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Normal differentiation and proliferation of cells are essential for maintaining homeostasis. Following the successful completion of whole genome sequencing, protein modification has been attracted increasing attention in order to understand the roles of protein diversification in protein function and to elucidate molecular targets in mechanisms of signal transduction. Vitamin A is an essential nutrient for health maintenance. It is present as β-carotene in green and yellow vegetables and retinyl ester in animal products and absorbed into the body from the intestines. After ingestion, it is converted to retinol and oxidized in target cells to retinal, which plays critical roles in vision. It is then further oxidized to retinoic acid (RA), which exhibits a number of effects prior to being metabolized by cytochrome P450 and excreted from the body. Since RA exhibits cell differentiation-inducing actions, it is used as a therapeutic agent for patients with acute promyelocytic leukemia. The current paper describes: (1) HL60 cell differentiation and cell differentiation induction therapy by RA; (2) roles played by RA and retinal and their mechanisms of action; (3) retinoylation, post-translational protein-modified by RA, a novel non-genomic RA mechanism of action without RA receptor; (4) new actions of β-carotene and retinol in vivo and (5) potent anticancer effects of p-dodecylaminophenol (p-DDAP), a novel vitamin A derivative created from the RA derivative fenretinide. We propose that nutritional management of vitamin A can be effective at preventing and treating diseases, and that p-DDAP is a promising anticancer drug.

Objective: The goal of this 12 week, double-blinded, controlled, clinical study was to compare the efficacy, tolerability, and consumer acceptance of three novel retinol serums to tretinoin., Method: Forty-five photoaged females ages 35-65, Fitzpatrick skin types I-IV, with moderate wrinkling were enrolled in the 12-week study. A step-up protocol for increasing the dose of retinol serum (0.25%, 0.5%, 1.0%) or tretinoin cream (0.025%, 0.05%, and 0.1%) in combination with a test moisturizer or currently marketed dermatologist-recommended moisturizing cream was used. Overall severity of investigator graded photodamage, subject assessed photodamage, and tolerability criteria were evaluated using a 5-point ordinal scale at weeks 4, 8, and 12. Facial photography occurred at each visit and TEWL was measured at baseline and week 12. Histologic evaluation of punch biopsies was completed on baseline and week 12 samples., Results: After 12 weeks of use, both retinol serum and tretinoin demonstrated parity across investigator and subject assessment measurements as well as diagnostic measures including TEWL. Retinol serum subjects showed significant week 4 improvement in visual skin smoothness compared to tretinoin subjects (P=0.031). There was highly significant improvement in skin dryness with the retinol serum (P<0.001) not seen in the tretinoin group. Histologic analysis of baseline and 12-week punch biopsies demonstrated newly formed collagen and greater epidermal thickening in retinol serum subjects compared to tretinoin treated subjects., Conclusion: Retinol serum (0.25%, 0.5%, 1.0%) was safe and effective with equivalent/or better performance and tolerability than tretinoin creams. J Drugs Dermatol. 2020;19(6): doi:10.36849/JDD.2020.5085.

Our previous studies demonstrated that vitamin A deficiency (VAD) can impair the postnatal cognitive function of rats by damaging the hippocampus. The present study examined the effects of retinoic acid (RA) on apoptosis induced by hypoxic-ischemic damage in vivo and in vitro, and investigated the possible signaling pathway involved in the neuroprotective anti-apoptotic effects of RA. Flow cytometry, immunofluorescence staining and behavioral tests were used to evaluate the neuroprotective and anti-apoptotic effects of RA. The protein and mRNA levels of RARα, PI3K, Akt, Bad, caspase-3, caspase-8, Bcl-2, Bax, and Bid were measured with western blotting and real-time PCR, respectively. We found impairments in learning and spatial memory in VAD group compared with vitamin A normal (VAN) and vitamin A supplemented (VAS) group. Additionally, we showed that hippocampal apoptosis was weaker in the VAN group than that in VAD group. Relative to the VAD group, the VAN group also had increased mRNA and protein levels of RARα and PI3K, and upregulated phosphorylated Akt/Bad levels in vivo. In vitro, excessively low or high RA signaling promoted apoptosis. Furthermore, the effects on apoptosis involved the mitochondrial membrane potential (MMP). These data support the idea that sustained VAD following hypoxic-ischemic brain damage (HIBD) inhibits RARα, which downregulates the PI3K/Akt/Bad and Bcl-2/Bax pathways and upregulates the caspase-8/Bid pathway to influence the MMP, ultimately producing deficits in learning and spatial memory in adolescence. This suggests that clinical interventions for HIBD should include suitable doses of VA.

Background: Topical retinoids are used to treat the visible signs of photoaging. While efficacious, they are irritating., Objective: Evaluate the effectiveness and tolerability of a double-conjugate retinoid cream (AlphaRet Overnight Cream; AHA-Ret) in improving visible signs of photoaging vs 1.0% retinol or 0.025% tretinoin., Methods: A 12-week, split-face, randomized trial was conducted in 48 female subjects, aged 30-65 years with mild to severe photodamage. AHA-Ret was applied to one side of the face and either retinol (n=24) or tretinoin (n=24) to the other side (PM). Expert blinded evaluation of images and Nova measurements occurred at 4, 8, and 12 weeks. Tolerability was assessed throughout the study., Results: Forty-seven subjects completed the study. AHA-Ret demonstrated significant reductions in average severity from baseline: Fine Lines/Wrinkles (P<.001; all time points); Erythema (P=.004, P<.0001; 8 and 12 weeks, respectively); Dyschromia (P<.0001; all time points); Skin Tone (P<.0001; all time points), and Pore Size (P=.035, P<.0001; 8 and 12 weeks, respectively). AHA-Ret induced less Erythema vs retinol at 8 (P=.008) and 12 (P<.02) weeks. AHA-Ret was noninferior to prescription tretinoin in all categories at 4 and 8 weeks, and for Fine Lines/Wrinkles, Erythema, Dyschromia, and Skin Tone at 12 weeks. Improvements in Hydration occurred at every time point with AHA-Ret only (P<.04, P<.03, P<.01). Less irritation was reported with AHA-Ret vs retinol or tretinoin., Conclusions: Treatment with a double-conjugate retinoid cream demonstrated early reductions in photodamage and improvements in Hydration. AHA-Ret induced less Erythema vs retinol and was more tolerable vs retinol and tretinoin., (© The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc.)

Preterm infants exposed to supra-physiological levels of oxygen often have poor executive and memory function associated with reductions in hippocampal volume later in life. We recently showed that adult mice exposed to neonatal hyperoxia have deficits in spatial navigation and increased exploratory behavior associated with hippocampal shrinkage. Retinoids attenuate hyperoxia-induced lung injury in animal models and reduce neonatal chronic lung disease in preterm infants. We hypothesized that retinoid (combination of Vitamin A+Retinoic Acid [VARA]) administration in mice during neonatal hyperoxia would attenuate oxygen-induced cognitive impairment when assessed in adult life. C57BL/6 mouse pups were exposed to hyperoxia (85% oxygen) or air (21% oxygen), in combination with VARA or canola oil (Vehicle) from postnatal day 2 to 14 and then returned to air. Neurobehavioral (Morris water maze, open field and zero maze tests), structural assessments (MRI and histology), and hippocampal protein measurements were performed. Neonatal hyperoxia resulted in spatial navigation deficits and increased exploratory behavior and accompanied by hippocampal shrinkage in adults, all of which were attenuated by VARA administration. During hyperoxia, VARA increased hippocampal phosphorylated and total mammalian target of rapamycin, and synaptophysin levels to a greater extent in hyperoxia compared to normoxia. In conclusion, VARA attenuated neonatal hyperoxia-induced neurobehavioral impairment and associated reductions in hippocampal volume in adult mice, possibly by increasing mTOR signaling and synaptic density. These novel data suggest that retinoids may be neuroprotective in extremely preterm infants at high risk of impairment, and may potentially be effective in other models of oxidant stress as well., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to explore the involvement of retinoids in the hypoactivity and hyporeactivity to stress of the hypothalamic-pituitary-adrenal (HPA) axis in LOU/C rats. We measured the effects of vitamin A deficiency administered or not with retinoic acid (RA) on plasma corticosterone in standard conditions and in response to restraint stress and on hypothalamic and hippocampal expression of corticosteroid receptors, corticotropin-releasing hormone and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in LOU/C rats. Interestingly, under control conditions, we measured a higher plasma concentration of retinol in LOU/C than in Wistar rats, which could contribute to the lower basal activity of the HPA axis in LOU/C rats. Vitamin A deficiency induced an increased HPA axis activity in LOU/C rats, normalized by RA administration. Compared with LOU/C control rats, vitamin A-deficient rats showed a delayed and heightened corticosterone response to restraint stress. The expression of corticosteroid receptors was strongly decreased by vitamin A deficiency in the hippocampus, which could contribute to a less efficient feedback by corticosterone on HPA axis tone. The expression of 11β-HSD1 was increased by vitamin A deficiency in the hypothalamus (+62.5%) as in the hippocampus (+104.7%), which could lead to a higher production of corticosterone locally and contribute to alteration of the hippocampus. RA supplementation treatment restored corticosterone concentrations and 11β-HSD1 expression to control levels. The high vitamin A status of LOU/C rats could contribute to their low HPA axis activity/reactivity and to a protective effect against 11β-HSD1-mediated deleterious action on cognitive performances during ageing.

We have recently shown that a combination of vitamin A (VA) and retinoic acid (RA) in a 10:1 molar ratio (VARA) synergistically increases lung retinoid content in newborn rodents, more than either VA or RA alone in equimolar amounts. We hypothesized that the increase in lung retinoids would reduce oxidative stress and proinflammatory cytokines, resulting in attenuation of alveolar simplification and abnormal lung function in hyperoxia-exposed newborn mice. Newborn C57BL/6 mice were exposed to 85% O₂ (hyperoxia) or air (normoxia) for 7 or 14 days from birth and given vehicle or VARA every other day. Lung retinol content was measured by HPLC, function was assessed by flexiVent, and development was evaluated by radial alveolar counts, mean linear intercept, and secondary septal crest density. Mediators of oxidative stress, inflammation, and alveolar development were evaluated in lung homogenates. We observed that VARA increased lung retinol stores and attenuated hyperoxia-induced alveolar simplification while increasing lung compliance and lowering resistance. VARA attenuated hyperoxia-induced increases in DNA damage and protein oxidation accompanied with a reduction in nuclear factor (erythroid-derived 2)-like 2 protein but did not alter malondialdehyde adducts, nitrotyrosine, or myeloperoxidase concentrations. Interferon-γ and macrophage inflammatory protein-2α mRNA and protein increased with hyperoxia, and this increase was attenuated by VARA. Our study suggests that the VARA combination may be a potential therapeutic strategy in conditions characterized by VA deficiency and hyperoxia-induced lung injury during lung development, such as bronchopulmonary dysplasia in preterm infants.

Vitamin A (VA) and its active form, retinoic acid (RA), are regulators of skeletal development. In the present study, we investigated if maternal VA intake during pregnancy and lactation, as well as direct oral supplementation of neonates with VA + RA (VARA) in early life, alters neonatal bone formation and chondrocyte gene expression. Offspring of dams fed 3 levels of VA (marginal, adequate, and supplemented) for 10 wk were studied at birth (P0) and postnatal day 7 (P7). One-half of the newborns received an oral supplement of VARA on P1, P4, and P7. Tissues were collected on P0 and 6 h after the last dose on P7. Pup plasma and liver retinol concentrations were increased by both maternal VA intake and VARA (P < 0.01). Although maternal VA did not affect bone mineralization as assessed by von Kossa staining, newborn femur length was increased with maternal VA (P < 0.05). VARA supplementation of neonates increased the length of the hypertrophic zone only in VA-marginal pups, close to that in neonates from VA-adequate dams, suggesting VARA caused a catching up of growth that was limited by low maternal VA intake. Maternal diet did not alter type X nor type II collagen mRNA. However, VARA-treated pups from VA-supplemented dams had reduced mRNA for aggrecan, a major component of cartilage matrix, and increased mRNA for matrix metalloproteinase (MMP)13, which catalyzes the degradation of aggrecan and collagens. These results suggest that moderately high maternal VA intake combined with neonatal VARA supplementation can reduce the ratio of aggrecan:MMP, which may unfavorably alter early bone development.

Recent investigations have demonstrated that elevated serum retinol-binding protein 4 (RBP4) secreted from adipose tissue plays a role in the development of systemic insulin resistance, and lowering RBP4 improves insulin sensitivity. These observations provide a rationale for the development of new antidiabetic agents aimed at reducing serum RBP4 concentrations. In this study, we sought to determine whether retinoic acid (RA) administration decreases serum RBP4 and suppresses insulin resistance in diabetic ob/ob mice. All-trans RA [100 mug/(moused) in corn oil] was administered by stomach intubation to a group of ob/ob mice, with the control group receiving the vehicle for 16 d. Body weight and food intake were monitored. Glucose and insulin tolerance tests were performed. We quantified serum RBP4 and retinol by Western blotting and HPLC, respectively. RA treatment reduced body weight (P < 0.05), basal serum glucose (P < 0.001), serum retinol (P < 0.01), and RBP4 (P < 0.05). It improved insulin sensitivity and decreased the retinol:RBP4 ratio (P < 0.05). These studies suggest that RA is an effective antidiabetic agent that could be considered in the treatment of type 2 diabetes.

Background: Near-infrared reflectance confocal microscopy (RCM) is a noninvasive tool that provides real-time images of thin virtual horizontal tissue sections., Aims/methods: We have used a rhino mouse model in combination with topical application of all-trans-retinoic acid and all-trans-retinol to investigate the usefulness of RCM as a noninvasive imaging tool to evaluate comedolysis in vivo and over time. Optical images were correlated with routine histology., Results: Our results demonstrate that RCM in vivo can visualize the process of transformation of utriculi (pseudocomedones) towards a normal-appearing follicular structure during retinoid treatment. The retinoic acid intervention group showed a dose-related response, while the vehicle-treated group did not show utricular changes., Conclusions: RCM represents a useful tool for in vivo morphological and quantitative evaluation of skin utriculi over time and could be used as an adjunct tool to histopathological techniques for comedolysis studies.

Vitamin A (VA, retinol) is essential for normal immune system maturation, but the effect of VA(1) on antibody production, the hallmark of successful vaccination, is still not well understood. In countries where VA deficiency is a public health problem, many children worldwide are now receiving VA along with immunizations against poliovirus, measles, diphtheria, pertussis, and tetanus. The primary goal has been to provide enough VA to protect against the development of VA deficiency for a period of 4-6 months. However, it is also possible that VA might promote the vaccine antibody response. Several community studies, generally of small size, have been conducted in children supplemented with VA at the time of immunization, as promoted by the World Health Organization/UNICEF. However, only a few studies have reported differences in antibody titers or seroconversion rates due to VA. However, VA status was not directly assessed, and in some communities children were often breast fed, another strategy for preventing VA deficiency. Some of the vaccines used induced a high rate of seroconversion, even without VA. In children likely to have been VA deficient, oral polio vaccine seroconversion rate was increased by VA. In animal models, where VA status was controlled and VA deficiency confirmed, the antibody response to T-cell-dependent (TD) and polysaccharide antigens was significantly reduced, congruent with other defects in innate and adaptive immunity. Moreover, the active metabolite of VA, retinoic acid (RA) can potentiate antibody production to TD antigens in normal adult and neonatal animals. We speculate that numerous animal studies have correctly identified VA deficiency as a risk factor for low antibody production. A lack of effect of VA in human studies could be due to a low rate of VA deficiency in the populations studied or low sample numbers. The ability to detect differences in antibody response may also depend on the vaccine-adjuvant combination used. Future studies of VA supplementation and immunization should include assessment of VA status and a sufficiently large sample size. It would also be worthwhile to test the effect of neonatal VA supplementation on the response to immunization given after 6 months to 1 year of age, as VA supplementation, by preventing the onset of VA deficiency, may improve the response to immunizations given later on.

Within the last several years, research scientists and clinicians have been intrigued with the potential use of an active form of vitamin A, retinoic acid (RA), for the treatment and prevention of emphysema. The interest in this area can be largely attributed to the work of Massaro and Massaro (1996, 1997, 2000) in which they presented evidence that RA partially protects against and to some degree restores elastase-induced emphysema in rats. The mechanism for this protective effect of RA is in part related to elastin metabolism. RA also inhibits inflammation, an upstream event that may lead to the development of emphysema. Although there is evidence of this protective effect in young rats and a mechanistic explanation, more studies are needed in humans in order to establish a role for vitamin A in protecting against emphysema. Too many unanswered questions remain to definitively state that vitamin A protects against this disease in humans. Nevertheless, the potential for this novel approach in prevention and treatment of emphysema is an exciting area of research.

RPE65 is essential in the operation of the visual cycle and functions as a chaperone for all-trans-retinyl esters, the substrates for isomerization in the visual cycle. RPE65 stereospecifically binds all-trans-retinyl esters with a K(D) of 47 nM. It is shown here by using a quantitative fluorescence technique, that Accutane (13-cis-retinoic acid), a drug used in the treatment of acne but that causes night blindness, binds to RPE65 with a K(D) of 195 nM. All-trans-retinoic acid binds with a K(D) of 109 nM. The binding of the retinoic acids to RPE65 is competitive with all-trans-retinyl ester binding, and this competition inhibits visual cycle function. A retinoic acid analog that binds weakly to RPE65 is not inhibitory. These data suggest that RPE65 function is rate-limiting in visual cycle function. They also reveal the target through which the retinoic acids induce night blindness. Finally, certain forms of retinal and macular degeneration are caused by the accumulation of vitamin A-based retinotoxic products, called the retinyl pigment epithelium-lipofuscin. These retinotoxic products accumulate during the normal course of rhodopsin bleaching and regeneration after the operation of the visual cycle. Drugs such as Accutane may represent an important approach to reducing the accumulation of the retinotoxic lipofuscin by inhibiting visual cycle function. The identification of RPE65 as the visual cycle target for the retinoic acids makes it feasible to develop useful drugs to treat retinal and macular degeneration while avoiding the substantial side effects of the retinoic acids.

Objectives: Vitamin A and D(3) have a very strong differentiation induction effect., Study Design: We examined the anti tumor effect on head and neck squamous cell carcinoma (HNSCC) by treatment with several vitamins having strong differentiation induction effects in vitro., Methods: We used KB cell that an oral floor squamous cell carcinoma, vitamins as all-trans retinoic acid (ATRA), 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), 1alpha,25(OH)(2)D(3) (calcitriol) and 22-oxa-1,25-(OH)(2)D(3) (OCT). We determined receptors of vitamin A and D(3) using RT-PCR. Furthermore, we investigated the proliferation of tumor cells in concentration dependency using [3H]TdR uptake method, apoptosis and apoptosis related factors using TUNEL method and real-time PCR, cell cycle changes using flow cytometry, changing of the sensitivity of using MTT method, cytokine production and the angiogenesis factor using ELISA, by treatment with these vitamins., Results: The deficit of RAR-beta was found in the KB cell. Each vitamin suppressed the cell proliferation, induced apoptosis, and cell cycle arrest, upregulated sensitivity of the chemotherapeutics drugs and downregulated several angiogenesis factors and an apoptotic factor; survivin., Conclusions: These results support the idea that vitamin A, D(3) and their derivatives are useful for preventing and/or treating patients with HNSCC.

Topical retinoic acid was introduced for acne treatment three decades ago. Since that time, researchers have discovered thousands of retinoids, originally defined as chemical analogs of vitamin A. After the identification of nuclear retinoid receptors in 1987, the definition of this class expanded to include molecules that bind to and activate such receptors. The receptor-selective retinoid agents, adapalene and tazarotene, were developed in the 1990s. Other innovations of the past decade include retinoid formulations and methods aimed at limiting retinoid absorption. Cutaneous irritation may be reduced without losing retinoid efficacy by inhibiting retinoid penetration into the deep epidermis and dermis. Examples include tretinoin in slow-release vehicles and the short-contact method of tazarotene gel therapy. Only trace amounts of adapalene are absorbed after topical application, perhaps explaining its relatively low irritancy. New formulations of existing agents, such as additional concentrations of tretinoin in microsphere gel and cream formulations of tazarotene, are now under investigation for acne. Current research focused on receptor selectivity holds the promise of yielding new retinoid molecules with improved benefits and safety.

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

Background: Normal embryonic development and survival in utero is dependent on an adequate supply of vitamin A. Embryos from vitamin A-deficient (VAD) pregnant rats fed an inadequate amount of all-trans retinoic acid (atRA; 12 microg per g of diet or approximately 230 microg per rat per day) exhibit severe developmental abnormalities of the anterior cardinal vein and hindbrain by embryonic day (E) 12.5 and die shortly thereafter., Methods: In the present study, we sought to determine whether supplementation of VAD-RA supported (12 microg per g of diet) pregnant rats with retinol (ROL) at the late-gastrula (presomite or rat E9.5) or early somite stages (E10.5), or provision of higher levels of atRA throughout this period could prevent abnormalities in the developing cardiovascular and nervous systems., Results: A newly described defect in the sinuatrial venus valve along with enlarged anterior cardinal veins and nervous system abnormalities and the later death of embryos are prevented by supplementing pregnant animals with ROL on the morning of E9.5. If ROL supplementation is delayed by 1 day (E10.5), most embryos are abnormal and die by E18.5. Supplementation of VAD rats with atRA (250 microg per g of diet) between E8.5 and E10.5 also prevents the cardiovascular and nervous system abnormalities and a significant number of these embryos survive to parturition. Thus, high levels of atRA can obviate the need for ROL between E9.5 and E10.5., Conclusions: These results support an essential role for retinoid signaling between the late gastrula and early somite stages in the rat embryo for normal morphogenesis of the primitive heart tube and the posterior hindbrain. Further, these results suggest that embryonic death occurring at midgestation in the VAD rat may be linked to the abnormal development of one or both of these embryonic structures., (Copyright 2000 Wiley-Liss, Inc.)

Retinoyl beta-glucuronide is a naturally occurring, biologically active metabolite of vitamin A. Although retinoyl beta-glucuronide is regarded as a detoxification product of retinoic acid, it plays several roles in the functions of vitamin A. It can serve as a source of retinoic acid, and it may be a vehicle for transport of retinoic acid to target tissues. Topically applied retinoyl beta-glucuronide is comparable in efficacy to retinoic acid in the treatment of acne in humans, without the same side effects. Retinoyl beta-glucuronide may or may not be teratogenic, depending on the mode of administration and the species in which it is used. It may be a valuable therapeutic compound for the treatment of skin disorders and certain types of cancers.

Vitamin A-deficient, pregnant rats resorb their fetuses around Day 15 of gestation even when given retinoic acid (RA) daily. This resorption is prevented by the administration of retinol. Retinol was found to be required no later than Day 10 of gestation, and up to 500 micrograms of retinol administered on Day 11 or later was not able to change the course of fetal resorption in these animals. Vitamin A-deficient pregnant rats supported on 40 micrograms all-trans-RA daily that are given 2 micrograms of retinol on Day 10 and then placed on a retinol-sufficient diet at 24 h after administration of the retinol dose gave birth to normal pups. When a single 2-micrograms dose of retinol was administered on Day 10 and the vitamin A-deficient, RA-supported animals continued on the deficient diet supplemented with RA, the fetal resorption did not occur and the fetuses appeared normal when examined on Day 20 of gestation. Experiments using radiolabeled retinol tracer indicated that while there was some accumulation of radioactivity through Day 14 in the fetus, the administered retinol was mostly eliminated from the animal by Day 16. Thus, retinol is clearly required by Day 10 for normal gestation.

Retinoids, which are derivatives of vitamin A, have a variety of effects on normal cellular differentiation and on the process of carcinogenesis. A number of novel endogenous retinol metabolites have been identified recently. The response of many cell types to retinoid treatment is mediated by retinoid receptors, and involves changes in gene expression, cell growth and cell differentiation. The gene encoding one of the retinoic acid receptors is disrupted by the chromosome translocations associated with acute promyelocytic leukemia, and the expression of another is altered in epithelial tumors; both of these findings have important implications for the use of retinoids as anti-carcinogenic agents. It has been demonstrated recently that certain homeobox genes are regulated by retinoids; these genes may also prove to be useful agents for anti-carcinogenic therapies.

Within the past few years, much has been learned about the metabolism and actions of vitamin A and the carotenoids. This article reviews the biochemical and cellular events in retinoid metabolism that lead to production of retinoic acid, an active metabolite of vitamin A. Retinoic acid functions in a hormone-like manner to regulate the expression of a number of genes. Beta carotene is now under study as an anticancer agent and for its possible beneficial effects in a number of chronic diseases. Current recommendations for carotene intake exceed the usual daily intake nearly fourfold.

The Vitamin A. derivatives known as Retinoids, are among the most exciting pharmacological agents used in the last few years. They strongly influence the keratinizing epithelia, have an antipromoting effect upon experimentally induced tumors and have immunomodulatory activities. Teratogenicity seems to be the most worrisome effect of the retinoids. However, it is reasonable to assume their release for physicians prescription in the near future. This review is intended to provide a general background for their correct use by dermatologists.

The clinical and histologic features of lifelong reactive perforating collagenosis in a twenty-five year old woman are presented. Experimentally induced lesions showed the expected evolution and regression, although total time for the experimental lesion to develop and regress was shorter than the time necessary for those occurring spontaneously. Therapeutic trials with a wide variety of topical and systemic medications were without benefit, with the exception of tretinoin cream (0.1 percent), which was regularly effective in reducing the total number of lesions present.

In a double-blind, randomized, group-comparative clinical trial, 31 patients with acne vulgaris received topical treatment for 6-8 weeks with a lotion containing either 0.05% retinoic acid or 0.1% of the retinoic acid derivative Ro 11-1430. The side-effects erythema, desquamation and burning were significantly less frequent with Ro 11-1430 than with retinoic acid. The treatments appeared to be approximately equally effective in reducing the number of acne elements, but due to the limited number of patients studied, the trial was admittedly not sufficient to detect differences with regard to therapeutic efficacy.

Oral retinoic acid successfully and rapidly helped two patients with erythrokeratoderma variabilis. Treatment had to be maintained to prevent recurrence and no side effects have been observed so far.

The properties of a new aromatic retinoic acid analog are described. The compound: all-trans-N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenamide = Ro 11-1430, exerts a therapeutic influence on chemically induced papillomas and carcinomas of the skin of mice. It leads to a marked regression of chemically induced epithelial tumors but does not inhibit the growth of transplantable tumors. The therapeutic use of retinoic acid and its analogs is limited by the appearance of the toxic side effects of the so-called hypervitaminosis A syndrome. The relationship between the anti-tumor activity and these toxic effects is considered a good inidicator for establishing the quality of a compound. The new retinoic acid analog posses a ten times more favorable therapeutic ratio than retinoic acid. The mechanism of action is discussed.

Ro 10-9359 is a retinoic acid derivative, selected for study because of a better tolerance than retinoic acid, shown in animal experiments. Earlier clinical experience has proved Ro 10-9359 to be an extremely potent antipsoriatic drug. The well-known association between psoriasis and pustulosis palmoplantaris was a motivation to evaluate Ro 10-9359 also in the last-mentioned disease, which is notoriously known to be resistant to treatment. In this study 30 patients were given either 75 mg/day of Ro 10-9359 or 200 mg twice every week according to a randomized pattern. All patients had suffered from the disease for at least 2 years without any spontaneous remission during the year preceding the trial. After a treatment period of about 2 weeks with Ro 10-9359 hyperkeratotic scales had usually disappeared, and 2 weeks later there were in general significantly less pustular lesions. The treatment continued for 8 weeks, and at this time the average reduction of the number of pustules was 80%. The daily dosage seemed to give better results and was also better tolerated than was the twice-weekly dosage. Side effects were common, but generally mild. On average, the remission lasted 1 month after cessation of therapy.

24 patients suffering from generalized lichen planus were treated systemically with a aromatic retinoid (RO 10-9359). Initially a dose of 100 mg retinoid per day was administered for 2 to 3 weeks, then the daily intake was reduced slowly. The average duration of treatment was 72 days. This therapy produced a significant improvement in all patients. Lesions recurred during reduction of administered retinoid in 3 patients and after stopping treatment in 5 cases. Initially side effects consisted of cheilitis and exfoliation of the skin over the palmar and plantar regions; later 50% of the patients developed an effluvium. The results of the present study indicate that the aromatic retinoid can be considered as an alternative drug to systemic steroids in the treatment of lichen planus.

In a patient with systematized verrucous epidermal nevus, marked improvement was obtained with oral administration of a new aromatic retinoid (Ro 10-9359). Mild cheilitis and thinning of scalp hair were the only side effects obser Withved. continuous treatment the good result was maintained for 10 months. Further investigation is needed to determine, whether long-term oral administration of this new drug is feasible.

The combined application of an oral retinoid (Ro 10-9359) and phototherapy with predominantly UVB radiation (Selective Ultraviolet Phototherapy=SUP) is a new, highly effective method of treating psoriasis. It has few side effects and can be performed on an out-patient basis. With the aid of this combined treatment we achieved good or very good improvement in 19 out of 23 patients with generalized psoriasis (=82.6%). The average number of radiation sessions required to achieve this was 22.9, and the mean total therapeutic dose (TTD) was 73 J/cm2. In a control group of 40 psoriasis patients, who received only radiation therapy, we achieved good or very good results in only 60% with an average of 26 radiation sessions and 94 J/cm2 TTD. The effect of the oral retinoid and UVB radiation therapy is apparently additive, since the retinoid does not increase the sensitivity of the skin to light.

According to the results obtained in a recent clinical trial over a four-year period retinoic acid represents the most effective single agent available for the topical management of acne vulgaris. Retinoic acid yields impressive therapeutic results not only in patients with manifest acne, but, provided it is applied early enough, it is also effective in preventing the severe inflammatory manifestations of this disease. In medium to severe cases of inflammatory acne, topical retinoic acid therapy should be combined with a low-dose, long-term systemic tetracycline regimen. The course of treatment may extend over months or years, depending on the severity of the condition. Particularly patients in the acne-prone age group are candidates for long-term therapy. Retinoic acid therapy, alone or in combination with tetracyclines, proved far superior to conventional regimens with respect to the effective treatment and prophylaxis of acne.

Thirteen patients with keratinising dermatoses were treated for 2-17 weeks with oral 13-cis retinoic acid. There was near complete clearing of the skin lesions beginning within 2 weeks of starting treatment in all five patients with lamellar ichthyosis (including two cases of non-bullous congenital ichthyosiform erythroderma), in two of the three patients with Darier's disease, and in one patient with pityriasis rubra pilaris. The patients with psoriasis and naevus comedonicus did not improve. The main form of toxicity was cheilitis. These results indicate that 13-cis retinoic acid may be more effective and is less toxic than naturally occurring retinoic acid (all-trans vitamin A acid), and that the synthetic retinoids may represent a potent new class of drugs in the treatment of cutaneous disease.

Tumorigenesis requires accelerated polyamine biosynthesis, and elevated levels of ornithine decarboxylase, the rate-limiting enzyme in this reaction chain. The primary goal of this study was to determine whether induction of oral cavity carcinoma by dimethylbenzanthracene was accompanied by increased ornithine decarboxylase. It has previously been demonstrated in an oral carcinogenesis model that cotreatment with vitamins A or E delayed tumor development. The second goal of this study was to determine whether this chemoprotective effect was associated with a decrease in ornithine decarboxylase activity. We found that dimethylbenzanthracene did stimulate ornithine decarboxylase. Vitamins A and E alone also stimulate ornithine decarboxylase, and this effect is additive with dimethylbenzanthracene. Use of both vitamins together prevents the additive effect of either, alone, and vitamin A inhibits the late-phase ornithine decarboxylase response to dimethylbenzanthracene in all animals. We conclude that pretreatment with vitamins A, or A and E together protects against the carcinogenic action of dimethylbenzanthracene, and that the mechanism of this protection is early truncation of the ornithine decarboxylase response to dimethylbenzanthracene.