metabolizing enzyme. In vivo, oral administration of R115866 (2.5 mg/kg) to rats induced marked and transient increases of endogenous RA levels in plasma, skin, fat, kidney, and testis. Consistent with its ability to enhance endogenous RA content in tissues, R115866 was found to exert retinoidal activities. Like RA, the title compound: 1) inhibited vaginal keratinization in estrogen-stimulated rats; 2) induced epidermal hyperplasia in mouse ear skin; 3) transformed mouse tail epidermis from a para- to an orthokeratotic skin type; and 4) up-regulated the CYP26 mRNA expression in rat liver. Furthermore, we found that the keratinization-suppressive and CYP26-inducing activities of R115866 could be reversed by concomitant administration of the RAR antagonist, AGN193109. Our data characterize R115866 as a potent, orally active inhibitor of RA metabolism, capable of enhancing RA levels and displaying retinoidal actions. These activities are reversed by RAR antagonism, supporting the idea that the actions of R115866 result from increased availability of endogenous RA and improved RAR triggering.

Topics: Animals; Aromatase Inhibitors; Benzothiazoles; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Epidermis; Female; Humans; Hyperplasia; Keratosis; Male; Mice; Ovariectomy; Rats; Rats, Wistar; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazoles; Tissue Distribution; Tretinoin; Triazoles; Vagina

Development of vein graft intimal hyperplasia has been associated with increased activity of matrix metalloproteinases (MMPs). All-trans-retinoic acid (atRA) decreases expression and activity of MMPs in tissue culture and has decreased intimal hyperplasia following arterial balloon catheter injury. We examined the effect of oral administration of atRA on intimal hyperplasia and MMP expression in an animal model of vein bypass grafting.. Interposition jugular vein bypass grafts were placed in the carotid artery of New Zealand white rabbits. Animals received either atRA (10 mg/kg/day) or vehicle (corn oil) for a period of 2 weeks. Retinoic acid serum levels were determined by HPLC. Intimal and medial areas were measured using morphometric analysis of perfusion-fixed vein graft specimens, and intimal thickness was calculated using circumferential measurements. Expression of MMP-2, MMP-9, and TIMP-1 in vein grafts and unoperated control veins was determined using Northern analysis, and proteolytic activity was determined using substrate gel zymography.. Animals treated with atRA had significantly elevated serum levels of this compound and its metabolites. A decrease in intimal to medial ratio was noted after 28 days in vein grafts from treated animals (0.63 vs 0.88, P < 0.01), and a decrease in calculated intimal thickness was noted at 7 and 28 days. Expression of MMP-2 was decreased in treated animals 7 days following surgery, and expression of both MMP-2 and MMP-9 was decreased at 28 days. A decrease in proteolytic activity was noted on zymography at 68 kDa, 7 and 28 days following surgery in vein grafts from animals treated with atRA, corresponding with a decrease in the active form of MMP-2. Increased expression of TIMP-1 was noted in vein grafts from both the treated and the control groups, 7 and 28 days following graft placement.. Oral administration of all-trans-retinoic acid resulted in decreased intimal hyperplasia in an animal model of vein bypass grafting. This was associated with decreased expression and activity of MMP-2 in treated animals.

Topics: Animals; Antineoplastic Agents; Blotting, Northern; Gene Expression Regulation, Enzymologic; Hyperplasia; Jugular Veins; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rabbits; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Tretinoin; Tunica Intima; Wound Healing

The 9-cis-retinoic acid (9cRA) is an endogenous ligand of retinoid X nuclear receptors (RXRs). Although the epidermis contains five times more RXRs than RARs, little is known on the activity of topical 9cRA. In order to circumvent surface isomerization of topically applied 9cRA into all-trans-retinoic acid (atRA), we used topical 9-cis-retinaldehyde (9cRAL) as a precursor of 9cRA, hypothesizing that keratinocytes would metabolize 9cRAL into 9-cis-retinoic acid (9cRA). Retinoid content was determined by HPLC analysis of mouse tail skin that had been washed after the application of 9cRAL (0.05% for 14 days) to evaluate the metabolites produced within the epidermis. Biologic activities of 9cRAL and atRAL were analysed by assessing hyperplastic and metaplastic responses, by determining epidermal thickness and the levels of mRNAs encoding for specific keratins. atRAL and derived retinoids were found in skin treated with either atRAL or 9cRAL. The metabolite pattern obtained with 9cRAL was similar to that obtained with atRAL except the presence in 9cRAL samples of an unidentified nonpolar metabolite. However, treatment with 9cRAL yielded higher atRAL and lower retinyl ester concentrations. The biologic activities (hyperplastic and metaplastic responses) resulting from topical application of 9cRAL were lower than those induced by atRAL or atRA at similar concentrations. Taken together, these data show that topical 9cRAL does not deliver significant amounts of 9cRA and exerts less biologic activity than atRAL. Contrary to atRAL, 9cRAL does not appear therefore as a pertinent candidate for topical use in humans.

Topics: Administration, Topical; Alitretinoin; Animals; Gene Expression; Hyperplasia; Keratins; Metaplasia; Mice; Mice, Inbred C57BL; Retinaldehyde; Retinoids; RNA, Messenger; Skin; Stereoisomerism; Tail; Tretinoin

Vitamin A and its derivatives (retinoids) are capable of inhibiting vascular smooth muscle cell proliferation in vitro. The present study examines the effect of two retinoids, all-trans retinoic acid and 13-cis retinoic acid, on intimal hyperplasia following arterial injury. After receiving varying doses of all-trans retinoic acid or 13-cis retinoic acid, 78 male Sprague-Dawley rats underwent standard balloon catheter denudation of the left common carotid artery. Morphometric analysis and immunohistochemistry for proliferating cell nuclear antigen was performed at early and late time points. Intimal/medial ratios were reduced in a dose-dependent fashion for animals treated with all-trans retinoic acid (P = 0.001) and 13-cis retinoic acid (P = 0.004). Proliferating cell nuclear antigen labeling indices were reduced after treatment with all-trans retinoic acid and 13-cis retinoic acid at early time points post-injury. At a dose of 10 mg/kg, both all-trans retinoic acid and 13-cis retinoic acid inhibited vessel remodeling as measured by increases in luminal diameter (P < 0.05) and external elastic lamina (P < 0.05). Retinoids are an attractive clinical option for the treatment of restenosis following angioplasty and arterial surgery.

Topics: Animals; Carotid Artery Injuries; Carotid Artery, Common; Catheterization; Hyperplasia; Isotretinoin; Male; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Tretinoin; Tunica Intima

To investigate the effects of oral administration of all-trans retinoic acid (ATRA) on inhibition of intimal thickening after balloon angioplasty in the rabbit iliac artery atherosclerotic model.. Iliac atherosclerosis was induced in 24 rabbits, and balloon angioplasty was performed. At angioplasty, 24 rabbits were randomly divided into four groups (n = 6 per group): Group 1: controls not receiving oral ATRA administration; Group 2: receiving oral ATRA (0.6 mg.kg-1.d-1) administration beginning 1 week prior to angioplasty and continuing for 4 weeks; Group 3: receiving oral ATRA (0.6 mg.kg-1.d-1) administration beginning immediately after angioplasty and continuing for 4 wk; Group 4: receiving oral ATRA (0.6 mg.kg-1.d-1) administration beginning 1 wk after angioplasty and continuing for 4 wk. Values of cross-sectional area, ratio of intimal/medial area and thickness were determined by a computer-based morphometric system, and cell proliferative activity was assessed by 3H-thymidine incorporation.. Both the cross-sectional area and the ratio of intimal/medial area and thickness were significantly reduced by ATRA administration compared with control group (P < 0.01). The inhibitory effect is less potent when ATRA is administered 1 week before angioplasty. The ATRA inhibitory effect when administered 1 week after angioplasty is not different significantly form that when administered immediately after angioplasty. The 3H-thymidine incorporation was also decreased in ATRA-treated rabbits compared with controls (P < 0.01).. Oral ATRA administration can be effective in inhibiting intimal thickening after balloon angioplasty. It is reasonable that ATRA should be administered immediately after angioplasty.

Topics: Angioplasty, Balloon; Animals; Arteriosclerosis; Hyperplasia; Iliac Artery; Male; Rabbits; Random Allocation; Tretinoin; Tunica Intima

Retinoids and phorbol esters have profound effects on proliferation and differentiation of epidermal keratinocytes when applied topically on rodent skin. Since both agents also modulate gap junction (GJ)-mediated cell-cell communication, we have examined the effects of all-trans retinoic acid (RA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) on the expression of alpha1 (Cx43) and beta2 (Cx26) connexins, the two major gap junction gene products in mature rat epidermis. In fully differentiated, mature epidermis, alpha1 is expressed in the lower, less differentiated portion, while beta2 is localized in upper, more differentiated layers. Dorsal skin of 21-day old rats was treated topically with a single dose of RA, TPA or vehicle alone and used for histological and molecular analyses at different time points. Keratinocytes in interfollicular epidermis were examined for proliferation and differentiation using specific antibodies for keratins (K10, K14) and proliferating cell nuclear antigen (PCNA). An increase in epidermal thickness was noticed within 4 hours after the application of RA or TPA. This increase, however, appeared to be primarily due to hypertrophy, since no substantial changes were observed in the proliferative index of epidermal keratinocytes. PCNA immunoreactivity significantly increased after 8 hours treatment of RA or TPA, suggesting a hyperproliferative growth response. Epidermal hyperplasia was confirmed by monitoring the expression patterns of K10 and K14 in RA- or TPA-treated skin. RA-induced hyperplasia lasted longer as compared to TPA induction. Changes in keratin phenotypes were paralleled by an increase in alpha1 and beta2 connexin expression as well as their colocalization in same epidermal layers. Differences in hyperplastic growth response kinetics were also confirmed at the connexin level, with beta2 antigen sustained for longer and at higher levels in suprabasal layers of RA-treated skin. Overall, this type of connexin expression resembled that observed in the non-differentiated rat epidermis during embryonic development. An increase in alpha1 and beta2 connexin abundance was also observed at the protein and RNA levels. At 96 hours after RA or TPA treatment, expression of both connexins was similar to that of the control epidermis. Taken together, these findings suggest that a higher level of GJ-mediated cell-cell communication, is required for the maintenance of homeostasis during periods of rapid epidermal growth and differen

Topics: Animals; Antineoplastic Agents; Carcinogens; Cell Differentiation; Connexin 26; Connexin 43; Connexins; Epidermis; Gap Junctions; Gene Expression; Hyperplasia; Keratinocytes; Keratins; Rats; Rats, Wistar; RNA, Messenger; Tetradecanoylphorbol Acetate; Tretinoin

The formation of all-trans retinoic acid is an oxidative process whereby retinol is converted to retinaldehyde and then to retinoic acid. Because retinol causes qualitative molecular changes similar to those produced by retinoic acid, we compared potency of retinol, retinaldehyde, and retinyl palmitate to retinoic acid and assessed the effects of occlusion. Retinoids were prepared in an experimental vehicle of 95% ethanol:propylene glycol (7:3) with anti-oxidant. Induction of retinoic acid 4-hydroxylase activity was the end point for comparison. Retinoic acid concentrations from 0.001% to 0.05% under occlusion produced a linear dose-response induction of 4-hydroxylase activity. The concentrations of the other retinoids under occlusion required to achieve significant induction of enzyme activity were 0.6% retinyl palmitate, 0.025% retinol, and 0.01% retinaldehyde. The linear dose-response was lost with retinoid concentrations in excess of 0.25% retinol or 0.5% retinaldehyde. Statistical analyses showed no difference in 4-hydroxylase activity between unoccluded and occluded retinol treated sites. By contrast, however, unoccluded sites treated with retinoic acid or retinyl palmitate had less induction of 4-hydroxylase activity than occluded sites. Retinol, retinaldehyde, and retinyl palmitate did not produce erythema but did increase epidermal thickness. Although retinol is a weaker retinoid than retinoic acid, the increased penetration of unoccluded retinol in comparison to unoccluded retinoic acid with this prototypic vehicle confers on retinol a more effective delivery of a retinoidal effect than unoccluded retinoic acid. Retinol at 0.25% may be a useful retinoid for application without occlusion because it does not irritate but does induce cellular and molecular changes similar to those observed with application of 0.025% retinoic acid.

Topics: Administration, Topical; Adult; Anticarcinogenic Agents; Antioxidants; Cell Membrane Permeability; Cytochrome P-450 Enzyme System; Diterpenes; Dose-Response Relationship, Drug; Enzyme Activation; Erythema; Humans; Hyperplasia; Retinoic Acid 4-Hydroxylase; Retinyl Esters; Skin; Tretinoin; Vitamin A

In order to assess the proliferative changes induced by all-trans retinoic acid (RA) and retinol (ROL), we have carried out a study of the DNA content of basal and suprabasal keratinocytes after epicutaneous application on the rhino mouse.. Skin sections were analyzed stereologically and cytophotometrically using the Feulgen technique. The diploid DNA value (2C) was obtained from hepatocyte nuclei of control animals. Whereas cells in phase G0-G1 will show a 2C content, cells during phase S and in phase G2-M will show DNA values ranging from 2C to 4C and 4C, respectively.. Although epidermal thickness (ET) increased significantly in all treated animals, surface density only increased in animals treated with all-trans RA. Quantification of DNA content of basal keratinocytes showed reduction of 2C and 2C-4C populations with a commensurate increase in proportions of cells with 4C and > 4C in the animals treated with 0.025% all-trans RA and ROL. Suprabasal keratinocytes of mice treated with 0.025% all-trans showed a decrease of the 2C population and an increased proportion of cells with 4C. Whereas 0.025% all-trans RA induced an increase of both basal and suprabasal DNA indices, ROL enhanced only the basal DNA index significantly.. Animals treated with 0.025% ROL showed a significant increase in the basal proliferative index (PI) while the suprabasal PI remained constant; treatment with 0.025% all-trans RA produced a significant increase of both basal and suprabasal PIs and parakeratotic hyperkeratosis probably due to incomplete differentiation.

Topics: Administration, Cutaneous; Animals; Cell Cycle; Cell Differentiation; DNA; Epidermis; Female; Hyperplasia; In Vitro Techniques; Keratinocytes; Keratolytic Agents; Mice; Mice, Hairless; Mice, Mutant Strains; Ploidies; Skin; Tretinoin; Vitamin A

In previous studies we have noted that mast cells are increased in tretinoin-treated photoaged hairless mouse skin. Because UV radiation is known to increase mast cell numbers, we were interested in whether tretinoin alone would modulate the mast cell population in unirradiated mice. Animals were treated topically with 0.05% tretinoin, 5 days a week, for 2, 4, 6, 8 and 10 weeks. Untreated and vehicle controls were included. Biopsies were processed for light microscopy and stained with toluidine blue. Mast cells in the upper and lower dermis were scored separately under high magnification. After 2 weeks of tretinoin, mast cells in the upper dermis were significantly increased, as indicated by the appearance of small, moderately metachromatically granulated cells near the dermal-epidermal junction. Mast cells in the lower dermis, the site of a granulomatous reaction, were large, densely granular and significantly increased after 6 weeks of treatment. Immunohistochemical evaluation for mast cell growth factor (MGF) revealed a marked increase in keratinocyte cytoplasmic staining by week 2. After 4-6 weeks, membrane-associated or intercellular staining was evident. Cells in the upper dermis also showed membrane reactivity for MGF. By 8-10 weeks, epidermal MGF reactivity had dissipated in the more basal keratinocytes. These findings show that topical tretinoin can induce epidermal MGF along with an associated mast cell hyperplasia. It is suggested that the two populations of dermal mast cells may have different functions.

Topics: Administration, Topical; Animals; Cell Count; Female; Hyperplasia; Mast Cells; Mice; Mice, Hairless; Stem Cell Factor; Tretinoin

Retinaldehyde, a natural metabolite of beta-carotene and retinol, has been proposed recently for topical use in humans. Because retinaldehyde does not bind to retinoid nuclear receptors, its biologic activity should result from enzymatic transformation by epidermal keratinocytes into ligands for these receptors, such as all-trans retinoic acid and 9-cis-retinoic acid. In this study, we analyzed by high performance liquid chromatography the type and amounts of tissue retinoids as well as several biologic activities resulting from topical application of either retinaldehyde or all-trans retinoic acid on mouse tail skin. Biologic activities of all-trans retinoic acid and retinaldehyde were qualitatively identical in metaplastic parameters (induction of orthokeratosis, reduction of keratin 65-kDa mRNA, increase in filaggrin and loricrin mRNAs) and hyperplastic parameters (increase in epidermal thickness, increase in bromodeoxyuridine (BrdU)-positive cells, increase in keratin 50-kDa mRNA, and reduction in keratin 70-kDa mRNA). Some quantitative differences, not all in favor of all-trans retinoic acid, were found in several indices. Cellular retinoic acid-binding protein II and cellular retinol-binding protein I mRNAs were increased by both topical retinaldehyde and all-trans retinoic acid. Whereas all-trans retinoic acid, 9-cis-retinoic acid, and 13-cis-retinoic acid were not detectable (limit 5 ng/g) in vehicle-treated skin, 0.05% retinaldehyde-treated skin contained 13 +/- 6.9 ng/g wet tissue of all-trans retinoic acid (mean +/- SD), 12.6 +/- 5.9 ng/g 13-cis-retinoic acid, and no 9-cis-retinoic acid. In contrast, 9-cis-retinoic acid was detectable in 0.05% of all-trans retinoic acid-treated skin, which also contained 25-fold more all-trans retinoic acid and 5-fold more 13-cis-retinoic acid than retinaldehyde-treated skin. Our results show that topical retinaldehyde is transformed in vivo into all-trans retinoic acid by mouse epidermis. The small amounts of ligand for retinoic acid nuclear receptors thus produced are sufficient to induce biologic effects similar to those resulting from the topical application of the ligand itself in much higher concentration.

Topics: Administration, Topical; Animals; Filaggrin Proteins; Hyperplasia; Keratins; Mice; Mice, Inbred C57BL; Receptors, Retinoic Acid; Retinaldehyde; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Skin; Tretinoin

Mouse-transformed epidermal cell line (Pam 212) generated the soluble mediators for promoting the growth of a mast cell line (MC9) in the presence of retinoic acid at a concentration of 10(-6)-10(-7) M. The effective molecule of MC9 cell growth promoting factor (MC9-GF) was non-dialyzable and eluted between the molecular weight of 45 K and 68 K on a TSK 2000 G column. Chromatofocusing analysis revealed that this factor had a pI range between 7.0 and 7.5. Anti-c-kit ligand antibody abrogated MC9-GF activity and RT-PCR analysis demonstrated that retinoic acid upregulates c-kit ligand mRNA expression by Pam cells. Several recombinant cytokines including IL1-alpha, IL-1 beta, IL-2, IL-3 or IL-4 did not promote MC9 cell growth at a concentration of 100 U/ml. The presence of anti-IL-1 alpha, -IL-1 beta, -IL-2, -IL-3 or -IL-4 antibodies did not abrogate the MC9-GF activity except for anti-c-kit ligand antibody.

Topics: Animals; Base Sequence; Cell Line; Cytokines; DNA; Growth Substances; Hyperplasia; In Vitro Techniques; Keratinocytes; Mast Cells; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; Receptor Protein-Tyrosine Kinases; Receptors, Colony-Stimulating Factor; RNA, Messenger; Skin; Tretinoin; Up-Regulation

The suprabasal keratin 6 (K6) is remarkable among the keratins as, in addition to being constitutively expressed in different stratified epithelia, it is induced in epidermis under hyperproliferative conditions, such as benign or malignant tumors, psoriasis, and wound healing. In addition, this keratin is also induced in skin treated with 12-O-tetradecanoylphorbol-13-acetate or retinoic acid (RA). These characteristics make the study of K6 regulatory elements an especially interesting issue, in particular because these elements could be useful in designing gene constructs for the therapy of skin diseases. We have analyzed by mobility shift and footprinting experiments the cell type-specific enhancer of the bovine K6 beta gene (Blessing, M., Jorcano, J. L., and Franke, W. W. (1989) EMBO J. 8, 117-126) and have identified an AP-2-like element, two AP-1 elements (one of them composite), and a retinoic acid-responsive element (RARE). Mutagenesis experiments and cotransfections with retinoic acid receptors show that the RARE mediates enhancer activation by RA. Chloramphenicol acetyltransferase assays show that under normal culture conditions, the AP-1 element retains most of the enhancer transcriptional activity, while the RARE and AP-2 are weakly active. However, following RA treatment, the AP-1 element is repressed and the RARE is activated, resulting in an overall stimulation of the enhancer by RA in the BMGE+H cells used in our study. These results explain in part the complex and sometimes contradictory response of keratin 6 to hyperproliferative stimuli.

Topics: Animals; Base Sequence; Cattle; Cell Division; Cells, Cultured; DNA; Enhancer Elements, Genetic; Gene Expression Regulation; Humans; Hyperplasia; Keratins; Molecular Sequence Data; Nuclear Proteins; Protein Binding; Sequence Homology, Nucleic Acid; Skin; Tetradecanoylphorbol Acetate; Tretinoin

Retinoic acid (RA) modulates epidermal homeostasis and affects differentiation-associated proteins such as keratin K1 and filaggrin. Because results from in vitro and in vivo studies have been conflicting with respect to RA effects on keratinization, we examined the terminal differentiation of epidermal cell cohorts after RA stimulation in vivo. Pulse-labelling with 5-bromo-2-deoxyuridine (BrdU) was performed by intraperitoneal injection of mice immediately or at 16 h after a single topical application of 100 nmol RA. The cell cohort labelled at the time of RA application consisted of previously unperturbed cells exposed to RA after initiation of S-phase, whereas the cohort labelled 16 h after RA application consisted of cells stimulated into the S-phase by RA. These two cohorts of partially synchronized cells were followed for up to 72 h after BrdU labelling. Such labelling combined with keratin K1 or filaggrin expression was scored by paired immunofluorescence staining of skin sections. The onset of keratin K1 expression was unchanged in both series after RA treatment, while filaggrin appeared earlier than in controls. The differential effect of RA on the maturation markers was related to the proliferative activity, the increased cell turnover, and the shortened epidermal transit time. The onset of keratin expression appeared to be regulated before the postmitotic period, whereas filaggrin expression appeared to be regulated during the late phase of the maturation process, thus being influenced by the actual epidermal kinetics and structural alterations. These results suggested that the effect of RA on epidermal differentiation is secondary to its effect on proliferation, as determined by the altered cellular age distribution following regenerative proliferation.

Topics: Administration, Topical; Animals; Cell Differentiation; Cell Division; Epidermis; Filaggrin Proteins; Hyperplasia; Intermediate Filament Proteins; Keratins; Mice; Mice, Hairless; Tretinoin

The long-term effects of butylated hydroxyanisole (BHA), in combination with various other chemicals on the development of forestomach lesions in rats were investigated. BHA is a synthetic antioxidant, and the other agents included the glutathione-depleting agent diethylmaleate (DEM), the anti-inflammatory drugs indomethacin (IM), dexamethazone (DEX), 6-aminocaproic acetate (6-ACA) and FOY (gabexate mesilate), and the vitamin all-trans-retinol acetate (RA). Concurrent treatment with BHA (1% in diet) and DEM, IM, DEX or FOY for 52 weeks inhibited development of forestomach epithelial hyperplasia as compared to BHA alone, while simultaneous treatment with RA enhanced hyperplastic development. However, the inhibition by DEX or FOY was only partial and in the DEX case, in particular, might have been due to weight loss. Since the most effective inhibitory influence on BHA-induced forestomach lesions exerted in this 1-year experiment was by DEM, a further 2-year experiment was conducted to confirm whether DEM actually can exert inhibitory effects on BHA (2% in diet)-induced forestomach carcinogenesis. The results demonstrated that induction of forestomach hyperplasias and papillomas by BHA was significantly reduced by combination treatment with DEM. Both multiplicity and incidence of forestomach papillomas were significantly decreased, while squamous cell carcinoma development showed a tendency for decrease only.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Butylated Hydroxyanisole; Dexamethasone; Drug Antagonism; Hyperplasia; Male; Maleates; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms; Tretinoin

Retinoic acid (RA) is an inducer of epidermal proliferation by a mechanism of action which is not fully known. We examined the proliferative response of hairless mouse epidermis to a single topical application of different doses of RA (0.1-1000 nmol). The mitotic rate was assessed using the stathmokinetic method, and change in epidermal cell numbers were scored per microscopic vision field in tissue sections. Cell cycle parameters were measured by bivariate bromodeoxyuridine/DNA flow cytometry on isolated epidermal basal cells after pulse labelling up to 10 days after RA treatment. The results showed a dose-dependent increase in mitotic activity with a maximum at 3 days after RA application, and a dose-dependent hyperplasia with a maximum at 4 days after RA application. Cell-cycle analysis showed an immediate proliferative response after RA application similar to that following various skin irritants. Although differences in the G2 phase transit were seen, this indicates a similar mechanism of action of RA-induced epidermal proliferation and that associated with epidermal regeneration in general.

Topics: Animals; Bromodeoxyuridine; Cell Division; Disease Models, Animal; DNA; Epidermal Cells; Epidermis; Flow Cytometry; Hyperplasia; Kinetics; Male; Mice; Mice, Hairless; Mice, Mutant Strains; Mitotic Index; Regeneration; Tretinoin

Preclinical studies pertaining to the pharmacology and toxicology of BMY 30123 (4-acetamidophenyl retinoate) are reported. BMY 30123 is a novel compound which has topical retinoid activity. This compound exhibits lower toxicity, both local and systemic, than other clinically used topical retinoids such as tretinoin (all-trans retinoic acid) in animal models. BMY 30123 is effective in a number of retinoid sensitive skin models including the rhino mouse utriculi reduction assay, the mouse epidermal hyperplasia model and in the suppression of DNA synthesis in mouse skin stimulated with phorbol ester. BMY 30123 was equipotent with tretinoin in these topical models. In the rhino mouse model the ED30 values for BMY 30123 and tretinoin were 0.037 and 0.015 mM, respectively. In addition, BMY 30123 was active in the UVB-induced photodamaged mouse model, another retinoid sensitive model. One of the problems associated with topically applied tretinoin is local irritation. Therefore, for topical therapy to be optimal, it is important to reduce or minimize local irritation. Repeated applications of BMY 30123 to rabbit skin resulted in low skin irritation. The first perceptible signs of skin irritation produced by BMY 30123 occurred at a dose 10 times higher than that observed for tretinoin. BMY 30123 also exhibits low retinoid activity after oral or i.p. administration in mice and produced no signs of hypervitaminosis A-related toxicity at twenty times the no effect dose of tretinoin. Because retinoids are effective modulators of epidermal growth and differentiation, this compound should be useful for the treatment of cutaneous disorders that exhibit altered epidermal differentiation such as acne, psoriasis, ichthyosis and epithelial tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetaminophen; Administration, Topical; Animals; Collagen; Dose-Response Relationship, Drug; Female; Hyperplasia; Hypervitaminosis A; Irritants; Mice; Mice, Hairless; Phorbol Esters; Rabbits; Retinoids; Saccule and Utricle; Tretinoin; Ultraviolet Rays

The discovery that topical tretinoin can reverse some of the effects of photodamage may lead to its chronic application. Examination of long-term effects was of interest. Three groups of hairless mice (age 6-8 weeks) were treated dorsally with 1) tretinoin (0.025%), 2) cream vehicle, 3) sham treatment. Applications were 3 times weekly and continued for up to 2 years until all mice were sacrificed or had died. Biweekly examinations showed no sign of retinoid toxicity, with growth and longevity similar in all groups. Tretinoin-treated skin was smooth and pink, resembling that of younger mice. Controls had yellowed, irregularly thickened skin. Histologically, tretinoin-treated skin had a hyperplastic epidermis consisting of plump, cytologically normal cells. Control skin had 3-4 compressed cell layers. Foci of new normally staining collagen were present in the subepidermal dermis of tretinoin-treated skin; fibroblasts were large and abundant in these areas. These foci were absent in controls. Mice treated with tretinoin also appeared to have increased amounts of elastic fibers and glycosaminoglycans.

Topics: Administration, Cutaneous; Animals; Basement Membrane; Collagen; Drug Evaluation, Preclinical; Elastic Tissue; Epidermis; Female; Follow-Up Studies; Hyperplasia; Mice; Mice, Hairless; Skin; Time Factors; Tretinoin

Dithranol-induced skin irritation and the modulatory effects of different pharmacological agents were studied using the mouse ear model. A single topical application of dithranol caused a dose-dependent skin irritation which resulted in delayed swelling of the mouse ear with two separate peak responses, 1-2 and 6-10 days after application. The irritation was most effectively and persistently inhibited by topical treatment with corticosteroids, the free radical scavenger DL-alpha-tocopherol (DLAT) and the serotonin antagonist metergoline. The effect of corticosteroids, however, was slightly diminished during the second peak irritation. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA), the dual lipoxygenase and cyclo-oxygenase inhibitor tolfenamic acid and the cyclo-oxygenase inhibitor indomethacin as well as trifluoperazine retained their inhibitory activity. Of these compounds, indomethacin was active only during the first irritation peak, NDGA during both peaks and trifluoperazine principally during the second peak. Retinoic acid did not inhibit the ear swelling. The results confirm and extend the observations that the formation of free radicals is essential for dithranol inflammation. The inflammation can also be suppressed by inhibiting the formation of arachidonic acid or its pro-inflammatory metabolites.

Topics: Administration, Topical; Adrenal Cortex Hormones; Animals; Anthralin; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dose-Response Relationship, Drug; Ear; Edema; Female; Hyperplasia; Indomethacin; Inflammation; Masoprocol; Mice; ortho-Aminobenzoates; Skin Diseases; Time Factors; Tretinoin; Trifluoperazine

The C3H strain of mouse has a high incidence of murine mammary tumor virus-induced mammary tumors, and tumorigenesis progresses via the intermediate formation of the preneoplastic, hyperplastic alveolar nodules (HANs). The C3H mouse also exhibits an elevation in 16 alpha-hydroxylation of estradiol which remains unaltered in relation to the age or presence of tumor, but which is detectable well before the emergence of overt mammary cancer. This metabolic pathway leads to the formation of 16 alpha-hydroxyestrone (16 alpha-OHE1), a putative promoter of mammary cancer. The present study examines the effect of two prototype chemopreventive agents, tamoxifen (TAM) and N-(4-hydroxyphenyl)retinamide (HPR), on 16 alpha-hydroxylation of estradiol and on the growth of HANs. Treatment with TAM, HPR, or a combination of TAM and HPR for 4 weeks in 6- to 8-week-old C3H mice resulted in a consistent elevation in the 16 alpha-hydroxylation pathway of estradiol metabolism relative to the placebo control group (20.50% +/- 2.35%, 21.46% +/- 1.49%, 18.00% +/- 1.75%, and 12.64% +/- 1.45% SD, respectively) and in a significant decrease in the mean frequency of HANs per mammary gland (1.4, 2.1, 0.0, and 5.8, respectively). Mice without any experimental manipulation exhibited an age-dependent progressive increase in HAN frequency from 1.5 per gland at 4 weeks of age to 12.1 per gland at 24 weeks of age. Administration of TAM, HPR, or a combination of TAM and HPR up to 22 weeks of age resulted in a continued suppression of HAN frequency, and the two agents in combination exerted an additive effect on the suppression of HAN development.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Drug Therapy, Combination; Estradiol; Female; Fenretinide; Hydroxylation; Hyperplasia; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Precancerous Conditions; Steroid 16-alpha-Hydroxylase; Tamoxifen; Tretinoin

Four different experiments were performed in order to examine the modifying effects of chlorogenic acid (CA), reserpine, polyprenoic acid (E-5166), and coffee on chemical carcinogenesis in rats or hamsters. Experiment 1: The numbers of hyperplastic liver cell foci and the incidence of colon tumors in male and female Syrian golden hamsters given a single intravenous injection of methylazoxymethanol (MAM) acetate and then fed the diet containing 0.025% CA for 24 wk were significantly lower than those of hamsters given MAM acetate alone. Experiment 2: The incidence of altered hepatocellular foci in female ACI/N rats given N-2-fluorenylacetamide (FAA, 0.02% in diet) for 10 wk and reserpine (weekly subcutaneous injections, 1 microgram/g body weight) during or after (17 wk) FAA exposure was significantly lower than that of rats given FAA alone. Experiment 3: The number of hepatocellular foci in male ACI/N rats given 0.02% FAA diet for 13 wk and E-5166 by gavage (40 mg/kg body weight, 3 times/wk) for 16 wk after the end of FAA exposure was significantly smaller than that in rats given FAA diet alone. Experiment 4: Incidences of liver tumors and hepatocellular foci of rats given concurrent dietary administration of aminopyrine (0.01%) and sodium nitrite (0.1%) and coffee solution as a drinking water for 630 da were significantly lower than those of rats given aminopyrine and sodium nitrite. Thus, the tested compounds had inhibitory effects on chemical carcinogenesis in liver or colon.

Topics: Animals; Carcinogens; Chlorogenic Acid; Coffee; Colonic Neoplasms; Cricetinae; Female; Hyperplasia; Liver; Liver Neoplasms, Experimental; Male; Mesocricetus; Rats; Rats, Inbred ACI; Reserpine; Tretinoin

When cells from normal human epidermis and from the human squamous cell carcinoma line SCC-13 were seeded on floating rafts of collagen and fibroblasts, they stratified and underwent terminal differentiation. Although the program of differentiation in SCC-13 cells was morphologically abnormal, the cultures resembled normal epidermal raft cultures by expressing the terminal differentiation-specific keratins, K1/K10, and by restricting their proliferative capacity to the basal-like cells of the population. In addition, the differentiating cells of both normal and SCC-13 raft cultures expressed keratins K6 and K16, which are not normally expressed in epidermis, but are synthesized suprabasally during wound-healing and in various epidermal diseases associated with hyperproliferation. While the behavior of normal and SCC-13 rafts was quite similar when they were cultured over normal medium, significant biochemical differences began to emerge when the cultures were exposed to retinoic acid. Most notably, while the SCC-13 cultures still stratified extensively, they showed a marked inhibition of both abnormal (K6/K16) and normal (K1/K10) differentiation-associated keratins, concomitantly with an overall disappearance of differentiated phenotype. Surprisingly, the reduction in K6/K16 in retinoid-treated SCC-13 cultures was not accompanied by a decrease in cell proliferation. Using immunohistochemistry combined with [3H]thymidine labeling, we demonstrate that while the expression of K6 and K16 are often associated with hyperproliferation, these keratins are only produced in the nondividing, differentiating populations of proliferating cultures. Moreover, since their expression can be suppressed without a corresponding decrease in proliferation, the expression of these keratins cannot be essential to the nature of the hyperproliferative epidermal cell.

Topics: Blotting, Northern; Carcinoma, Squamous Cell; Cell Division; DNA; Electrophoresis, Gel, Two-Dimensional; Epidermal Cells; Epidermis; Gene Expression Regulation; Humans; Hyperplasia; Keratins; Molecular Weight; Skin Diseases; Tretinoin; Tumor Cells, Cultured

The food and fragrance additive citral (3,7-dimethyl-2,6-octadienal) inhibits the oxidation of retinol to retinoic acid in mouse epidermis on local application. This inhibitory property was used to test the hypothesis that oxidation to retinoic acid is rate limiting for the biological activity of vitamin A (retinol) in epithelial tissues. Citral was tested as a modulator of the biological activities of retinol and retinoic acid using two bioassays performed in Skh/hr1 (hairless) mice: (a) the ability to induce epidermal hyperplasia; (b) the ability to inhibit the induction of epidermal ornithine decarboxylase activity by tumor promoters. Citral treatment inhibited the ability of retinol, but not of retinoic acid, to induce epidermal hyperplasia. Similarly, citral treatment decreased the ability of retinol, but not of retinoic acid, to inhibit the induction of epidermal ornithine decarboxylase activity by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Although citral had little effect on epidermal ornithine decarboxylase activity when applied alone, it potentiated the induction of ornithine decarboxylase activity by 12-O-tetradecanoylphorbol-13-acetate. The ability of citral to inhibit retinoic acid formation from retinol and the specificity of citral for inhibition of the biological activities of retinol but not retinoic acid are evidence that oxidation to retinoic acid is obligatory for the measured biological activities of retinol. Furthermore, the ability of citral to potentiate the induction of ornithine decarboxylase activity by 12-O-tetradecanoylphorbol-13-acetate suggests that modulation of the retinol oxidation pathway by such agents may enhance susceptibility to tumor promoters.

Topics: Acyclic Monoterpenes; Animals; Epidermis; Hyperplasia; Mice; Mice, Hairless; Monoterpenes; Ornithine Decarboxylase Inhibitors; Oxidation-Reduction; Terpenes; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin A

Twenty seven women with mild, moderate or severe cervical dysplasia proven by pathology were treated by retinamide RII suppository. Retinamide RII suppository, 10 mg QD, was given intravaginally for six months (three months as a course). Clinical examination, Papanicolaou cytology and tissue biopsy under colposcope were carried out before and after treatment. The results indicated that after the second course, 26 out of 27 patients responded; of them, precancerous lesions disappeared in 24 and even normal squamous epithelium was observed in 3. The overall response rate was 96.29% and the marked response rate was 88.89%. The general side effects were mild. There was little cervical and vaginal irritation which was well tolerated. The results of this clinical trial make available a practical base for chemoprevention of cervical cancer.

Topics: Antineoplastic Agents; Cervix Uteri; Female; Humans; Hyperplasia; Precancerous Conditions; Suppositories; Tretinoin; Uterine Cervical Neoplasms

We report the case of a young man with extreme sebaceous gland hyperplasia that occurred in a diffuse pattern of aggregated papular lesions involving the entire face, neck and upper chest, together with marked seborrhoea oleosa. Oral therapy with 13-cis-retinoic acid (isotretinoin) resulted in remarkable improvement within a few weeks. Parallels from our case are drawn to familial sebaceous hyperplasia, reported by Dypre et al. in 1980 [6], and to a case of a young man with severe sebaceous gland hyperplasia and facial seborrhoea, reported by de Villez et al. in 1982. We suggest that these types of seboglandular proliferative disorders be classified as diffuse (presenile) sebaceous gland hyperplasia in contrast to the well-defined senile circumscribed variant, and that they be regarded as a separate entity.

Topics: Adult; Humans; Hyperplasia; Isotretinoin; Male; Sebaceous Glands; Skin Diseases; Tretinoin

All-trans-retinoic acid formation from topically applied retinol has been demonstrated in the skin of skh/hr1 (hairless) mice. The all-trans-retinoic acid was identified on the basis of its chromatographic properties on HPLC at various pH values, its photoisomerization to reaction products identical to those formed from authentic all-trans-retinoic acid, and its co-chromatography with methyl retinoate after methylation with diazomethane. Topically applied retinol is about 2-fold less potent at inducing epidermal hyperplasia and 7-fold less potent at inhibiting the induction of epidermal ornithine decarboxylase by phorbol esters than all-trans-retinoic acid in this strain of mice. To elucidate the possible role all-trans-retinoic acid formation from retinol may have in these pharmacological activities, the epidermal and dermal all-trans-retinoic acid levels were compared in mice treated topically with retinol or [11-3H]-all-trans-retinoic acid. The levels of all-trans-retinoic acid found after retinol treatment were several orders of magnitude lower than those found after [11-3H]-all-trans-retinoic acid treatment, and they were insufficient to account for the difference in potencies between all-trans-retinoic acid and retinol. Retinol was eliminated from the epidermis at a rate similar to that of all-trans-retinoic acid after topical administration, but the initial tissue levels achieved were lower. These results suggest that the lower potencies of retinol may simply reflect lower tissue uptake.

Topics: Animals; Chromatography, High Pressure Liquid; Enzyme Induction; Epidermis; Female; Half-Life; Hydrogen-Ion Concentration; Hyperplasia; Mice; Mice, Hairless; Ornithine Decarboxylase; Skin; Spectrophotometry; Tretinoin; Vitamin A

The effects of daily topical application onto guinea pig ears of a therapeutic concentration of all trans-retinoic acid (RA) on epidermal thickness and dermal collagen and glycosaminoglycan (GAG) biosynthesis rates were studied during a 40-day period. Clinically, the RA-treated skin became erythematous and scaly beginning at 5-6 days, conditions which persisted throughout the experiment. The epidermis became thickened and hyperplastic with marked psoriasi-form histologic features, and the phenomenon was dependent on RA concentration. The initial hyperplasia resulted from a transient 4-fold increase in epidermal basal cell replication during the first 3-4 days, as shown by the rise and fall of [3H]thymidine labeling index which preceded the hyperplasia. The extent of epidermal hyperplasia as measured by epidermal thickness was not constant throughout the 40-day treatment period, but exhibited maxima on days 11, 25, and 36. These maxima were followed by periods of decreased thickness, although the minima were always greater than the untreated controls. Retinoic acid induced similar temporal cycles in GAG and collagen biosynthesis rates, but the collagen cycles occurred at different times with maxima on days 6, 20, and 34. After 8 weeks' treatment, the blood flow rates in the ear microcirculation (laser Doppler photometry) were increased 81% above that of the water-treated controls. The demonstration of these RA-induced cyclic changes in epidermal hyperplasia and dermal fibroblast biosynthetic activities have revealed the presence of control mechanisms in these tissues which normally operate to maintain tissue homeostasis.

Topics: Animals; Collagen; Epidermis; Glycosaminoglycans; Guinea Pigs; Homeostasis; Hyperplasia; Male; Microcirculation; Periodicity; Skin; Tretinoin

Hyperplasia of sebaceous glands is a common cause of papulonodular facial lesions that occur in middle-aged and older patients. Recently, several cases of premature sebaceous gland hyperplasia have been reported. In these patients the lesions had persisted despite vigorous attempts at therapy. We present a case of premature sebaceous gland hyperplasia that was successfully treated with isotretinoin.

Topics: Adult; Dermatologic Agents; Humans; Hyperplasia; Isotretinoin; Male; Sebaceous Glands; Skin Diseases; Tretinoin

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Dexamethasone; DNA Replication; Hyperplasia; Indomethacin; Mice; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Two cases of diffuse multiple lesions of sebaceous hyperplasia of the face are reported. The results of both medical and surgical therapies had been unsatisfactory. The patients were treated with low dose systemic isotretinoin (13-cis-retinoic acid) which resulted in complete clearing in one case and substantial clearing in the second. We suggest that in those patients cosmetically bothered by diffuse multiple lesions of sebaceous hyperplasia, for which other therapies are unsuccessful or unamenable to the patient, isotretinoin offers a safe, rational therapeutic option.

Topics: Aged; Facial Dermatoses; Humans; Hyperplasia; Isotretinoin; Male; Middle Aged; Sebaceous Glands; Skin Diseases; Tretinoin

Ultraviolet (UV) irradiation induces excessive accumulations of elastic fibers in animal and human skin. Collagen is damaged and glycosaminoglycans are vastly increased. Formerly considered an irreversible change, we recently showed, post-irradiation, that a band of normal connective tissue was laid down subepidermally . Because of its ability to stimulate fibroblasts and enhance healing of wounds, we thought it likely that retinoic acid (RA) would promote the formation of this subepidermal zone of reconstruction. Hairless mice were irradiated for 10 weeks with Westinghouse FS20 sunlamps for a total UV dose of 7 J/cm2. Then, 0.05% RA was applied for 5 and 10 weeks. Observations were made by light and electron microscopy. In contrast to controls treated with vehicle, the reconstruction zone was significantly wider in RA-treated mice. The enhanced repair was dose related. Histochemically and ultrastructurally, collagen was normal, fibroblasts were numerous and in a configuration of high metabolic activity.

Topics: Animals; Connective Tissue; Hyperplasia; Mice; Mice, Nude; Radiation Injuries, Experimental; Radiation-Protective Agents; Skin; Tretinoin; Ultraviolet Rays

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Benzoates; Cell Differentiation; Cell Division; Guinea Pigs; Humans; Hyperplasia; In Vitro Techniques; Isotretinoin; Neoplasms, Experimental; Rabbits; Retinoids; Skin; Skin Neoplasms; Tretinoin; Vitamin A

The rate of cell proliferation in the basal cell layer by epidermal hyperplasia of guinea pig ear was investigated with cytofluorometric method. Epidermal hyperplasia was caused by tape stripping or the application of n-hexadecane or retinoic acid. In non-treated epidermis, the mean of the relative numbers of cell in each phase to the total cell number was 62.8% (G1), 34.6% (S) and 2.6% (G2 + M), respectively. In the case of tape stripping, growth in the relative number of S phase cells showed approximately the same proportions at 3 to 12 h. At 24 h, the relative number of S phase cells was lower than that in non-treated epidermis. By the application of n-hexadecane, the relative number of S phase cells was highest at 6 h. It was highest at 3 h by the retinoic acid application. On the other hand, the value of nuclear protein in G1 cells was highest at 6 h by both tape stripping and n-hexadecane application, while the value by retinoic acid was similar to that in non-treated epidermis.

Topics: Alkanes; Animals; Cell Division; Cell Nucleus; DNA; Epidermis; Flow Cytometry; Guinea Pigs; Hyperplasia; Male; Tretinoin

There is a correlation between the ability to induce the polyamine-biosynthetic enzyme ornithine decarboxylase (ODC) and the tumor-promoting ability of various carcinogens in mouse epidermis. Some agents which inhibit skin carcinogenesis also inhibit ODC induction. In this study, all-trans-retinoic acid (RA) regimens that inhibited the induction of epidermal ODC by ultraviolet-B (UVB) were tested for their ability to inhibit UVB skin carcinogenesis. Hairless mice were irradiated once daily with UVB for 20 days, receiving a total dose of UVB (17.1 kJ/sq m). Topical RA was applied immediately (RA, one dose) or applied 0, 1, 2, 3, and 4 hr (RA, five doses) after each irradiance. The mice were maintained for 52 weeks and then sacrificed. Groups treated with RA tended to have fewer mice with tumors, fewer tumors per mouse, smaller tumor diameters, and slower growing tumors than did appropriate irradiated control groups. RA given five times was more effective than was RA given one time at inhibiting UVB skin carcinogenesis. These results show that RA treatments that inhibit epidermal ODC induction may be effective in reducing the carcinogenicity of UVB.

Topics: Animals; Carboxy-Lyases; Enzyme Induction; Female; Hyperplasia; Mice; Ornithine Decarboxylase; Skin; Skin Neoplasms; Time Factors; Tretinoin; Ultraviolet Rays

In order to investigate the role that hyperplasia plays in the induction of the keratin modifications by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), the effects of several inhibitors of tumor promotion and cycloheximide on the TPA-induced protein changes were studied. The antiinflammatory steroid fluocinolone acetonide and cycloheximide, which prevent the induction of hyperplasia, were found to prevent the appearance of the TPA-induced keratin modifications. Retinoic acid and tosylphenylalanylchloromethyl ketone, which have minor influence on hyperplasia, were found to have essentially no effect on these protein changes. These results provided further evidence that the TPA-induced epidermal keratin changes were associated with the induction of hyperplasia by TPA and not necessarily related to promoting ability.

Topics: Animals; Carcinogens; Cycloheximide; Electrophoresis, Polyacrylamide Gel; Epidermis; Female; Fluocinolone Acetonide; Hyperplasia; Keratins; Mice; Molecular Weight; Phorbols; Skin; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

Topics: Female; Humans; Hyperplasia; Isotretinoin; Middle Aged; Sebaceous Glands; Skin Diseases; Tretinoin

A study was conducted to investigate the in vitro binding affinity of new synthetic polyprenoids to cellular retinoid-binding proteins. Among 10 synthetic polyprenoic acid derivatives, 3,7,11,15-tetramethyl-2,4,6,10,14 hexadecapentaenoic acid (compound 1) was found to have the strongest binding affinity to cellular retinoic acid-binding protein (CRABP) from rat testis. As regards the chemical structure of the polyprenoic acids, it was found that suitable carbon chain length and double bond arrangement are both essential for binding affinity to CRABP. Moreover, compound I displayed a binding affinity to cellular retinoid receptors obtained from precancerous tissues such as mouse skin papillomas and rat liver hyperplastic nodules experimentally induced.

Topics: Animals; Binding, Competitive; Cell Fractionation; Chemical Phenomena; Chemistry; Diterpenes; Female; Hyperplasia; Liver; Male; Mice; Papilloma; Precancerous Conditions; Rats; Rats, Inbred Strains; Retinol-Binding Proteins; Terpenes; Testis; Tretinoin

Topics: Animals; DNA; Epidermis; Female; Hyperplasia; Hypertrophy; Mice; Skin; Time Factors; Tretinoin; Ultraviolet Rays

The inhibitory effect of an aromatic retinoic acid analog, ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate, on bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was evaluated. Administration of 50 ppm of aromatic retinoid in the diet before BBN in the drinking water reduced the incidence of papillary or nodular hyperplasia as a preneoplastic lesion of the bladder epithelium (P < 0.05). When given before, during or after BBN, it also greatly reduced the incidence of papilloma (P < 0.001 before BBN, P < 0.01 during or after BBN treatment), and slightly inhibited the development of cancer. Administration of 100 ppm of aromatic retinoid before or during BBN administration also reduced the incidences of papillary or nodular hyperplasia (P < 0.01 before BBN, P < 0.05 during BBN treatment), and its administration before, during or after BBN treatment greatly reduced the incidences of papilloma (P < 0.001), and cancer (P < 0.01 before or after BBN, P < 0.001 during BBN treatment). Similar results were obtained by assessing the effect of the retinoid on the average numbers of various epithelial lesions per 10 cm length of basement membrane of the bladder in tissue slices. These results show that the aromatic retinoid inhibits both the initiation and promotion of bladder carcinogenesis induced in rats by BBN, and that its effect is dose-dependent.

Topics: Animals; Butylhydroxybutylnitrosamine; Cricetinae; Etretinate; Hyperplasia; Male; Mice; Nitrosamines; Papilloma; Precancerous Conditions; Rats; Tretinoin; Urinary Bladder; Urinary Bladder Neoplasms

The effects of 3-methylcholanthrene (MCA) and retinoic acid (RA) on the fine structure of AKR mouse prostate epithelium in organ culture were correlated with changes in cell proliferation. In intact glands before explantation, the epithelial cytoplasm showed concentric flat or globular cisternae of endoplasmic reticulum in both supranuclear and basal areas, a well-developed Golgi complex, secretory vesicles, and numerous microvilli at the luminal surface. After explantation, the cytoplasmic organelles, particularly the endoplasmic reticulum, regressed and tonofilaments appeared. The regression was largely prevented by RA. MCA induced considerable epithelial hyperplasia and squamous metaplasia. The fine structure of the newly formed cells revealed a complete loss of endoplasmic reticulum, Golgi apparatus, secretory vesicles, and microvilli, with the appearance of bundles of tonofilaments and a striking increase in the number of desmosomes. Administration of RA to explants pretreated with the carcinogen partially reversed the hyperplasia and squamous metaplasia. The tonofilaments disappeared and the number of desmosomes greatly decreased, whereas endoplasmic reticulum, Golgi complex, secretory vesicles, and microvilli were largely reestablished. Planimetric measurements of the alveolar epithelium showed that the squamous transformation and its partial reversal by RA coincide with the rise and decline of epithelial hyperplasia. The data suggest that the restoration of secretory differentiation by RA was responsible for the initial breakdown of the hyperplastic epithelium, whereas the lowering of DNA synthesis by RA prevented further hyperplasia and kept cell replication within normal limits.

Topics: Animals; Cell Differentiation; Epithelium; Hyperplasia; Male; Methylcholanthrene; Mice; Mice, Inbred AKR; Microscopy, Electron; Organ Culture Techniques; Prostate; Tretinoin; Vitamin A

Topics: Animals; Cell Division; Hyperplasia; Male; Mice; Organ Culture Techniques; Prostatic Hyperplasia; Testosterone; Tretinoin; Vitamin A

Topics: Animals; Cell Division; Drug Eruptions; Guinea Pigs; Humans; Hyperplasia; Ointments; Petrolatum; Skin; Sulfur; Tretinoin

The antihyperplastic activity of beta-retinoic acid (RA) and nine synthetic analogues (retinoids) was examined in organ cultures of mouse prostate made hyperplastic by treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 8 or 10 days, when most explants developed hyperplasia, the carcinogen was withdrawn and explants were incubated in control medium and medium containing different concentrations of a retinoid. The antimitotic activity of retinoids was compared with that of RA. Different retinoids produced variable degrees of mitotic inhibition in the hyperplastic prostate epithelium. The methylketo cyclopentenyl and 1-methoxyethyl cyclopentenyl analogues of RA were at least 50-fold more active than RA in reversing MNNG-induced hyperplasia. The trimethylmethoxyphenyl analogue of RA and retinyl methyl ether were significantly more active than RA. Three analogues, N-acetyiretinylamine, retinal acetyl hydrazone, and retinal oxime, were as active as RA. The chlorotrimethylphenyl analogue showed less activity than RA, and alpha-retinyl acetate was completely devoid of mitotic inhibitory activity.

Topics: Cell Division; Epithelium; Hyperplasia; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Organ Culture Techniques; Precancerous Conditions; Prostate; Prostatic Neoplasms; Structure-Activity Relationship; Tretinoin; Vitamin A

The effect of beta-retinoic acid (RA) on carcinogen-induced hyperplasia was studied in organ cultures of mouse prostate gland. 3-Methylcholanthrene (MCA), requiring metabolic activation, or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), not requiring activation, were used to induce hyperplastic changes. Treatment of cultures with MCA or MNNG stimulated cell proliferation and caused the alveolar epithelium to become hyperplastic. The development of this hyperplasia was inhibited when RA was added simultaneously with MCA or MNNG. However, RA had no significant effect on cell proliferation in untreated control cultures. Elimination of carcinogen from the hyperplastic cultures after 8 days of treatment did not reverse hyperplasia of the alveolar epithelium. When the withdrawal of MCA or MNNG was followed by treatment of the cultures with RA, hyperplasia was markedly reversed within 96 hours. Thus RA actively inhibited and reversed the effect of MCA and MNNG, two carcinogens that may have different mechanisms of action.

Topics: Animals; Cell Division; Epithelial Cells; Epithelium; Hyperplasia; Male; Methylcholanthrene; Methylnitronitrosoguanidine; Mice; Organ Culture Techniques; Prostate; Prostatic Diseases; Time Factors; Tretinoin; Vitamin A

The influence of vitamin A-related compounds on hyperplasia and metaplasia induced by methylcholanthrene was studied in mouse prostate glands in organ culture. Methylcholanthrene was found to cause extensive hyperplasia and squamous metaplasia of the prostatic epithelium which persisted after withdrawal of the carcinogen. The retinoids included retinoic acid and 6 of its structural analogues synthesized in an attempt to enhance the anticarcinogenic action and reduce the toxicity of the parent compound. These where the cyclopentenyl analogus 7699, A2-retinoic acid, 13-cis-alpha-retinoic acid and 3 aromatic analogues. Administration of the compounds following the carcinogen reduced the extent and incidence of hyperplasia significantly and with the exception of one compound reversed the squamous metaplasia. Two of the aromatic analogues, one with a terminal ethylamide group (1430), and the other with a terminal ethylester group (9369), proved to be the most potent inhibitors, followed by compound 7699 and (9369), proved to be the most potent inhibitors, followed by compound 7699 and retinoic acid. A2-retinoic acid and 13-cis-alpha-retinoic acid showed the lowest activity. The inhibition of hyperplasia appeared to be mediated via a reduction of DNA synthesis. It seemed unrelated to either the biological growth-promoting activity of the compounds or their surface-active properties. It is tentatively suggested that vitamin A and its analogues may act as hormones.

Topics: Animals; DNA; Hyperplasia; In Vitro Techniques; Male; Metaplasia; Methylcholanthrene; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Prostate; Prostatic Neoplasms; Thymidine; Tretinoin; Vitamin A