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7,12-Dimethylbenz[a]anthracene
About: 7,12-Dimethylbenz[a]anthracene is a research topic. Over the lifetime, 1717 publications have been published within this topic receiving 40892 citations.
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TL;DR: Findings show that dietary cholesterol inhibits mammary tumorigenesis induced by either MNU or DMBA and that the inhibition is independent of the type or extent of mutations in the Ha-ras gene.
Abstract: Dietary cholesterol has previously been shown to inhibit rat mammary tumorigenesis but the mechanisms remain unclear. Uptake of serum low density lipoprotein cholesterol by tissues leads to down-regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate limiting enzyme in cholesterol biosynthesis that catalyzes the formation of mevalonate. In addition to being a precursor of cholesterol, mevalonate is necessary for DNA synthesis and cell proliferation. Isoprenoids, also derived from mevalonate, are required for the post-translational modification of Ras proteins that are mutated in a number of carcinogen-induced rat mammary tumors. The purpose of this study, therefore, was to determine whether inhibition of tumorigenesis by cholesterol is dependent on the frequency of mutations in the Ha-ras gene. Female Sprague-Dawley rats (30/group) were given a single dose of either N-methyl-N-nitrosourea (MNU, 50 mg/kg i.p.) or 7, 12-dimethylbenz[a]anthracene (DMBA, 100 mg/kg intragastrally), carcinogens that produce tumors with either a high (MNU) or low (DMBA) frequency of Ha-ras mutations in codon 12 or 61, respectively. Rats were fed either a control AIN-93G diet or the control diet supplemented with 0.3% cholesterol for 14 weeks. Dietary cholesterol significantly decreased the final tumor incidence in rats given DMBA (83 versus 100%, P < 0.05) or MNU (53 versus 77%, P < 0.05). HMG-CoA reductase activity was higher in mammary tumors than in normal mammary glands, but the activity of this enzyme was reduced by cholesterol feeding only in mammary glands and not in tumors. Tumors induced by MNU had a high frequency of Ha-ras mutations in both the control (65%) and cholesterol-fed (68%) groups. Tumors induced by DMBA had a low frequency of Ha-ras mutations that also did not differ between the control (21%) and cholesterol-fed (18%) groups. These findings show that dietary cholesterol inhibits mammary tumorigenesis induced by either MNU or DMBA and that the inhibition is independent of the type or extent of mutations in the Ha-ras gene.
38 citations
TL;DR: The flavonoid apigenin, which was previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model, suggesting that Apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins.
Abstract: The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague-Dawley rats by 7,12-dimethylbenz(a)anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA-induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor levels, or the number of estrogen receptor-positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor-positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins.
38 citations
TL;DR: The protection afforded by EO may be associated with its antioxidant capacity and through its modulatory effect on hepatic activation and detoxifying enzymes, which emphasizes its protective effect against the carcinogen.
Abstract: Ethanolic extract of Emblica officinalis (EO) fruit extract was evaluated for protection against genotoxicity induced by the rodent carcinogen, 7,12-dimethylbenz(a)anthracene (DMBA). Oral administr...
38 citations
TL;DR: Treatment with intraperitoneal alpha-naphthoflavone (ANF), a competitive inhibitor of polycyclic aromatic hydrocarbon metabolism by microsomal monooxygenases, inhibited oocyte destruction and suggested that the ovary contains the enzymes necessary to biotransform xenobiotics like 3-MC and DMBA to ovotoxic metabolites.
Abstract: Bilateral or unilateral intraovarian injection with the polycyclic aromatic hydrocarbons 3-methylcholanthrene (3-MC), or 7,12-dimethylbenz(a)anthracene (DMBA) destroys oocytes in C57BL/6N and DBA/2N mice. The threshold for small oocyte destruction following bilateral intraovarian treatment with 3-MC was between 0.1 and 1 microgram/ovary in both DBA/2N amd C57BL/6N mice. After intraovarian treatment with DMBA, a more potent ovotoxin, the thresholds for small oocyte destruction were between 0.01 and 0.1 microgram/ovary. Calculated ED50's for small oocyte destruction following bilateral intraovarian treatment with 3-MC were C57BL/6N, 0.33 micrograms/ovary; DBA/2N, 1.02 micrograms/ovary--for DMBA the ED50's were C57BL/6N, 0.11 micrograms/ovary; DBA/2N, 0.03 micrograms/ovary. Unilateral intraovarian treatment also destroyed oocytes in the treated ovary. Treatment with intraperitoneal alpha-naphthoflavone (ANF), a competitive inhibitor of polycyclic aromatic hydrocarbon metabolism by microsomal monooxygenases, inhibited oocyte destruction. Intraovarian treatment with ANF decreased oocyte destruction produced by intraovarian DMBA. These data suggest that both 3-MC and DMBA are indirect acting ovotoxins requiring metabolic activation before oocyte destruction occurs. In addition, these data also suggest that the ovary contains the enzymes necessary to biotransform xenobiotics like 3-MC and DMBA to ovotoxic metabolites. Metabolic activation of xenobiotics to reactive products within the ovary may represent a special threat to the integrity of oocyte DNA.
38 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.
38 citations