RESUMEN
ICR/Ha Swiss mice, 30 females/group, were given a single application of 20 mug 7,12-dimethylbenz(a)anthracene, followed 2 weeks later by three times weekly applications of phorbol myristate acetate (PMA), 2.5 mug/application. In the accompanying inhibition experiments, sulfur mustard [SM; bis(2-chloroethyl)sulfide] was applied at a dose of 20 mug/application during the promotion phase, either on the same day as PMA, i.e., three times weekly, or on alternate days, i.e., twice weekly. The experiments were continued for 385 days. The control group, i.e., without SM, resulted in 27 of 30 mice with a total of 281 papillomas. Sixteen of these mice also bore squamous cell carcinomas. In the two groups also receiving SM, two or three times weekly, 2 of 30 and 1 of 30 mice, respectively, bore papillomas. Carcinomas were not observed in these groups. The inflammatory response of mouse skin to the combined treatments of SM and PMA was no greater than with PMA alone.
Asunto(s)
9,10-Dimetil-1,2-benzantraceno/antagonistas & inhibidores , Benzo(a)Antracenos/antagonistas & inhibidores , Carcinoma de Células Escamosas/inducido químicamente , Compuestos de Mostaza/farmacología , Papiloma/inducido químicamente , Forboles/antagonistas & inhibidores , Neoplasias Cutáneas/inducido químicamente , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Femenino , Ratones , Ratones Endogámicos ICR , Neoplasias Experimentales/inducido químicamente , Sulfuros/farmacologíaRESUMEN
The induction of mouse epidermal ornithine decarboxylase, 1 of the earliest and largest phenotypic changes following treatment of mouse skin with the tumor-promoting agent, 12-O-tetradecanoyl-phorbol-13-acetate, can be inhibited by prior administration of colchicine. Maximal inhibition of this enzyme induction was observed when colchicine was injected i.p. 90 or 120 min before promoter treatment, although time intervals up to 20 hr between colchicine and promoter treatment were effective. The effect of colchicine was dose dependent, with a dose as low as 25 nmoles/mouse causing an inhibition of 35%. Other microtubule-disrupting agents, vinblastine, vincristine, and Colcemid, had a similar effect on ornithine decarboxylase activity. However, beta, gamma-lumicolchicine, a photochemical derivative of colchicine with no antimitotic or microtubule-disrupting ability, and cytochalasin B, an inhibitor of microfilament-dependent processes, had no effect. N6, O2'-dibutyryl 3',5'-cyclic adenosine monophosphate, when administered just before colchicine, blocked the inhibitory action of colchicine. The results of these studies suggest that colchicine-sensitive structures, most likely containing microtubules, may be mediating elements between the binding of tumor promoters, perhaps to specific cell surface receptors, and the subsequent induction of ornithine decdaboxylase.
Asunto(s)
Carboxiliasas/biosíntesis , Colchicina/farmacología , Ornitina Descarboxilasa/biosíntesis , Forboles/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Colchicina/análogos & derivados , Colchicina/antagonistas & inhibidores , Citocalasina B/farmacología , Demecolcina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Piel/enzimología , Factores de Tiempo , Vinblastina/farmacología , Vincristina/farmacologíaRESUMEN
The induction of epidermal ornithine decarboxylase (EC 4.1.1.17) (ODC) following topical application of the tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) to mice can be inhibited by topical application of putrescine, the product of the enzyme. The degree of inhibition depended on both the dose and the time of putrescine application; application of 20 mumol of putrescine 2 hr after TPA treatment inhibited the induction of ODC activity by 50%. TPA-induced activity of another polyamine-biosynthetic enzyme, S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), was unaffected by application of putrescine. Among several amines tested for their ability to inhibit the induction of ODC activity, spermidine, 1,7-diaminoheptane, and spermine were the most effective, causing a 90% inhibition at the 20-mumol dose. Putrescine, when added directly to the assay medium at a 100-mumol dose level inhibited by 97% the TPA-induced ODC activity, but the amount of putrescine (20 mumol) which gave 50% inhibition of the induction of ODC activity in vivo had no effect when added to the assay system. Mixing of soluble extracts from TPA-treated mouse epidermis posttreated either with acetone or putrescine or with mouse epidermis treated with putrescine alone gave essentially additive ODC activity. Furthermore, putrescine did not elicit production of detectable ODC-antizyme activity in mouse epidermis. Putrescine inhibited the formation of mouse skin papillomas promoted with TPA. Topical application of 20 and 100 mumol of putrescine 2 hr after each application of TPA to mice initiated with 7,12-dimethylbenz[a]anthracene resulted in a 30 and 80% inhibition, respectively, of papilloma formation compared to animals receiving no putrescine.
Asunto(s)
Carboxiliasas/biosíntesis , Epidermis/enzimología , Ornitina Descarboxilasa/biosíntesis , Forboles/antagonistas & inhibidores , Putrescina/farmacología , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Adenosilmetionina Descarboxilasa/biosíntesis , Animales , Cocarcinogénesis/tratamiento farmacológico , Inducción Enzimática/efectos de los fármacos , Ratones , Neoplasias Cutáneas/inducido químicamenteRESUMEN
Retinol (vitamin A) in concentrations above (5 microgram/ml inhibits the stimulation of human lymphocytes by phytohemagglutinin and phorbol myristate acetate. This is in contrast to bovine lymphocytes in which retinol inhibits only phorbol myristate acetate stimulation of lymphocytes. The cause of the inhibition does not appear to be due to a direct toxic action because the viability and ultrastructure of lymphocytes exposed to a concentration of 20 microgram/ml for 72 hr were normal. The mechanism of action of the retinol is not known, but it may be mediated by a retinol-binding protein in the cells.
Asunto(s)
Linfocitos/efectos de los fármacos , Forboles/antagonistas & inhibidores , Fitohemaglutininas/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Vitamina A/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Activación de Linfocitos/efectos de los fármacosRESUMEN
The tumor-promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA), accelerates choline phospholipid synthesis in bovine lymphocytes by an oxygen-dependent mechanism. This action is prevented by high concentrations of the cyclooxygenase inhibitor, indomethacin (1 to 3 mM), suggesting a possible involvement of lipid oxidation in the response. The acetylenic analog of arachidonic acid, 5,8,11,14-eicosatetraynoic acid (ETYA), at concentrations in the 10 to 50 microM range also prevents the acceleration of the incorporation of [methyl-3H]choline hydrochloride into choline phospholipids, and it appears more selective in its action. This antagonistic effect of ETYA, an agent which inhibits both the cyclooxygenase and lipoxygenase routes of arachidonic acid oxidation, can be precluded by arachidonic acid but not by other unsaturated or saturated fatty acids. If ETYA is added to lymphocyte cultures after 1 hr of TPA treatment, the established rate of [methyl-3H]choline hydrochloride incorporation is unaffected, but further acceleration is blocked. The inhibition by ETYA cannot be counteracted by any of the prostaglandins, Types A, B, D, E, or F alpha, or by the prostacyclin compounds, PGI1 and 6,9-thia-PGI2. The thromboxane pathway also appears not to be involved since 9,11-azoprosta-5,13-dienoic acid (Azo I), a selective inhibitor of thromboxane synthetase, does not affect the TPA response. These results suggest that TPS may activate the lipoxygenase rather than the cyclooxygenase pathway for lipid oxidation and that an arachidonic acid hydroperoxide or a subsequent metabolite plays a key role in the stimulation of choline phospholipid synthesis by the tumor-promoting phorbol ester, TPA.
Asunto(s)
Ácido 5,8,11,14-Eicosatetrainoico/farmacología , Ácidos Grasos Insaturados/farmacología , Forboles/antagonistas & inhibidores , Fosfolípidos/metabolismo , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Ácido 5,8,11,14-Eicosatetrainoico/antagonistas & inhibidores , Animales , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Bovinos , Colina/metabolismo , Epoprostenol/farmacología , Prostaglandinas/farmacologíaRESUMEN
Palmitoylcarnitine, which has been reported to be an inhibitor of calcium-activated, phospholipid-dependent protein kinase (protein kinase C), inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase in mouse skin in a dose-dependent manner. Neither acetylcarnitine nor palmitic acid inhibited TPA-caused ornithine decarboxylase induction. In addition, palmitoylcarnitine markedly inhibited skin tumor promotion induced by TPA. Palmitoylcarnitine inhibited epidermal protein kinase C activity which was stimulated by Ca2+ in the presence of phosphatidylserine but failed to inhibit the enzyme activity which was stimulated by TPA in the presence of either phosphatidylserine or Ca2+ plus phosphatidylserine. Therefore, it seems unlikely that the potent anti-tumor-promoting action of palmitoylcarnitine, which is shown in the present study, is explained solely by its effect on protein kinase C.
Asunto(s)
Carnitina/análogos & derivados , Inhibidores de la Ornitina Descarboxilasa , Palmitoilcarnitina/farmacología , Forboles/antagonistas & inhibidores , Neoplasias Cutáneas/prevención & control , Piel/enzimología , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Calcio/farmacología , Relación Dosis-Respuesta a Droga , Ácido Egtácico/farmacología , Femenino , Ratones , Ratones Endogámicos , Ornitina Descarboxilasa/análisis , Proteína Quinasa C/análisis , Proteína Quinasa C/antagonistas & inhibidores , Neoplasias Cutáneas/inducido químicamente , Factores de TiempoRESUMEN
Several retinoids including retinoic acid effectively inhibit phorbol ester-mediated tumor promotion and ornithine decarboxylase (ODC) induction in mouse epidermis. To understand better the possible cellular site of action of retinoids, the inhibitory action of retinoic acid on the induction of ODC was compared for two distinctly different inducers, namely, 12-O-tetradecanoylphorbol-13-acetate (TPA) and germicidal ultraviolet light (UV), in primary mouse epidermal cell cultures. It was found that the induction of ODC by TPA is almost completely prevented by 0.1 to 1 microM retinoic acid while the induction by UV is only moderately inhibited. Maximum inhibition is achieved by treating cells continuously with retinoic acid from 4 hr after plating, although pretreatment or simultaneous treatment relative to either inducer is almost as effective. When added after the inducer, retinoic acid loses its effectiveness as an inhibitor more rapidly for TPA induction than for UV induction of ODC. The differential inhibition of enzyme induction cannot be accounted for by selective retinoid inhibition of DNA, RNA, or protein synthesis either alone or in concert with TPA or UV. Other agents known to modulate the induction of ODC by TPA (fluocinolone acetonide, tosyl-L-lysylchloromethane, and local anesthetics) do not act differentially on UV induction. These agents possibly act at transcription or translation, both of which are required for ODC induction by TPA or UV. The preferential inhibition by retinoic acid of ODC induction by TPA is interpreted to result from specific interference at a unique and early site of interaction of TPA with the cell.
Asunto(s)
Carboxiliasas/biosíntesis , Ornitina Descarboxilasa/biosíntesis , Forboles/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Tretinoina/farmacología , Animales , Células Cultivadas , Replicación del ADN/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Inducción Enzimática/efectos de la radiación , Células Epidérmicas , Ratones , Rayos UltravioletaRESUMEN
The ability of 5,6-epoxyretinoic acid, a biologically active metabolites of retinoic acid, to inhibit both the induction of ornithine decarboxylase (ODC) activity and skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was evaluated. Application of 5,6-epoxyretinoic acid either concurrently with or 1 hr after each application of TPA to the initiated mouse skin inhibited the formation of skin tumors as effectively as did retinoic acid. 5,6-Dihydroretinoic acid, which is a poor substrate for epoxidation, also inhibited skin tumor promotion. 5,6-Epoxyretinoic acid, 5,6-dihydroretinoic acid, and retinoic acid were equally effective in inhibiting the induction of ODC activity by TPA. Insect juvenile hormones inhibited neither the induction of ODC activity nor skin tumor promotion by TPA. These results indicate that (a) epoxidation of retinoic acid at the 5,6-position is not a rate-limiting modification for the anti-promoting activity of retinoic acid and that (b) inhibition of the induction by TPA of mouse epidermal ODC activity may be a simple test for screening the potential prophylactic activities of new retinoids.
Asunto(s)
Ésteres del Forbol/antagonistas & inhibidores , Forboles/antagonistas & inhibidores , Neoplasias Cutáneas/inducido químicamente , Tretinoina/farmacología , Animales , Femenino , Hormonas Juveniles/farmacología , Ratones , Inhibidores de la Ornitina Descarboxilasa , Papiloma/inducido químicamente , Papiloma/enzimología , Papiloma/patología , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Factores de Tiempo , Tretinoina/metabolismoRESUMEN
12-O-Tetradecanoylphorbol-13-acetate (TPA) is an effective comitogen in phytohemagglutinin-treated bovine lymphocytes. Concurrent addition of 10(-8) M TPA gives a greater than 6-fold increase in DNA synthesis over cultures treated with the lectin alone. The delayed addition of phorbol ester, relative to the start of the lectin treatment, eliminates this synergistic action. Structure-function studies show that the comitogenic activity of different phorbol diesters runs parallel to their tumor-promoting activity. A nontoxic level (50 micronM) of retinoic acid selectively antagonizes this synergistic effect of phorbol ester. This inhibitory action requires the near-concurrent addition of retinoic acid with TPA. In contrast, the TPA-mediated induction of RNA and protein synthesis is unaffected by retinolic acid. A number of natural and synthetic retinoids were evaluated; none were as inhibitory as was retinoic acid. Lymphocyte cultures appear to provide a useful system for exploring the mechanisms of action of both TPA and retinoic acid.
Asunto(s)
Diterpenos/antagonistas & inhibidores , Activación de Linfocitos/efectos de los fármacos , Ésteres del Forbol/antagonistas & inhibidores , Forboles/antagonistas & inhibidores , Tretinoina/farmacología , Vitamina A/análogos & derivados , Animales , Bovinos , ADN/biosíntesis , Sinergismo Farmacológico , Técnicas In Vitro , Lectinas/farmacología , Linfocitos/metabolismo , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Vitamina A/farmacologíaRESUMEN
Chemiluminescence (CL) is an index of both the generation of and reactions mediated by O2-. and 1O2. The tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), is a potent stimulator of CL by human polymorphonuclear leukocytes; treatment with TPA (100 ng/ml) provokes a CL response that peaks within five min and persists for over 30 min. The response is proportional to concentration over the range of one to 100 ng/ml. The ability of different phorbol diesters to stimulate both CL and O2-. production correlates with their relative activities as tumor promoters in vivo. Non-phorbol diester tumor promoters such as iodoacetic acid, anthralin, and tween 60 are inactive in this system. The TPA-mediated stimulation of CL can be inhibited by retinoids; cells preincubated for 15 min with 100 microM retinoic acid show only a marginal CL response to TPA. Addition of retinoic acid to resting polymorphonuclear leukocytes results in a transient burst of CL without concomitant O2-. release, observations indicative of an excitable substrate. A similar CL response is seen when retinoic acid is incubated with potassium superoxide in a cell-free system. 5,6-Epoxyretinoic acid, and even more effective inhibitor of TPA-stimulated CL than retinoic acid when added simultaneously with TPA, does not undergo these two CL reactions. Thus, it appears that retinoic acid may undergo oxidative activation to a species that exert enhanced antipromoter activities. Polymorphonuclear leukocytes provide a useful system for exploring the roles of reactive oxygen species in the mechanism of action of both TPA and retinoic acid.
Asunto(s)
Neutrófilos/efectos de los fármacos , Ésteres del Forbol/antagonistas & inhibidores , Forboles/antagonistas & inhibidores , Membrana Celular/efectos de los fármacos , Compuestos Epoxi , Humanos , Mediciones Luminiscentes , Fagocitosis/efectos de los fármacos , Relación Estructura-Actividad , Superóxidos/metabolismo , Tretinoina/análogos & derivadosRESUMEN
Incubation of the tumor-promoting phorbol diester, 12-O-tetradecanoyl-phorbol-13-acetate with Madin-Darby canine kidney cells (MDCK) stimulated deacylation of phospholipids, prostaglandin production and altered cell morphology. alpha-Tocopherol, if present during the incubation, inhibited these effects. For inhibition, alpha-tocopherol had to be present during incubation of 12-O-tetradecanoyl-phorbol-13-acetate and cells; pretreatment or posttreatment of the cells with alpha-tocopherol was not effective. Inhibition of the 12-O-tetradecanoyl-phorbol-13-acetate effects was specific for the tumor promoter extracted from the Croton tiglium L. plant of the family Euphorbiaceae. Stimulated prostaglandin production by another tumor promotor (phorbol-12, 13-didecanoate), a semisynthetic product of that plant, was also inhibited by alpha-tocopherol. But that of structurally related diterpenoid esters isolated from plants of the family Thymelaeaceae, such as mezerein, gnidimacrin, gnilatimacrin, and gnilatimacrin-20-palmitate, were not. Stimulation of prostaglandin production in MDCK cells by compounds such as benzo(a)pyrene, adriamycin and 17 beta-estradiol or even the basal synthetic activity of MDCK cells was not affected by alpha-tocopherol.
Asunto(s)
Neoplasias Renales/inducido químicamente , Ésteres del Forbol/antagonistas & inhibidores , Forboles/antagonistas & inhibidores , Vitamina E/farmacología , Animales , Células Cultivadas , Perros , Relación Dosis-Respuesta a Droga , Riñón/metabolismo , Fosfolípidos/metabolismo , Prostaglandinas/biosíntesisRESUMEN
The mechanisms by which topically applied retinoic acid to mouse skin inhibits tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced epidermal ornithine decarboxylase activity were analyzed. Retinoic acid inhibition of the induction of epidermal ornithine decarboxylic activity was not the result of nonspecific cytotoxicity, production of a soluble inhibitor of ornithine decarboxylase, or direct effect on its activity. In addition, inhibition of TPA-caused increased ornithine decarboxylase activity does not appear to be due to enhanced degradation and/or post-translational modification of ornithine decarboxylase by transglutaminase-mediated putrescine incorporation. We found that retinoic acid inhibits the synthesis of ornithine decarboxylase caused by TPA. Application of 10 nmol TPA to mouse skin led to a dramatic induction of epidermal ornithine decarboxylase activity which was paralled by increased [3H]difluoromethylornithine binding and an increased incorporation of [35S]methionine into the enzyme. Application of 17 nmol retinoic acid 1 h prior to application of 10 nmol TPA to skin resulted in inhibition of the induction of activity which accompanied inhibition of [3H]difluoromethylornithine binding and [35S]methionine incorporation into ornithine decarboxylase protein as determined by the tube-gel electrophoresis of the enzyme immunoprecipitated with monoclonal antibodies to it. Inhibition of ornithine decarboxylase synthesis was not the result of the inhibitory effect of retinoic acid on general protein synthesis. The results indicate that retinoic acid possibly inhibits TPA-caused synthesis of ornithine decarboxylase protein selectively.
Asunto(s)
Ornitina Descarboxilasa/biosíntesis , Forboles/antagonistas & inhibidores , Piel/efectos de los fármacos , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Tretinoina/farmacología , Aciltransferasas/metabolismo , Animales , Anticuerpos Monoclonales , Inducción Enzimática/efectos de los fármacos , Femenino , Masculino , Ratones , Ornitina Descarboxilasa/inmunología , Piel/enzimología , Acetato de Tetradecanoilforbol/farmacología , TransglutaminasasRESUMEN
The addition of the amphipathic polycationic antibiotic polymyxin B to a suspension of rabbit neutrophils results in inhibiton of the agonist (secretion of secondary granules) and antagonist (inhibition of chemotactic factor induced degranulation) properties of phorbol 12-myristate 13-acetate. On the other hand, polymyxin B does not inhibit the degranulation of the neutrophils that is induced by chemotactic factors. These results imply that the role of protein kinase C in the initiation of neutrophil functions in response to the addition of chemotactic factors is less critical than previously thought. In addition, the reversal of the inhibitory properties of phorbol esters by polymyxin B indicates that the former are mediated by the ability of the tumor promoters to activate protein kinase C. These results thus strengthen the hypothesis that protein kinase C plays important roles in the regulation (as contrasted to initiation) of neutrophil functions.
Asunto(s)
Factores Quimiotácticos/antagonistas & inhibidores , Neutrófilos/efectos de los fármacos , Forboles/antagonistas & inhibidores , Polimixina B/farmacología , Polimixinas/farmacología , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Gránulos Citoplasmáticos/efectos de los fármacos , Técnicas In Vitro , Muramidasa/sangre , Neutrófilos/enzimología , Proteína Quinasa C/fisiología , ConejosRESUMEN
The effects of naturally occurring sweetening agents, which inhibited the induction of Epstein-Barr virus-associated early antigen (EBV-EA) induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), and related compounds on the induction of ornithine decarboxylase (ODC) by TPA is examined. Application of glycyrrhetinic acid or steviol to mouse skin 1 h before TPA treatment showed a remarkable decrease in TPA-induced ODC activity. Post-treatment with glycyrrhetinic acid or steviol 1 h after application of TPA also resulted in a considerable depression in the induction of ODC activity. Neither glycyrrhetinic acid nor steviol alone induced epidermal ODC activity. These results suggest that glycyrrhetinic acid and steviol interfere with the process of induction of epidermal ODC by TPA treatment of mouse skin. cis-Abienol, frullanolide and norambreinolide, which have a partially similar structure in the moiety with glycyrrhetinic acid or steviol, were tested. cis-Abienol and frullanolide showed an inhibitory effect when applied 1 h before TPA treatment, but norambreinolide was not effective. A relationship between suppression of ODC activity and inhibition of EBV-EA induction is discussed.
Asunto(s)
Ornitina Descarboxilasa/análisis , Forboles/antagonistas & inhibidores , Piel/enzimología , Edulcorantes/farmacología , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Antígenos Virales/análisis , Células Cultivadas , Femenino , Herpesvirus Humano 4 , Ratones , Ratones Endogámicos , Factores de TiempoRESUMEN
The effects of glucocorticoids and cholesterol on morphological transformation have been studied using hamster embryo cells. The cells were exposed sequentially to benzo[a]pyrene (BP) (3 days) and the tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) (4 days) before scoring for morphologically transformed colonies. Dexamethasone and hydrocortisone strongly inhibited the formation of morphologically transformed colonies when applied to the cells in the second period of exposure together with TPA, but had no effect when present with BP during the first period. Corticosterone had only a weak effect, while cortisone had no effect on the transformation frequency. Cholesterol gave rise to an enhanced number of transformed colonies. Dexamethasone, being the most potent compound tested, inhibited morphological transformation by more than 50% when present in a concentration of 0.25 nM. The finding that dexamethasone reduced the frequency of transformation even when added only 6 h prior to staining, indicates that the glucocorticoids may also reduce the transformation frequency by reversing morphologically transformed cell colonies to a normal appearance.
Asunto(s)
Transformación Celular Neoplásica/inducido químicamente , Glucocorticoides/farmacología , Forboles/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Benzo(a)pireno , Benzopirenos , Línea Celular , Cocarcinogénesis , Corticosterona/farmacología , Cricetinae , Dexametasona/farmacología , Embrión de Mamíferos , Hidrocortisona/farmacología , MesocricetusRESUMEN
Diazepam (Valium) had previously been shown to enhance the growth rate of some transplantable tumors although studies in other systems have suggested an inhibitory effect. Skin tumor promotion studies were therefore carried out to determine the effect of diazepam on 12-O-tetradecanoyl phorbol-13-acetate (TPA) promotion in SENCAR mice. A sex-independent dose response inhibition occurred over a dose range of 100 g to 5 mg, both in number of papillomas and percent of mice bearing tumors. Furthermore, a dose-response reduction in tumor size was observed. By itself, diazepam had no tumor promoting activity.
Asunto(s)
Diazepam/farmacología , Papiloma/inducido químicamente , Forboles/antagonistas & inhibidores , Neoplasias Cutáneas/inducido químicamente , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Papiloma/patología , Factores Sexuales , Neoplasias Cutáneas/patologíaRESUMEN
The present study was undertaken to determine the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent tumor promoter known to inhibit superoxide dismutase (SOD) (superoxide: superoxide oxidoreductase, EC 1.15.1.1) and catalase (CAT) (H2O2: H2O2 oxidoreductase, EC 1.11.1.6) activities, on mouse epidermal glutathione (GSH) peroxidase (glutathione: H2O2 oxidoreductase, EC 1.11.1.9) activity in vivo and in vitro. TPA led to a rapid and transient increase in GSH peroxidase specific activity within 30 min followed by a decrease from 1 to 12 h. Incubation of isolated epidermal cells with GSH level-raising agents and/or selenium-containing compounds increased remarkably basal GSH peroxidase activity, and thus, abolished totally the prolonged inhibitory effects of TPA on this enzyme. The inhibitory effects of 0.2 mM cysteine (Cys) or 0.5 mM GSH and 2.5 microM Na2 SeO3 or 50 microM selenocystamine on TPA-decreased GSH peroxidase activity were additive, in relation with their additive inhibitory effects on TPA-induced ornithine decarboxylase (ODC) (L-ornithine carboxylase, EC 4.1.1.17) activity. These data support the hypothesis that the stimulators of the GSH-dependent antioxidant protective system of the epidermal cells may inhibit the oxidative challenge linked to skin tumor promotion by TPA.
Asunto(s)
Glutatión Peroxidasa/análisis , Glutatión/análisis , Ornitina Descarboxilasa/análisis , Forboles/antagonistas & inhibidores , Selenio/farmacología , Piel/enzimología , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Animales , Cisteína/farmacología , Femenino , Ratones , Ratones Endogámicos , Piel/efectos de los fármacosRESUMEN
Utilizing the phenomenon of metabolic cooperation in Chinese hamster V79 cells, we have studied the effects of agents which suppress the 12-tetradecanoyl-phorbol-13-acetate (TPA) enhancement of transformation in vitro, on the TPA suppression of cell-cell communication. None of the agents tested, namely all-trans-retinoic acid, the trimethyl methoxyphenyl analogue of N-ethyl-retinamide, soybean trypsin inhibitor, antipain nor superoxide dismutase, decreased the enhanced recovery effect of TPA on metabolic cooperation. One of the compounds, retinoic acid, significantly increased the % recovery above that observed for TPA alone.
Asunto(s)
Antipaína/farmacología , Comunicación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Oligopéptidos/farmacología , Forboles/antagonistas & inhibidores , Superóxido Dismutasa/farmacología , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Tretinoina/análogos & derivados , Tretinoina/farmacología , Inhibidores de Tripsina/farmacología , Animales , Línea Celular , Cricetinae , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
From an anti-inflammatory Chinese medicinal plant, Glechoma hederaceae L., two triterpene carboxylic acids, ursolic acid (UA) and oleanolic acid (OA) have been isolated as inhibitors of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus (EBV) activation in Raji cells. Both acids significantly inhibited the activation at a 1000-fold molar ratio to TPA, and also teleocidin B-4. The dose responses of the acids were very similar to those of the antitumor promoters, retinoic acid (RA) and glycyrrhetinic acid (GA). However, a characteristic property that UA and OA possess, far higher cell viability to the Raji cells than RA to the Raji cells, has been pointed out. Furthermore, enhancement of the inhibitory activity was found in 3-keto derivatives of UA and OA, while either loss of oxygen functionality at C-3 position of UA or oxidation at C-3 of GA led to reduction of the activity. Binding assay suggested that the inhibitory activity should be exhibited by some event caused after binding of TPA to the receptor in the cells.
Asunto(s)
Herpesvirus Humano 4/efectos de los fármacos , Medicina Tradicional China , Medicina Tradicional de Asia Oriental , Ácido Oleanólico/farmacología , Forboles/antagonistas & inhibidores , Plantas Medicinales , Sapogeninas/farmacología , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Triterpenos/farmacología , Activación Viral/efectos de los fármacos , Bioensayo/métodos , Relación Dosis-Respuesta a Droga , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Toxinas de Lyngbya/antagonistas & inhibidores , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/aislamiento & purificación , Relación Estructura-Actividad , Triterpenos/aislamiento & purificación , Cultivo de Virus , Ácido UrsólicoRESUMEN
To clarify the mechanisms of O2- formation by polymorphonuclear leukocytes (PMNs), the effects of clinically employed drugs on PMNs were investigated by measuring changes in membrane potential and rates of O2- production. These variables were effectively diminished with antihistaminic agents, adrenergic beta-antagonists, and antiarrhythmic drugs when guinea pig peritoneal PMNs were stimulated by either phorbol myristate acetate (PMA) or n-formyl-methionyl-leucyl-phenylalanine (FMLP). The order of potency of the inhibitory effects of these chemicals on the PMA-induced O2- formation was as follows: azelastine (IC50 = 4.1 microM) less than clemastine less than dl-propranolol less than chlorpheniramine maleate less than dichlorisoproterenol less than quinidine less than diphenhydramine less than indomethacin (IC50 greater than 400 microM). Similar phenomena were observed when FMLP was employed instead of PMA, but the FMLP-stimulated O2- production was effectively inhibited by indomethacin. Changes in membrane potential, using the cyanin dye method, also indicated that most of these drugs cancelled functional changes of plasma membrane of PMNs. From these observations, it was demonstrated that changes in membrane potential by the stimuli were essential for the initiation of O2- generation from plasma membrane of PMNs, although the initiation mechanisms were not identical for the two stimuli.