tretinoin and temarotene

Human colorectal tumor cells expressing differing metastatic potential and tissue transglutaminase (TGA) activity were tested for the ability of various pharmacological agents to enhance TGA activity. The most effective stimulant was tetradecanoylphorbol-13-acetate (TPA), which in human colon carcinoma cells (SW620) caused a 5-fold, protein synthesis dependent increase in activity over 3 days. In WiDr and SW480 cells TGA activity was less susceptible to induction by TPA, possibly owing to the higher basal levels of TGA. Retinoic acid and a synthetic retinoid, [RO 15-1570; (E)-4-[2(5,6,7,8-tetramethylnaphthalene-2-yl)propen-1-yl] benzenesulphonyl-ethane)], also induced TGA activity to a lesser extent in SW620 cells, whereas other differentiation inducers [sodium butyrate and hexamethylene bis-acetamide (HMBA)] were ineffective. In LS174T cells, TGA activity was resistant to induction by all of the agents. The synthetic retinoid (RO 15-1570) inhibited in vitro invasiveness of SW620 cells, however, TPA treatment or addition of exogenous TGA did not inhibit invasiveness of these cells. Hence, the invasive behavior of a metastatic human colon tumor cell line (SW620) does not appear to be dependent on the TGA activity which the cells express. The anti-invasive activity of the retinoid in SW620 cells therefore may be mediated by some other mechanism.

Topics: Adenocarcinoma; Colonic Neoplasms; Colorectal Neoplasms; Humans; Neoplasm Invasiveness; Retinoids; Tetradecanoylphorbol Acetate; Transglutaminases; Tretinoin; Tumor Cells, Cultured

Melanin, the natural pigment found in human skin, absorbs and protects against the ultraviolet (UV) components of sunlight. Melanin production (melanogenesis) is increased by exposure to sunlight, causing a darker skin colour which is regarded as aesthetically pleasing by many humans, who therefore expose themselves to large amounts of potentially damaging sunlight. We have found that topically applied all-trans retinoic acid, a metabolic derivative of vitamin A, greatly enhances UV light-induced melanogenesis: the same preparation on its own had no effect on skin pigmentation. An orally administered retinoid, temarotene, did not have this effect. These observations were made using a lightly pigmented mouse strain, HRA: Skh-2, and confirmed in 2 human volunteers. This is the first time that metabolic derivatives of vitamin A have been shown to augment UV light-induced melanogenesis, suggesting a role for vitamin A in this process.

Topics: Animals; Humans; Melanins; Mice; Mice, Hairless; Retinoids; Skin Pigmentation; Tretinoin; Ultraviolet Rays

The human sebocyte model offers several advantages over the current animal models. Foremost among these is the correlation of in vitro activity with clinical results, which was not true for arotinoids in the animal models. It is also possible to study several parameters (total cell number, [3H]thymidine uptake, protein and lipid composition/synthesis, hormone response, receptor regulation, etc.) in the same system. The proliferation of isolated sebocytes is inhibited by retinoids, such as isotretinoin and tretinoin, which are known to be clinically active in human acne. Sebocytes are not responsive to the arotinoid temarotene, which is active in the aforementioned animal models and against dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinoma but inactive clinically in acne. Additionally, this model is not responsive to etretinate, a compound known to be active in psoriasis but inactive in acne. The in vitro model is, therefore, more predicative of clinical efficacy than the animal models alone.

Topics: Cell Division; Cell Separation; Cells, Cultured; Culture Techniques; Etretinate; Humans; Isotretinoin; Retinoids; Sebaceous Glands; Tretinoin

Modulation of ornithine decarboxylase (ODC) gene expression by retinoids was analyzed in human keratinocyte cultures maintained in serum-free medium containing 0.15 mM Ca++. Cells were incubated with all-trans-retinoic acid, 13-cis-retinoic acid or arotinoid Ro15-0778 (10(-10) to 10(-5) M), total RNA was isolated, and mRNA transcripts for ODC were analyzed by Northern and slot blot hybridizations with a human ODC cDNA. Treatment of cells for 24 h resulted in a dose-dependent decrease in ODC mRNA levels, with an estimated IC50 of approximately 1 X 10(-8) M for all-trans- and 13-cis-retinoic acid, while Ro15-0778 was somewhat less effective (IC50 approximately 1-5 X 10(-7) M). The suppression of ODC mRNA levels by retinoids was detectable at approximately 3 h of incubation, with essentially a maximal inhibition at 12 h. Reduced ODC mRNA levels noted after 24 h of incubation with 5 X 10(-7) M all-trans-retinoic acid were accompanied by a reduction in ODC enzyme activity. To determine if all-trans-retinoic acid was regulating ODC gene expression directly, or if protein synthesis was required, ODC expression was analyzed in cultures treated with protein synthesis inhibitors. In the presence of cycloheximide or puromycin, all-trans-retinoic acid did not suppress ODC mRNA levels. These findings suggest that suppression of ODC gene expression is not a direct effect of all-trans-retinoic acid, but depends on ongoing protein synthesis.

Topics: Cells, Cultured; Cycloheximide; Gene Expression Regulation, Enzymologic; Humans; Keratinocytes; Ornithine Decarboxylase; Puromycin; Retinoids; RNA, Messenger; Stereoisomerism; Time Factors; Tretinoin

A new approach studying the characteristics of the stratum corneum is presented: the electrophoretic mobility of corneocytes by laser Doppler spectroscopy. The detergent scrub technique was used for harvesting corneocytes from three body regions (forehead, palm, and sole) of normal persons (n = 20) under casual conditions and after thorough defattening of the skin with 70% isopropyl alcohol or petrol. Similarly, cells from the forehead, shoulder, and palm were obtained from 22 acne patients treated with isotretinoin (13-cis retinoic acid) 0.5-0.7 mg/kg body weight (b.wt.)/day for 12-16 weeks, and in patients receiving arotinoid (Ro 15-0778) 192 mg (n = 5) or 500 mg (n = 5) per kg/b.wt./day for 6 weeks (forehead and shoulder). In another experiment, cell suspensions with a pH ranging from 5.0-7.3 were evaluated. Measurements were performed by dynamic laser light scattering. This laser application allows exact electrophoretic mobility measurements in a short time (3 min). When cells pass the laser beam, the scattered light is frequency-shifted due to the optical Doppler effect. These frequency shifts are analyzed by the heterodyne light beating technique. The analog signal of the photodetector is converted into a power spectrum by Fourier analysis. This power spectrum represents the spectrum of electrophoretic cell mobility distribution. Results showed different electrophoretic mobility values for corneocytes dependent on the topographic region: forehead 1.18 +/- 0.16, palm 1.10 +/- 0.14, and sole 0.83 +/- 0.10 (means +/- SEM) micron cm/Vs. Defattening with isopropyl alcohol decreased the mobility values to 0.90 +/- 0.09 (p less than or equal to 0.01), 0.95 +/- 0.10, and 0.77 +/- 0.10 micron cm/Vs respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acne Vulgaris; Adolescent; Adult; Epidermis; Female; Humans; Isotretinoin; Male; Retinoids; Rheology; Sebaceous Glands; Tetrahydronaphthalenes; Tretinoin

The effects of four retinoids, all-trans-retinoic acid (tretinoin), 13-cis-retinoic acid (isotretinoin), R0 10-1670 (etretin) and the arotinoid, R0 15-0778, on fibroblast proliferation and glycosaminoglycans (GAG) secretion in vitro were studied. Fibroblasts lines cultured from normal skin (HSF) were compared with those from lesional (PSA) and non-lesional (PSB) psoriatic skin. In general, the retinoids inhibited proliferation; the action was cytostatic, in rank order tretinoin greater than isotretinoin greater than etretin greater than arotinoid. The psoriatic cells tended to be more sensitive than the HSF lines, overall mean proliferation values (+/- SEM), as a percentage of untreated controls being: HSF 72 ++- 3, PSA 61 +/- 3 and PSB 54 +/- 3. Stimulation of GAG secretion at low concentrations (10(-7) M) of all four retinoids, declined as concentrations increased, and secretion was inhibited at 10(-4)M in PSB fibroblasts. Calculation of effects on GAG secretion due to changes in cell density confirmed the rank order for direct stimulation of secretion as arotinoid greater than etretin greater than isotretinoin greater than tretinoin. Electrophoresis of [3H]-labelled glycosaminoglycans secreted in the presence of 10(-7) M arotinoid showed that it was predominantly hyaluronic acid, as in untreated cells. These data confirm that different retinoids have contrasting levels of effects on mesenchymal cells and suggest a greater sensitivity to drugs in fibroblasts from psoriatic skin.

Topics: Acitretin; Cell Division; Cell Line; Fibroblasts; Glycosaminoglycans; Humans; Isotretinoin; Psoriasis; Retinoids; Skin; Tretinoin

The influence of an arotinoid without a polar end group (Ro 15-0778) on rat mammary carcinogenesis was investigated. Mammary tumors were induced by oral administration of 15 mg, 7,12-dimethylbenz-(a) anthracene (DMBA) to 50-day-old female Sprague-Dawley rats. Ro 15-0778 inhibited the development of mammary adenocarcinomas. The percentage of tumor-bearing rats, the mean number of tumors per rat as well as the mean total volume of tumors per rat were dose-dependently reduced by Ro 15-0778. The results are of particular interest, since this compound--probably because of the lack of a polar end group--does not induce the signs and symptoms of hypervitaminosis A. The inhibition of mammary cancer development by Ro 15-0778 compares favorably with that of N-(4-hydroxyphenyl) retinamide the hitherto most effective retinoid for prevention of chemically-induced mammary cancers in rats.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Body Weight; Dose-Response Relationship, Drug; Female; Fenretinide; Mammary Neoplasms, Experimental; Rats; Rats, Inbred Strains; Retinoids; Time Factors; Tretinoin