Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1988"
Journal Article•
TL;DR: The effects of dietary supplementation of flavonol quercetin on both 7,12-dimethylbenz( a )anthracene (DMBA)- and N -nitrosomethylurea-induced mammary cancer in female Sprague-Dawley rats were determined as discussed by the authors.
Abstract: The effects of dietary supplementation of flavonol quercetin on both 7,12-dimethylbenz( a )anthracene (DMBA)- and N -nitrosomethylurea-induced mammary cancer in female Sprague-Dawley rats were determined. Quercetin diet was started 1 wk before intragastric instillation of DMBA (65 mg/kg of body weight) or i.v. injection of N -nitrosomethylurea (50 mg/kg of body weight) and was continued during the entire period (20 wk) of the experiment. Dietary quercetin inhibited both the incidence and the number of palpable rat mammary tumors; rats fed on 2% quercetin had 25% less incidence of mammary cancer, while the average number of mammary tumors per rat was reduced by 39% at 20 wk post-DMBA administration compared to animals on a control diet. In a separate experiment, a 5% quercetin diet elicited a greater inhibitory effect on the induction of rat mammary tumors by DMBA than was observed with a 2% quercetin diet. The inhibitory effect of quercetin on mammary tumor incidence in rats on 2% and 5% diets and on tumor multiplicity in animals on a 5% diet was statistically significant ( P < 0.05). In addition, the risk of the development of a palpable tumor (as determined by the nonparametric estimate of the hazard function) in the quercetin-fed group was lower than the group on control diet throughout the course of the experiment. Furthermore, 5% dietary quercetin significantly inhibited ( P < 0.05), although to a lesser extent than observed in DMBA-induced tumor formation, both the incidence and the number of palpable mammary tumors per rat induced by N -nitrosomethylurea. Dietary quercetin did not elicit any detectable sign of toxicity. The gain in body weight in rats on the quercetin diet and the quantity of diet consumed per rat per week were similar to those for rats on the control diet.
305 citations
Journal Article•
TL;DR: The results suggest that these plant phenols have substantial though variable potential for modifying the risk of skin tumorigenicity induced by a wide variety of chemicals and of these tannic acid was shown to have maximal chemoprotective effects.
Abstract: Our recent studies have shown that naturally occurring dietary plant phenols such as tannic acid, quercetin, myricetin, and anthraflavic acid are capable of inhibiting polycyclic aromatic hydrocarbon (PAH) metabolism and subsequent PAH-DNA adduct formation in epidermis of SENCAR mice (M. Das, et al., Cancer Res., 47: 760-766, 1987, and 47: 767-773, 1987). In this study these plant phenols were tested for their effects against PAHs and N-methyl-N-nitrosourea-induced skin tumorigenesis in mice. Each plant phenol was evaluated as a possible anticarcinogen in an initiation and promotion and a complete skin tumorigenesis protocol. In the two-stage tumor protocol in SENCAR mice using 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene, and N-methyl-N-nitrosourea as the initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate as tumor promoter each plant phenol afforded significant protection against skin tumorigenicity. The protective effects were verified both by prolongation of latency period and by subsequent tumor development. In the complete carcinogenesis protocol in BALB/c mice using 3-methylcholanthrene as a tumorigen the applications of each of the plant phenols 30 min prior to each PAH application afforded significant protection by delaying the onset and the subsequent development of skin tumors. Our results suggest that these plant phenols have substantial though variable potential for modifying the risk of skin tumorigenicity induced by a wide variety of chemicals and of these tannic acid was shown to have maximal chemoprotective effects.
193 citations
TL;DR: The effect of dietary brussels sprouts on mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied in Sprague-Dawley female rats and showed regression of small mammary tumors after 6 weeks on this dietary treatment.
93 citations
TL;DR: Four 7,12-dimethylbenz[a]anthracene--deoxyribonucleoside adducts formed in mouse epidermis in vivo arise from the syn dihydrodiol epoxide metabolite of this carcinogen.
Abstract: Four 7,12-dimethylbenz[a]anthracene--deoxyribonucleoside adducts formed in mouse epidermis in vivo arise from the syn dihydrodiol epoxide metabolite of this carcinogen. With the synthetic syn dihydrodiol epoxide it was possible to identify three of these as deoxyadenosine adducts and to establish their structures. These three adducts account for the large majority of DNA adduct arising from this metabolite in vivo. The in vivo metabolite is unusual, therefore, in that it reacts almost exclusively with adenine residues in DNA while most carcinogen metabolites react preferentially with guanine residues.
65 citations
TL;DR: The results suggest that the inhibitory action of MPA toward the angiogenic activity of RMTs, at least in part, involves its antitumor activity toward the R MTs.
50 citations
TL;DR: Mammary tumor development was reduced by diet containing TMPD, PG, TBMP, TBHQ or GG, although this could be partly due to antioxidant treatment-associated decrease in body wt gain.
Abstract: The effects of the antioxidants tetramethyl-p-phenylenediamine (TMPD), propyl gallate (PG), quercetin (QC), 2-tert-butyl-4-methylphenol (TBMP), tert-butylhydroquinone (TBHQ), 3,3'-thiodipropionic acid (TDPA), guaiac gum (GG) and caffeic acid (CA) on 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mammary gland, ear duct and forestomach carcinogenesis were examined in female Sprague--Dawley rats. Fifty-day-old rats were treated with 2.5 mg/100 g body wt of DMBA and, commencing 1 week thereafter, were given diets supplemented with 0.1% TMPD, 1.0% PG, 1.0% QC, 1% TBMP, 0.8% TBHQ, 1.0% TDPA, 1.0% GG or 0.5% CA for 51 weeks and then killed. Mammary tumor development was reduced by diet containing TMPD, PG, TBMP, TBHQ or GG, although this could be partly due to antioxidant treatment-associated decrease in body wt gain. The incidence of ear duct tumors was not affected by any of the antioxidant treatments. Development of forestomach tumors was enhanced in the group given DMBA followed by CA.
47 citations
Journal Article•
TL;DR: This study examined the influence of methyl groups on the velocity and stereochemical course of enzymatic benz(a)anthracene (BA) trans-dihydrodiol oxidation and suggested that methylation of BA at C-7 greatly enhances the oxidation of the 3S,4S-dhydrodio, while the presence of a bay-region methyl group at C -12 completely blocks the oxidationof the 3R,4R-stereoisomer.
Abstract: The homogeneous 3α-hydroxysteroid-dihydrodiol dehydrogenase of rat liver cytosol catalyzes the NADP-dependent oxidation of a wide variety of polycyclic aromatic trans -dihydrodiols and has been implicated in their detoxification (T. E. Smithgall, R. G. Harvey, and T. M. Penning, J. Biol. Chem., 261: 6184–6191, 1986). This study examined the influence of methyl groups on the velocity and stereochemical course of enzymatic benz( a )anthracene (BA) trans -dihydrodiol oxidation. The racemic trans -3,4-dihydrodiols of BA and 7-methylbenz( a )anthracene (7-MBA) were completely consumed by the purified dehydrogenase, indicating that both stereoisomers are substrates. However, 50% of the (±)- trans -3,4-dihydrodiols of 12-methylbenz( a )anthracene (12-MBA) and 7,12-dimethylbenz( a )-anthracene (DMBA) were oxidized, suggesting that only one stereoisomer is utilized in each case. At low substrate concentrations, enzymatic oxidation of the trans -3,4-dihydrodiois of BA, 12-MBA, and DMBA followed simple first-order kinetics. By contrast, oxidation of the 3,4-dihydrodiol of 7-MBA was of higher order, due to differences in the rate of oxidation of each stereoisomer. Rate constants estimated for each reaction indicate that the non-bay-region methyl group at position 7 has a greater enhancing effect on the rate of oxidation than the bay-region methyl group at position 12 (10- versus 4-fold, respectively). The 3,4-dihydrodiol of DMBA, which possesses both non-bay- and bay-region methyl groups, is oxidized more than 30 times faster than the unmethylated parent hydrocarbon. The absolute stereochemistry of the preferentially oxidized dihydrodiols was assigned by circular dichroism spectrometry. For the 3,4-dihydrodiols of DMBA and 12-MBA, the stereoisomer oxidized has the 3 S ,4 S configuration. A large negative Cotton effect was observed in the circular dichroism spectrum of the 7-MBA 3,4-dihydrodiol which remained at the end of the rapid phase of oxidation of this racemic substrate, indicating that the dehydrogenase displays partial stereochemical preference for the 3 S ,4 S enantiomer. These results suggest that methylation of BA at C-7 greatly enhances the oxidation of the 3 S ,4 S -dihydrodiol, while the presence of a bay-region methyl group at C-12 completely blocks the oxidation of the 3 R ,4 R -stereoisomer. Rapid, stereoselective oxidation of methylated polycyclic aromatic trans -dihydrodiols by this route in vivo may significantly influence their carcinogenicity.
45 citations
TL;DR: The effects of the immunosuppressive polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA) were studied directly by in vitro exposure of splenic lymphocytes to suggest that DMBA may act on immunocytes by mechanisms largely independent of the Ah locus and associated metabolic processes.
45 citations
TL;DR: In this paper, the tumor promotor 12-O-tetradecanoylphorbol 13-acetate (TPA) but not the initiator urethane depletes Ia-positive Langerhans cells from BALB/c murine ear epidermis, and β-glucuronidase-positive LC from C57BL mouse tail skin.
40 citations
TL;DR: The fact that a functional suppression of humoral immunity was accompanied by a decrease in the number of mature B-cells and T-cells in the spleen suggests that cell surface markers may be useful indicators of immunotoxicity in animals receiving DMBA in sub-chronic studies.
39 citations
Journal Article•
TL;DR: Evidence is provided that caffeine and/or caffeinated coffee consumption can significantly influence mammary carcinoma multiplicity in female rats treated with DMBA, an effect that is dependent upon the dose level, duration, and time-span of caffeine administration.
Abstract: The effect of caffeine and/or coffee consumption (via the drinking water) during the initiation phase and promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a commercial laboratory animal chow was examined. In the initiation studies, DMBA was administered once at 53-55 days of age; caffeine (100-860 mg/liter of drinking water) and/or coffee (moderate or high dose, sole source of drinking water) treatments were for 32 consecutive days, commencing 29 days prior to DMBA treatment and terminating 3 days after DMBA treatment. In the promotion studies, DMBA was administered once at 54-55 days of age; caffeine and/or coffee treatments were daily from 57-58 days of age to termination of experiments (12-21 weeks after carcinogen treatment). In the initiation studies, either moderate (100-400 mg) or high (860 mg) dose levels of caffeine or moderate to high dose levels of caffeinated coffee significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat). Consumption of high or moderate dose levels of decaffeinated coffee did not significantly alter mammary carcinoma multiplicity. The addition of caffeine to the moderate dose level of decaffeinated coffee resulted in a significant (P less than 0.05) reduction in mammary carcinoma multiplicity. In the promotion studies, prolonged consumption of moderated dose levels of caffeine or moderate or high dose levels of caffeinated coffee or decaffeinated coffee did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, however, a significant (p less than 0.05) stimulatory effect of caffeine on mammary carcinoma multiplicity was observed; an effect that was temperate and transitory. In both the initiation and promotion studies caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance. These results provide evidence that caffeine and/or caffeinated coffee consumption can significantly influence mammary carcinoma multiplicity in female rats treated with DMBA, an effect that is dependent upon the dose level, duration, and time-span of caffeine administration.
TL;DR: Examination of DMBA metabolism and DNA binding in mammary epithelial cells isolated from each rat strain suggests that the genes controlling susceptibility and resistance to mammary carcinogenesis in these rat strains are likely to be active at later stages of the carcinogenic process.
Abstract: The capacity of polycyclic aromatic hydrocarbons such as 7,12-dimethylbenz[a]anthracene (DMBA) to induce mammary carcinomas has been studied in three rat strains. Wistar/Furth (WF) rats are highly susceptible to DMBA-induced mammary carcinogenesis, Copenhagen (Cop) rats are completely resistant, and Fischer 344 (F344) rats have an intermediate susceptibility. We have previously shown that WF rats possess 'enhancer genes', which enhance susceptibility to induced mammary cancer. Cop rats, however, possess a single 'suppressor' gene which confers complete resistance to mammary cancer. Both gene types are apparently absent in F344 rats. In order to determine possible mechanisms of action of these enhancer and suppressor genes, we have examined DMBA metabolism and DNA binding in mammary epithelial cells isolated from each rat strain. Quantitative analyses of both metabolism and DNA binding indicate no significant differences among the strains. In addition, HPLC analyses of DMBA metabolites and DMBA-DNA adducts were essentially identical. These data suggest that the genes controlling susceptibility and resistance to mammary carcinogenesis in these rat strains are likely to be active at later stages of the carcinogenic process.
TL;DR: Stable pre-tumorigenic, benign tumor and squamous cell carcinoma stages have been isolated after treatment of a cloned mouse keratinocyte line with 7,12-dimethylbenz[a]anthracene.
Abstract: Stable pre-tumorigenic, benign tumor and squamous cell carcinoma stages have been isolated after treatment of a cloned mouse keratinocyte line with 7,12-dimethylbenz[a]anthracene. Intraperitoneal injection and skin grafting of athymic nude mice were suitable for growth of these well-differentiated tumor cells, whereas subcutaneous injection was not.
Journal Article•
TL;DR: In female rats fed a chemically defined standard or high fat diet, caffeine consumption can significantly influence chemical carcinogenesis of the mammary gland; an effect that is dependent upon the duration and time-span of caffeine administration.
Abstract: The effect of caffeine (430–500 mg/liter of drinking water) on the initiation and promotion phases of 7,12-dimethylbenz( a )anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a chemically defined diet containing standard (5%) or high (20%) levels of fat (corn oil) was examined. In the initiation studies, caffeine and the standard or high fat diet treatments were provided for 34 days, from 24–29 days of age to 58–63 days of age. Three days prior to termination of caffeine-fat diet treatments, each rat received a single dose of DMBA. In the promotion studies, caffeine and the standard or high fat diets were provided commencing 3 days after a single dose of DMBA (at 56–61 days of age) and until termination of the study. Caffeine consumption, during the initiation phase significantly ( P < 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat), in rats fed either a standard or high fat diet. In the promotion studies, prolonged consumption of caffeine in rats fed either a standard or high fat diet did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, an apparent increase in mammary carcinoma multiplicity was observed; this increase in mammary carcinoma multiplicity did not, however, reach the 5% level of statistical probability. When caffeine was administered during both the initiation and promotion phases, no significant effect on mammary carcinoma multiplicity was observed. Treatment of rats during the initiation or promotion phases with caffeinated coffee (via drinking water) mimicked the mammary tumor modulating activities of caffeine. Decaffeinated coffee consumption did not effect either the initiation or promotion phases of this tumorigenic process. In both the initiation and promotion studies, caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance.
Thus, in female rats fed a chemically defined standard or high fat diet, caffeine consumption can significantly influence chemical carcinogenesis of the mammary gland; an effect that is dependent upon the duration and time-span of caffeine administration.
TL;DR: Results demonstrate that angiogenic activity is an early manifestation of hamster pouch carcinogenesis and suggests that type II keratinocytes, presumptive preneoplastic cells in this model, are the principal source of this activity.
Abstract: The evolution of squamous epithelial neoplasms induced by 7,12-dimethylbenz[a]anthracene (DMBA) in Syrian hamster buccal pouch epithelium (HBPE) and the angiogenic potential of a subpopulation of presumptive preneoplastic keratinocytes was evaluated by examining the ability of whole cell dissociates of HBPE and subpopulations of keratinocytes, or their 72-h serum-free conditioned media (CM), to induce neovascularization in rat corneas and directional migration of bovine adrenal gland capillary endothelial cells (BCE) in culture. Buccal pouches were treated in vivo twice weekly for 5 weeks with either DMBA, paraffin oil (PO) or received no treatment. Hamsters were killed at various times after the last application of carcinogen and single-cell suspensions were prepared by enzymatic dissociation. Angiogenesis was assayed by injecting HBPE cells, or by implanting Hydron pellets containing CM in corneas and observing directional ingrowth of capillary blood vessels. Directional migration of BCE under agarose was tested with CM. Angiogenic activity of DMBA-initiated HBPE dissociates was detected initially at 4 and 5 weeks after treatment, was markedly depressed between weeks 8 and 16 and re-emerged in squamous papillomas at week 25. The pattern of expression of angiogenic activity was observed to parallel the frequency of development of a morphologically unique population of keratinocytes that was detected exclusively in cultures of DMBA-exposed HBPE. These unique cells, designated type II keratinocytes, potently stimulated neovascularization in vivo and directional migration of BCE in culture. These results demonstrate that angiogenic activity is an early manifestation of hamster pouch carcinogenesis and suggests that type II keratinocytes, presumptive preneoplastic cells in this model, are the principal source of this activity.
Journal Article•
TL;DR: The results strongly indicate that an abnormal endocrine milieu caused by neonatal treatment with estrogen may induce a high frequency of transformation of some ovarian tissues and rapid growth of the ovarian tumors after DMBA treatment.
Abstract: Groups of female C3H/HeMs x 129/J F1 mice were given injections of either 20 micrograms of 17 beta-estradiol or sesame oil (vehicle) for the first 5 days after birth. Half of each group was then given gastric intubations of 20 mg/kg of 7,12-dimethylbenz(a)anthracene (DMBA) at 70, 77, and 84 days of age. The other half of each group was given sesame oil. Thus, this design yielded four experimental groups: oil + oil; 17 beta-estradiol + oil; oil + DMBA; and 17 beta-estradiol + DMBA. They were sacrificed at approximately 144 days of age (Experiment 1) or the day of palpable ovarian tumor detection or 360 days of age (Experiment 2). In Experiment 1, the total number of oocytes (follicles) per ovary in mice of the 17 beta-estradiol + oil group was maintained at the same level as mice of the oil + oil group. A significant reduction of oocytes, however, was observed in mice of the 17 beta-estradiol + DMBA group in comparison with mice of the oil + DMBA group (P less than 0.01), and neoplastic nodules of the granulosa cell type developed in the unilateral ovary in 10 of 17 mice of the 17 beta-estradiol + DMBA group. No tumors were detected in the mice of the other groups. The plasma levels of both follicle-stimulating and luteinizing hormones as determined by radioimmunoassay were significantly higher (P less than 0.01) in mice of the 17 beta-estradiol + oil group than in mice of the oil + oil group. In Experiment 2, more ovarian tumors of the granulosa cell type were detected before 360 days of age in mice of the 17 beta-estradiol + DMBA group (14 of 18) than in mice of the oil + DMBA group (5 of 15) (P less than 0.05). No tumors developed in mice of the other two groups. These results strongly indicate that an abnormal endocrine milieu caused by neonatal treatment with estrogen may induce a high frequency of transformation of some ovarian tissues and rapid growth of the ovarian tumors after DMBA treatment.
TL;DR: The metabolism of 7,12-dimethylbenz(a)anthracene by primary cultures of human ovarian cells has been studied to identify the cell type(s) responsible for biotransformation of this carcinogen.
Abstract: 1. The metabolism of 7,12-dimethylbenz(a)anthracene (DMBA) by primary cultures of human ovarian cells has been studied to identify the cell type(s) responsible for biotransformation of this carcinogen. The rate of DMBA metabolism was maximal in granulosa cells prestimulated in vivo with antiestrogen, hMG (human menopausal gonadotropin) and hCG (human chorionic gonadotropin), i.e., treatments required for maximal oocyte maturation and, thus, granulosa cell proliferation. In cells from unstimulated ovaries, the metabolism was maximal in granulosa-lutein cells isolated from corpus luteum.2. Steroid (progesterone and estradiol) levels were determined in the spent culture media or in media in parallel with DMBA metabolism to find out whether elevated steroid levels in vivo are required for the rapid metabolism of DMBA. In granulosa cell cultures from stimulated cycles, the concentrations of both progesterone and estradiol were at least 2 or 3 times higher, respectively, than in any of the other cell types test...
TL;DR: Calcium glucarate and N-(4-hydroxyphenyl)retinamide were evaluated individually and in combination in the diet as preventative chemical agents, by using the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene as the test system.
Abstract: Calcium glucarate and N-(4-hydroxyphenyl)retinamide were evaluated individually and in combination in the diet as preventative chemical agents, by using the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene as the test system. When tested separately over 18 weeks, optimal doses of calcium glucarate (128 mmol/kg of diet) or N-(4-hydroxyphenyl)retinamide (1.5 mmol/kg of diet) administered daily inhibited tumor incidence by 50% or 57% and tumor multiplicity by 50% or 65%, respectively. Suboptimal doses of calcium glucarate (32 mmol/kg) and of N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence by 15% and 5% but had no inhibitory effect on tumor multiplicity. In contrast, the combination of calcium glucarate (32 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence and tumor multiplicity by 50%. Similar synergism was observed with the combination of calcium glucarate (64 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg), the inhibition being 55-60%. HPLC analysis of the bile of female rats injected intraperitoneally with a single dose of the retinamide [60 mg/kg (body weight)] showed that the excretion of the retinamide and its glucuronide were markedly suppressed by pretreatment with an oral dose of calcium glucarate [4.5 mmol/kg (body weight)].
TL;DR: Tumorigenicity assays indicate that the 9,10-dihydrodiol derivatives of cholanthrene and its 3- and 6-methyl derivatives are all potent tumor initiators on mouse skin, consistent with the hypothesis that the diol epoxide metabolites of these dihydrodiols are the active carcinogenic forms of the parent hydrocarbons.
Abstract: Syntheses of the trans-dihydrodiol derivatives implicated as the proximate carcinogenic metabolites of the polycyclic hydrocarbons cholanthrene, 6-methylcholanthrene, benz[a]anthracene, and 7- and 12-methylbenz[a]anthracene are described. These compounds are useful models for research to determine the molecular basis of the strong enhancement of carcinogenicity consequent upon methyl substitution in nonbenzo bay molecular sites and meso regions of polycyclic hydrocarbons. Synthesis of the bay region anti-diol epoxide derivative of cholanthrene, its putative ultimate carcinogenic metabolite, is also described. Tumorigenicity assays indicate that the 9,10-dihydrodiol derivatives of cholanthrene and its 3- and 6-methyl derivatives are all potent tumor initiators on mouse skin. The most active member of the series is the dihydrodiol derivative of 6-methylcholanthrene, which contains a bay region methyl group. The ability of the dihydrodiols 3a-c and the trans-3,4-dihydrodiol of 7,12-dimethylbenz[a]anthracene (3d) to induce chromosomal aberrations in rat bone marrow cells was also examined. The observed order of activity was 3d greater than 3c greater than 3b greater than 3a. These findings are consistent with the hypothesis that the diol epoxide metabolites of these dihydrodiols are the active carcinogenic forms of the parent hydrocarbons.
TL;DR: It was demonstrated on hairless mouse skin that 5% benzoyl peroxide in a gel (Panoxyl), or gel alone, applied just before UV radiation had a protective effect against UV-induced tumorigenesis, but both enhanced 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumors.
Abstract: In a previous paper it was demonstrated on hairless mouse skin that 5% benzoyl peroxide (BP) in a gel (Panoxyl), or gel alone, applied just before UV radiation had a protective effect against UV-induced tumorigenesis, but both enhanced 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis. Groups of hairless (hr/hr) mice were therefore given ultraviolet (UV) irradiation with or without additional treatment with Panoxyl or gel in order to see whether Panoxyl or the gel given long time before, or after, irradiation influenced UV-induced tumorigenesis. Consequently, in some animals Panoxyl or gel was applied in the evening and the mice were irradiated the next day; in others, Panoxyl or gel was applied 5-30 min after UV irradiation. Enhancement of DMBA-induced carcinogenesis in hr/hr mice by the gel alone (assumed to be inert) was unexpected, and hence one group of hr/hr mice was first given 51.2 micrograms DMBA in acetone and thereafter treated twice a week with gel alone. All mice were tested and observed for skin tumors and other lesions for 52 weeks. Neither Panoxyl nor gel influenced UV tumorigenesis or carcinogenesis under these experimental conditions. In hr/hr mice there was this time no enhancement of DMBA-induced tumorigenesis by the gel, and a slight reduction of carcinogenesis. In addition, several groups of SENCAR mice (which have been bred for high sensitivity to skin carcinogenesis) were also treated, with acetone alone, with a single application of DMBA alone, with Panoxyl alone, or with DMBA followed by treatment with the ointment gel or with Panoxyl twice a week throughout the experiment. In SENCAR mice there was no difference between the results of treatment with DMBA followed by Panoxyl, or DMBA followed by gel, and both substances tended to reduce the tumorigenicity of DMBA alone, and Panoxyl or gel showed no tumorigenicity of their own. The total dose of UV used in this study was lower than that used in the first study. This reduction in dose significantly increased the tumorigenic effect of UV.
TL;DR: It is suggested that increasing dietary fat enhanced the promotion of 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis over a wide range of protein intake.
Abstract: A 3 X 3 factorial experiment was conducted to examine the effects of dietary protein (8, 16 or 32% of energy from casein) and dietary fat (12, 24 or 48% of energy from corn oil) on the promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis in rats. A purified diet with protein and fat supplying 16 and 24% of energy, respectively, was fed to 360 rats. After 4 wk each rat received DMBA (20 mg/kg) via gastric intubation. Forty rats were then randomly assigned to each of the nine dietary treatments for 28 wk. We observed no effects of protein or interactions between protein and fat on mammary tumorigenesis. At necropsy, rats fed diets containing 12, 24 and 48% of energy from corn oil following DMBA administration showed tumor prevalences of 53, 60 and 70% with 109, 127 and 140 total tumors, respectively. Linear logistic statistical modeling indicated that each doubling of dietary fat concentration multiplied the odds of finding a tumor of any histologic type at necropsy by 1.52. Dietary fat had no significant effects on the prevalence of adenomas or fibroadenomas, whereas those fed corn oil at 12, 24 and 48% of dietary energy showed adenocarcinoma prevalences of 34, 41 and 52% with total adenocarcinoma counts of 66, 75 and 96, respectively. Our results suggest that increasing dietary fat enhanced the promotion of DMBA-induced breast carcinogenesis over a wide range of protein intake.
Journal Article•
TL;DR: 7 alpha-APTA is effective in reducing tumor volumes in the estrogen-dependent 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma rat model, and these results encourage further development of these steroids as potential medicinal agents for the treatment of estrogen- dependent disease states such as breast and endometrial cancer.
Abstract: Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. 7 alpha-Substitution of androstenedione results in inhibitors of enhanced affinity for aromatase, with 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione (7 alpha-APTA) exhibiting an apparent Ki of 18 nM and being among the most potent competitive inhibitors produced. The effects of this potent competitive 7 alpha-substituted C19 aromatase inhibitor on reduction of the number and size of the 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats was investigated. Tumor-bearing rats receiving 25 or 50 mg 7 alpha-APTA/kg/day demonstrated reductions in tumor volumes during the first week. Tumor volumes continued to decrease during the studies, resulting in tumor volume reductions of approximately 40 and 80%, respectively. Tumors in rats of the control group receiving only vehicle steadily increased in size during the studies. The tumor reductions in a 50-mg/kg/day-treated group were reversed by coadministration of 7 alpha-APTA at 50 mg/kg/day and estradiol at 0.3 microgram/kg/day for the last 3 weeks, indicating that the tumors were still responsive to estrogen. Plasma levels of estradiol were lower in the animals treated with 7 alpha-APTA at the end of the treatments. Thus, 7 alpha-APTA is effective in reducing tumor volumes in the estrogen-dependent 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma rat model. These results encourage further development of these steroids as potential medicinal agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer.
TL;DR: Ki‐ras activation in the DMBA‐transformed bladder cell lines may not be a direct consequence of interaction of activated DMBA metabolites with the Ki‐ras gene, according to Southern analysis of DNA from NIH 3T3 primary and secondary transformants.
Abstract: DNA from five lines of transformed bladder epithelial cells derived from cultures of primary cells that had been treated with 7,12-dimethylbenz[a]anthracene (DMBA) can transform NIH 3T3 mouse fibroblasts in DNA transfection experiments. Southern analysis of DNA from NIH 3T3 primary and secondary transformants established that four of the DMBA-transformed cell lines contained activated cellular Ki-ras, while the remaining cell line contained a transforming gene that is unrelated to Ki-ras, N-ras, and Ha-ras. The point mutations responsible for Ki-ras activation were detected using oligonucleotide probes following selective amplification of Ki-ras specific sequences using the polymerase chain reaction. The results showed that activation of Ki-ras invariably involved a GC----AT transition mutation of the first position of codon 12. Surprisingly, a Ki-ras gene that was activated by a GC----AT transition mutation at the same position was also detected in a single transformed bladder urothelial cell line derived from control cultures of mouse bladder cells. Together, our results indicate that Ki-ras activation in the DMBA-transformed bladder cell lines may not be a direct consequence of interaction of activated DMBA metabolites with the Ki-ras gene.
TL;DR: The data suggest that chemicals which depress NKC are likely to enhance susceptibility toMCMV, and conversely that effects on NKC should be suspected when chemical exposure enhances susceptibility to MCMV.
TL;DR: In this article, the results of comparative studies of BaP and DMBA assimilation, elimination, tissue disposition and metabolism in rainbow trout after administration of known doses of these contaminants via the digestive tract were reported.
TL;DR: Comparison of these results with previously reported results in mammalian systems suggests that there are similarities and differences between the fungal and mammalian oxidation of DMBA and that the overall balance of fungal metabolism is towards a detoxification rather than a bioactivation pathway.
Abstract: Six strains of fungi grown on Sabouraud dextrose broth in the presence of 7,12-dimethylbenz[a]anthracene (DMBA) were surveyed for their ability to metabolize DMBA. Experiments with [14C]DMBA indicated that the extent of formation of organic-soluble metabolites ranged from 6 to 28% after 5 days of incubation, depending on the organism tested. The yields of water-soluble metabolites also varied, and ranged from 1 to 33% after 5 days.Cunninghamella elegans ATCC 36112 andSyncephalastrum racemosum UT-70 exhibited the highest DMBA-metabolizing activity among the organisms surveyed.S. racemosum metabolized DMBA primarily to 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA)_ and 7,12-dihydroxymethylbenz[a]anthracene (7,12-diOHMBA). Minor metabolites included 7-OHM-12-MBA-trans-5,6-, 8,9- and 10,11-dihydrodiols, and glucuronide and sulfate conjugates of phenolic derivatives of DMBA. In contrast, the major DMBA metabolites produced byC. elegans were water-soluble. The predominant organic-soluble metabolites produced byC. elegans included 7-OHM-12-MBA-trans-5,6-, 8,9- and 10,11-dihydrodiols. DMBA-trans-3,4-dihydrodiol was also detected. Circular dichroism spectral analysis revealed that the major enantiomer of the 7-OHM-12-MBA-trans-8,9-dihydrodiol formed by each organism has anS,S absolute configuration, while the major enantiomers of the 5,6-, 10,11- and 3,4-dihydrodiols had anR,R configuration. The mutagenic activity of extracts fromS. racemosum exposed to DMBA were determined inSalmonella typhimurium TA98. The mutagenicity of DMBA decreased by 36% over a period of 5 days as 33% of the compound was metabolized. Comparison of these results with previously reported results in mammalian systems suggests that there are similarities and differences between the fungal and mammalian oxidation of DMBA and that the overall balance of fungal metabolism is towards a detoxification rather than a bioactivation pathway.
TL;DR: Results indicate that the regimen of biweekly DMBA applications commits HBPE to neoplastic development within three weeks and that subsequent cellular or molecular changes occurring during greater than or equal to 2 succeeding weeks of DMBA treatment are necessary to manifest the transformation associated phenotypes of continuous passageability, anchorage-independent growth, and induction of NIH3T3 transformants following DNA transfection.
Abstract: Experiments were performed to determine the rate at which hamster buccal pouch epithelium (HBPE) is committed to neoplastic development during a regimen of biweekly topical applications of 7,12-dimethylbenz[a]anthracene (DMBA) in mineral oil, administered for 1, 2, 3, 5 or 10 weeks. Evaluated indices of neoplastic commitment were: (i) primary tumor formation, (ii) passageability of HBPE cells in surface culture, (iii) anchorage-independent growth in soft agar and (iv) induction of the transformed phenotype in NIH3T3 cells following transfection with HBPE DNA. Groups of 12-15 hamsters, exposed to DMBA for 1, 2 and 3 weeks, developed buccal pouch tumor incidences of 13%, 42% and 71% respectively within 44 weeks. Buccal pouches of ten control hamsters treated for three weeks with mineral oil did not develop buccal pouch neoplasms during an observation period of 44 weeks. Whereas cultured HBPE cells obtained following three weeks of in vivo DMBA exposure were negative in assays for anchorage-independent growth, passageability in surface culture and induction of NIH3T3 transformants following DNA transfection, similarly cultured cells obtained following five and ten weeks of in vivo exposure were positive, or marginally positive, in each of these assays. These results indicate that (i) the regimen of biweekly DMBA applications commits HBPE to neoplastic development within three weeks and that (ii) subsequent cellular or molecular changes occurring during greater than or equal to 2 succeeding weeks of DMBA treatment are necessary to manifest the transformation associated phenotypes of continuous passageability, anchorage-independent growth, and induction of NIH3T3 transformants following DNA transfection.
Journal Article•
TL;DR: The data suggest that DMBA in desensitizing lactotrophs to dopamine and in releasing PRL, by direct estrogen-like actions on anterior pituitary, may provide a hormonal state conducive to tumor development.
Abstract: The ability of 7,12-dimethylbenz( a )anthracene (DMBA), a potent inducer of mammary tumors, to mimic short term effects of estradiol (17β-E2) on the anterior pituitary, was tested in vitro . Incubation of anterior pituitaries from ovariectomized rats with DMBA resulted in a marked depletion of membrane dopamine receptors (labeled with [3H] spiperone) and a parallel stimulation of prolactin (PRL) release. Maximal receptor depletion and PRL release were obtained after 15–30 min of incubation with 10-8 m DMBA. These effects were reversible and already significant after a 5-min incubation. Their magnitude, dose dependency, and time course were identical to those reported for 17β-E2. A structurally related noncarcinogenic polycyclic aromatic hydrocarbon, phenanthrene, had no effect on [3H]spiperone binding or PRL release. When DMBA and 17β-E2, at suboptimal concentrations, were simultaneously added to the culture medium, no synergistic effect could be observed. When 10-8 m of both compounds were introduced simultaneously, the decrease in dopamine receptors and the increase in PRL release were not greater than those observed in the presence of 10-8 m of only one compound, indicating that the same mechanism(s) can be involved. These data suggest that DMBA in desensitizing lactotrophs to dopamine and in releasing PRL, by direct estrogen-like actions on anterior pituitary, may provide a hormonal state conducive to tumor development.
TL;DR: It is demonstrated that mouse mammary epithelial cells cultured inside collagen gels with serum-free media can metabolize DMBA to putative carcinogenic forms.
Journal Article•
TL;DR: The study suggests that the DMBA-induced hamster cheek pouch carcinoma may be useful in some molecular in vivo studies of chemical-DNA interactions in carcinogenesis.
Abstract: Studies examined the in vivo binding of radiolabeled 7,12-dimethylbenz(a)anthracene (DMBA) to hamster cheek pouch epithelial DNA. Adduct formation was studied as functions of [3H]DMBA dose and of the time after single [3H]DMBA applications in mineral oil. Total DMBA-DNA adduct formation was determined by DNA-bound 3H activity, and qualitative binding characteristics were further studied by high-pressure liquid chromatography. Adduct formation 24 h after single [3H]DMBA applications rapidly increased from DMBA concentrations of 0.05-5.0 micrograms. While binding also increased from DMBA concentrations of 5.0-50.0 micrograms, the variability in adduct formation at 50.0 micrograms was considerable. Adduct formation following single 5.0-micrograms [3H]DMBA applications rose slowly to a peak value of 76 pmol DMBA/mg DNA at 36 h. This level decreased very slowly in a biphasic manner through 240 h, at which time the adduct levels were 23% of maximum. Adduct levels of 1.5 pmol/mg DNA were measured as late as 5 wk after a single 5.0-micrograms [3H]DMBA application. Chromatographic analyses of the 24-, 36-, and 96-, and 240-h samples showed three major peaks which are likely to be 1,2,3,4-tetrahydro-3,4-dihydroxy-1,2-oxide-deoxyribonucleoside adducts. While these analyses were limited by the small amounts of radioactivity which could be retrieved from [3H]DMBA-treated pouches, the study suggests that the DMBA-induced hamster cheek pouch carcinoma may be useful in some molecular in vivo studies of chemical-DNA interactions in carcinogenesis.