Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1992"
TL;DR: The effects of topical administration of curcumin on the formation of benzo,[a]pyrene (B[a]P)-DNA adducts and the tumorigenic activities of B[a?]P and 7,12-dimethylbenz[a].anthracene (DMBA) in epidermis were evaluated in female CD-1 mice.
Abstract: The effects of topical administration of curcumin on the formation of benzo[a]pyrene (B[a]P)-DNA adducts and the tumorigenic activities of B[a]P and 7,12-dimethylbenz[a]anthracene (DMBA) in epidermis were evaluated in female CD-1 mice. Topical application of 3 or 10 mumol curcumin 5 min prior to the application of 20 nmol [3H]B[a]P inhibited the formation of [3H]B[a]P-DNA adducts in epidermis by 39 or 61% respectively. In a two-stage skin tumorigenesis model, topical application of 20 nmol B[a]P to the backs of mice once weekly for 10 weeks followed a week later by promotion with 15 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 21 weeks resulted in the formation of 7.1 skin tumors per mouse, and 100% of the mice had tumors. In a parallel group of mice, in which the animals were treated with 3 or 10 mumol curcumin 5 min prior to each application of B[a]P, the number of tumors per mouse was decreased by 58 or 62% respectively. The percentage of tumor-bearing mice was decreased by 18-25%. In an additional study, topical application of 3 or 10 mumol curcumin 5 min prior to each application of 2 nmol DMBA once weekly for 10 weeks followed a week later by promotion with 15 nmol TPA twice weekly for 15 weeks decreased the number of tumors per mouse by 37 or 41% respectively.
286 citations
Journal Article•
TL;DR: The results of the present study suggest that GTP possesses anti-skin tumor-promoting effects, and that the mechanism of such effects may involve inhibition of tumor promoter-induced epidermal ornithine decarboxylase, cyclo oxygengenase and lipoxygenase activities, edema, and hyperplasia.
Abstract: Our laboratory has been studying cancer chemopreventive effects of polyphenolic fraction isolated from green tea (GTP). In prior studies we have shown that (a) GTP possesses antigenotoxic effects in various test systems; (b) topical application of GTP protects against UV radiation and chemical carcinogen-induced tumorigenesis in murine skin; and (c) feeding of GTP in drinking water p.o. to mice protects against carcinogen-induced forestomach and lung tumorigenesis. Recently, we showed that in a dose-dependent manner GTP inhibits tumor promoter-caused induction of epidermal ornithine decarboxylase activity in SENCAR mice (R. Agarwal et al., Cancer Res., 52: 3582-3588, 1992). In the present study, we assessed the effect of GTP on TPA-induced skin tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated SENCAR mouse. Topical application of varying doses of GTP (1-24 mg) 30 min prior to that of each TPA application resulted in highly significant protection against skin tumor promotion in a dose-dependent manner. The animals pretreated with GTP showed substantially lower tumor body burden such as decrease in total number of tumors per group, number of tumors per animal, tumor volume per mouse, and average volume per tumor, as compared to the animals that did not receive GTP. Since TPA-induced epidermal cyclooxygenase and lipoxygenase activities and edema and hyperplasia are conventionally used markers of skin tumor promotion, we also assessed the effect of preapplication of GTP on these parameters. As quantitated by the formation of prostaglandin and hydroxy-eicosatetraenoic acid metabolites from, respectively, cyclooxygenase- and lipoxygenase-catalyzed metabolism of arachidonic acid, skin application of GTP to SENCAR mice resulted in significant inhibition of TPA-caused effects on these 2 enzymes. Prior application of GTP to mouse skin also resulted in 30-46% inhibition of TPA-induced epidermal edema and hyperplasia. The results of the present study suggest that GTP possesses anti-skin tumor-promoting effects, and that the mechanism of such effects may involve inhibition of tumor promoter-induced epidermal ornithine decarboxylase, cyclooxygenase and lipoxygenase activities, edema, and hyperplasia. Further studies are in progress to define which component present in GTP is responsible for its anti-skin tumor-promoting effects.
169 citations
Journal Article•
TL;DR: The inhibitory effect of sesamin on DMBA-induced mammary carcinogenesis may be ascribed, at least in part, to immunopotentiation and increased antioxidative activity.
Abstract: The effects of dietary supplementation of sesamin on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats were studied. Experimental diets containing 0.2% sesamin (an equiweight mixture of sesamin and episesamin) or 0.2% alpha-tocopheryl acetate were given to rats starting 1 week before intragastric administration of DMBA (10 mg/rat). Sesamin significantly (p less than 0.05) reduced the cumulative number of palpable mammary cancers by 36% at 12 weeks post-DMBA administration compared with animals on a control diet. Alpha-tocopheryl acetate inhibited both the incidence and the cumulative number of mammary tumors by 20% and 45%, respectively. Concentrations of lipid peroxides in plasma, liver and tumors were all decreased in both sesamin and alpha-tocopheryl acetate groups. The activity of peripheral blood mononuclear cells (PBMC) increased in rats fed sesamin (140 to 150% of the control and alpha-tocopheryl acetate groups). Fatty acid compositions of plasma, liver and tumor phosphatidylcholine showed a decreased tendency of the metabolism of linoleic acid to arachidonic acid and hence of the plasma concentration of prostaglandin E2 in the sesamin group. The inhibitory effect of sesamin on DMBA-induced mammary carcinogenesis may be ascribed, at least in part, to immunopotentiation and increased antioxidative activity.
166 citations
Journal Article•
TL;DR: The finding that XSC acts as a chemopreventive agent in the DMBA mammary tumor model prompted us to examine the effect of dietary XSC on DMBA-DNA binding in both the liver and mammary tissue under conditions identical to those described for the bioassay.
Abstract: We synthesized a novel organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (XSC), possessing low toxicity by comparison with inorganic Na 2 SeO 3 , and several other synthetic organoselenium compounds (K. El-Bayoumy, Cancer Res., 45: 3631–3636, 1985). We tested the effect of XSC treatment during the initiation phase on 7,12-dimethylbenz( a )anthracene (DMBA)-induced mammary carcinoma formation. A semipurified high-fat diet containing 80 ppm of XSC (40 ppm as selenium) was fed to 6-wk-old virgin female Sprague-Dawley rats for 2 wk, starting 1 wk before and ending 1 wk after carcinogen treatment. At 7 wk of age, rats were given a single dose of DMBA (5 mg) in 0.2 ml of olive oil by gastric intubation; the experiment was terminated 16 wk later. The development of mammary tumors in those rats that received XSC-supplemented diets was significantly inhibited when compared with the control group (fed the same diet without XSC supplements). This was evident from tumor incidence (percentage of tumor-bearing rats, 88 versus 20) and multiplicity of tumors (mean number of tumors/rat, 3.96 versus 0.28). The finding that XSC acts as a chemopreventive agent in the DMBA mammary tumor model prompted us to examine the effect of dietary XSC on DMBA-DNA binding in both the liver and mammary tissue under conditions identical to those described above for the bioassay. Rats (four/group) were killed 6, 24, 48, and 168 h after [ 3 H]DMBA (5 mg/rat; specific activity, 51.2 mCi/mm) administration. Liver and mammary tissue were obtained and DNA was isolated. Dietary XSC was found to inhibit total DMBA-DNA binding in the mammary tissue, but not in the liver. The most profound effect was observed at early time points, i.e. , 24 to 48 h after [ 3 H]DMBA administration. The inhibition in total binding was attributed to a reduction in the formation of the three major adducts derived from bay-region diol-epoxides of DMBA; these were identified as anti -diol-epoxide:deoxyguanosine, syn -diol-epoxide:deoxyadenosine, and anti -diol-epoxide:deoxyadenosine adducts on the basis of their chromatographic characteristics on high-pressure liquid chromatography and on a boronate affinity column. The inhibition of the DMBA-DNA binding in the target tissue provides a plausible explanation for the chemopreventive effect of XSC during the initiation stage of carcinogenesis.
121 citations
TL;DR: It is demonstrated that garlic powder is effective in inhibiting DMBA-induced mammary tumors, possibly by reducingDMBA-DNA binding.
Abstract: The present studies determined the influence of dietary supplements of garlic powder (0, 1, 2 or 4%) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors and on the in vivo occurrence of mammary DMBA-DNA adducts in rats. Diets were offered 2 weeks before and 2 weeks following DMBA treatment (25 mg/kg body wt). An additional group was fed the 2% garlic powder diet throughout the 20 week study. Although food intake and weight gain were not influenced, dietary garlic powder supplementation did significantly delay the onset of first tumors (P < 0.01) and did reduce the final mammary tumor incidence (P < 0.01). Consumption of garlic powder also significantly depressed the in vivo binding of DMBA to mammary cell DNA. Binding of both anti- and syn-dihydrodiol epoxides to DNA was depressed in rats fed supplemental garlic powder. The activity of glutathione S-transferase (GST) in mammary and liver tissue from rats fed 2% dietary garlic powder was higher than observed in tissues from rats fed the basal diet. No further increase in GST activity occurred when the dietary garlic content was increased from 2 to 4%. Final mammary tumor incidence was found to correlate positively with total DMBA-DNA binding and the quantities of individual DMBA-DNA adducts. The present studies demonstrate that garlic powder is effective in inhibiting DMBA-induced mammary tumors, possibly by reducing DMBA-DNA binding.
106 citations
TL;DR: identification of several new DMBA-DNA adducts formed by one-electron oxidation, including twoAdducts lost from DNA by depurination, DMBA bound at the 12-methyl to the N-7 of adenine (Ade) or guanine (Gua) [7-methylbenz[a]anthracene (MBA-12-CH2-N7Ade or 7-MBA
Abstract: The DNA adducts of 7,12-dimethylbenz[a]anthracene (DMBA) previously identified in vitro and in vivo are stable adducts formed by reaction of the bay-region diol epoxides of DMBA with dG and dA. In this paper we report identification of several new DMBA-DNA adducts formed by one-electron oxidation, including two adducts lost from DNA by depurination, DMBA bound at the 12-methyl to the N-7 of adenine (Ade) or guanine (Gua) [7-methylbenz[a]anthracene (MBA-12-CH2-N7Ade or 7-MBA-12-CH2-N7Gua, respectively]. The in vitro systems used to study DNA adduct formation were DMBA activated by horseradish peroxidase or 3-methyl-cholanthrene-induced rat liver microsomes. The biologically-formed depurination adducts were identified by high-pressure liquid chromatography and by fluorescence line narrowing spectroscopy. Stable DMBA-DNA adducts were analyzed by the 32P-postlabeling method. Quantitation of DMBA-DNA adducts formed by microsomes showed about 99% as depurination adducts: 7-MBA-12-CH2-N7Ade (82%) and 7-MBA-12-CH2-N7Gua (17%). Stable adducts (1.4% of total) included one adduct spot that may contain adduct(s) formed from the diol epoxide (0.2%) and unidentified adducts (1.2%). Activation of DMBA by horseradish peroxidase afforded 56% of stable unidentified adducts and 44% of depurination adducts, with 36% of 7-MBA-12-CH2-N7Ade and 8% of 7-MBA-12-CH2-N7Gua. Adducts containing the bond to the DNA base at the 7-CH3 group of DMBA were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)
64 citations
Journal Article•
TL;DR: The results indicate that SENCAR mice have a short latency period for 7,12-dimethylbenz(a)anthracene-induced mammary tumor development and that rat and mouse mammary tumors development is modified by dietary LA in a similar manner, although in the SENCAR mouse dietary LA did not have a saturating effect.
Abstract: We recently reported (J. Leyton et al. , Cancer Res., 51: 907–915, 1991) an inverse correlation between skin tumor number and level of dietary linoleic acid (LA) in SENCAR mice following an initiationpromotion protocol. These results differed from the reported (C. Ip et al. , Cancer Res., 45: 1997–2001, 1985) positive correlation between dietary LA and tumor incidence for the rat mammary gland. The goal of the study reported here was to determine whether this dissimilarity was due to organ site or species differences. Female SENCAR mice were fed 1 of 3 15% fat diets containing LA at levels of 0.8, 4.5, and 8.4% before, during, and after intragastric administration of 6 mg (1 mg/week) 7,12-dimethylbenz(a)anthracene. A positive correlation between level of dietary LA and mammary tumor incidence was observed such that for the first 15 weeks, the incidence was greatest in the 8.4% LA diet group, followed by the 4.5% and then the 0.8% LA groups. Distinct dietary effects on latency were also noted in that 15, 12, and 8 weeks after cessation of 7,12-dimethylbenz(a)anthracene were required for a 40% carcinoma incidence in the 0.8, 4.5, and 8.4% LA diet groups, respectively. A histopathological analysis of all tumors revealed that the predominant type was the adenosquamous carcinoma, which comprised 46.6, 54.1, and 77.7% of all mammary tumors for diets containing 0.8, 4.5, and 8.4% LA, respectively. The second most common tumor was the adenocarcinoma type B, which was found with a frequency of 33% in the 0.8% and 4.5% LA diet groups and 22% in the 8.4% LA diet group. These results indicate that SENCAR mice have a short latency period for 7,12-dimethylbenz(a)anthracene-induced mammary tumor development and that rat and mouse mammary tumor development is modified by dietary LA in a similar manner, although in the SENCAR mouse dietary LA did not have a saturating effect. In addition, high dietary LA was found to be associated specifically with an increased incidence of adenosquamous carcinomas but not of other types of mammary tumors.
55 citations
TL;DR: Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7, 12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative as mentioned in this paper.
Abstract: Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative of 7,12-DMBA: 7-methylbenz[a]anthracene (MBA)-12-CH 2 -C8dG (13%), 7-MBA-12-CH 2 -N7Gua (55%), 12-MBA-7-CH 2 -N7Gua (12%), 7-MBA-12-CH 2 -C8Gua (10%), and 7,12-(CH 2 OH) 2 -BA (10%). The first three are primary products of the electrochemical reaction, whereas the last two are secondary products
52 citations
Journal Article•
TL;DR: The data indicate that DHEA stimulates the growth of DMBA-induced mammary tumors in ovariectomized rats, while it reduces the tumor progression in intact animals.
Abstract: The effect of dehydroepiandrosterone (DHEA) (2 mg, twice daily p.o.) on the growth of the dimethylbenz (a) anthracene (DMBA)-induced mammary carcinoma was studied in intact and ovariectomized adult female rats. DHEA treatment stimulated the tumor growth in ovariectomized animals. Conversely, the tumors of intact rats treated with DHEA progressed to a lesser extent than those of intact untreated animals (p < 0.01). Plasma levels of DHEA were higher in DHEA-fed than in untreated animals (p < .01), whereas E2 concentrations were unchanged after DHEA administration. Estrogen receptor (ER) concentrations in tumor tissue of ovariectomized animals given DHEA were no different form those found in intact rats, whereas ER were undetectable in untreated ovariectomized rats. The data indicate that DHEA stimulates the growth of DMBA-induced mammary tumors in ovariectomized rats, while it reduces the tumor progression in intact animals.
37 citations
TL;DR: It was concluded that the inhibitory effect of vitamin E in combination with selenium on tumorigenesis might be causally related to reduction of carcinogen treatment associated with lipid peroxidation, the latter presumably playing an important role in DMBA-induced mammary carcinogenesis.
Abstract: The effects of combined dietary vitamin E supplementation and a relatively low increase in selenium levels on 7,12-dimethylbenz[a]anthracene (DMBA) induction of lipid peroxidation in the short term and development of mammary tumors in the long term were investigated in female Sprague-Dawley rats. Control animals were fed the basal diet (20 mg/kg vitamin E and 0.6 mg/kg selenium) throughout the experiment. Three other groups received a high vitamin E diet (235 mg/kg vitamin E and 0.6 mg/kg selenium) at different times, the first two from three weeks after DMBA treatment and the other throughout the experiment. When the vitamin E diet with selenium supplementation was applied until three weeks after DMBA or until the termination of the experiment, tumor yields (tumors per rat) were significantly inhibited compared with the control group. On the other hand, delaying the supplementation of vitamin E until three weeks postcarcinogen produced no prophylactic effect. The elevation of lipid peroxidation levels observed immediately after DMBA administration was also significantly inhibited in both mammary fat pads and livers of animals in the high vitamin E group. It was therefore concluded that the inhibitory effect of vitamin E in combination with selenium on tumorigenesis might be causally related to reduction of carcinogen treatment associated with lipid peroxidation, the latter presumably playing an important role in DMBA-induced mammary carcinogenesis.
30 citations
TL;DR: The results suggested that the antitumor effect of 1α(OH)D3 on DMBA-induced mammary tumors was not related to ER status, and the side effects can be reduced by treatment schedule.
Abstract: 1α-hydroxyvitamin D3 [1α(OH)D3] was administered to female Sprague-Dawley rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. 1α(OH)D3 suppressed the growth of the rat mammary tumors dose-dependently, and in the high dose groups treated with 0.5–1.0µg/kg of 1α(OH)D3, significant inhibition of tumor growth was observed. But daily oral administration of 1α(OH)D3 for four consecutive weeks caused side effects such as hypercalcemia and weight loss. We compared 0.5 µg/kg of 1α(OH)D3 three times weekly with the same dose six times weekly to discover whether or not the side effects can be reduced by treatment schedule. Both groups showed a significant oncostatic effect, compared with the control group, while the side effects were relieved in the three times weekly group. Regarding estrogen receptors (ER) in the tumors, there was no significant difference among the groups. These results suggested that the antitumor effect of 1α(OH)D3 on DMBA-induced mammary tumors was not related to ER status. Combined use of 1α(OH)D3 with 5-fluorouracil (5-FU) or medroxyprogesterone acetate (MPA) was also examined. No significant augmentation of the antitumor effect was seen in the two combinations, although the combined therapy with MPA showed a significant inhibition of weight loss in the rats.
TL;DR: Morphometric analysis of this animal model further defines the dynamic changes in the mouse ovary in response to DMBA as a dose-dependent decrease in ovarian volume and number of corpora lutea in each ovary.
TL;DR: The data from a limited number of skin tumors suggests that ras gene mutation may not be critically involved in this transmission and confirms the previous finding that initiation of skin and lung tumorigenesis can be transmitted transgenerationally.
Abstract: Transgeneration transmission of the carcinogenic action of 7,12-dimethylbenz[a]anthracene (DMBA) was studied in two generations of mice using transplacental DMBA initiation followed by postnatal skin tumor promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) in the first generation (F0) and only promotion in the second generation (F1). Local application of TPA resulted in increased skin tumor yield in both the in utero DMBA-exposed mice and their progeny (P = 0.0002 and P = 0.0941 respectively compared to control). Similarly, lung tumor incidence was increased in the two generations of mice (P less than 0.0001 and P = 0.0080 respectively). The results suggest transgeneration transfer of the effect of DMBA. A to T mutation at the second base of codon 61 of the Ha-ras oncogene was found in skin tumors of DMBA-exposed mice, but not in tumors induced by TPA without initiation. Analysis of Ki-ras codon 61 in seven lung tumors from DMBA-treated mice revealed three types of mutation: two cases with CA[C or G or T], one case with CCA and one case with CTA (the remaining cases having only the wild type). Six of these mice also had skin tumors, which contained A to T mutation at the second base of codon 61 of the Ha-ras gene in five cases. Thus mutations of different ras genes were found in skin and lung tumors from the same animals. In the progeny (F1) of DMBA-exposed F0 mice, only skin tumor samples were available for oncogene analysis and none contained the Ha-ras mutation. The results confirm our previous finding that initiation of skin and lung tumorigenesis can be transmitted transgenerationally. On the other hand, our data from a limited number of skin tumors suggests that ras gene mutation may not be critically involved in this transmission.
TL;DR: The ability of dietary selenium to inhibit the in vivo metabolism of DMBA under a variety of conditions was confirmed, as well as the ability of supplemental selenite to lower DMBA binding to mammary cell DNA increased as the quantity of the carcinogen administered increased.
Abstract: The present studies determined the impact of age, dietary selenium and 7,12-dimethylbenz(a)anthracene (DMBA) dosage on the occurrence of DMBA-DNA adducts in rat mammary tissue. Diets formulated to contain selenium, as sodium selenite, at 0.1 (control) or 2.0 mg/kg were fed for 2 wk before DMBA treatment. Food intake and weight gain were not influenced by selenium intake. Anti- and syn-dihydrodiol epoxide adducts reached maximum binding by 24 and 36 h, respectively, after treatment with DMBA. Consumption of the diet containing 2.0 mg Se/kg inhibited the appearance of both anti- and syn-adducts by approximately 50% compared with controls. The occurrence of DMBA-DNA adducts correlated with a dosage of DMBA from 5 to 50 mg/kg body wt (r greater than or equal to 0.95). The ability of supplemental selenite to lower DMBA binding to mammary cell DNA increased as the quantity of the carcinogen administered increased. DMBA-DNA binding was found to increase with the increasing age of the rat. Nevertheless, dietary selenium supplementation was effective in reducing DMBA binding to DNA in all ages examined. These data confirmed the ability of dietary selenium to inhibit the in vivo metabolism of DMBA under a variety of conditions.
TL;DR: Results indicate that DMBA affects the organization of neuronal plasma membrane in the hypothalamus of Sprague-Dawley rats, and it appears that the estrogen-sensitive mechanism of DMBA activation may be lacking in Wistar rats.
Journal Article•
TL;DR: The results indicate that SMANCS should have less systemic toxicity and a better therapeutic effect than NCS, and red blood cell counts and hemoglobin amounts decreased significantly in rats receiving NCS but no such effects were apparent in the SMAN CS group.
Abstract: We previously found that a high-molecular-weight anticancer agent, polystyrene-co-maleic acid conjugated neocarzinostatin (SMANCS), in which two chains of styrene/maleic acid copolymer are conjugated to the anticancer protein neocarzinostatin (NCS), accumulated more selectively in tumor tissue than in normal tissue and was more stable than NCS in blood. These results indicate that SMANCS should have less systemic toxicity and a better therapeutic effect than NCS. In this study, the antitumor activity and adverse effects of SMANCS were compared with those of NCS by using rat mammary tumor induced by 7,12-dimethylbenz[a]anthracene. When tumors of rats, that had received 7,12-dimethylbenz[a]anthracene (20 mg/kg, one dose, p.o. in oily formulation), became palpable usually after 4–20 weeks, SMANCS treatment was initiated. Thirty days after i.v. administration of SMANCS (0.1 mg/kg 3 times and 0.3 mg/kg 3 times), tumors had shrunk in 35 of 37 rats (a mean weight was about 10% of control value; or decreased to about 30% of the value of before treatment in tumor weight); tumor size had not changed in 1 rat, and in the remaining 1 rat the tumor had enlarged. Thirty days after i.v. administration of NCS, tumors had shrunk in 8 of 14 rats, but the tumor size was unchanged in 1 rat and was enlarged in 5. In the control group, all tumors had enlarged. Development of new tumors was completely prevented by the administration of SMANCS. Histological examination of sequential slices of tumor revealed clear finding of degeneration and tumor encapsulation at 30 days after initial administration of SMANCS, with an accompanying fatty degeneration, but these effects were not observed for tumors treated with NCS. Although red blood cell counts and hemoglobin amounts decreased significantly in rats receiving NCS, no such effects were apparent in the SMANCS group.
TL;DR: Data suggest that controlled-release formulations giving constant and low blood levels of MPA could be used for the treatment of breast cancer in women and should avoid the side effects observed with the high doses of the compound.
Abstract: Since our previous findings had indicated that the androgenic steroid medroxyprogesterone acetate (MPA) exerts potent inhibitory effects on 7,12-dimethylbenz(a)anthracene (DMBA)-induced tumor growth, we have studied the effect of low doses of MPA released from Depo-Provera and from 50:50 poly[DL-lactide-co-glycolide] microspheres in the same DMBA-induced tumor model. The present data show that single subcutaneous injection of a 4-month controlled-release formulation of biodegradable 50:50 poly[DL-lactide-co-glycolide] microspheres containing 10 mg of MPA giving serum levels of 3.14±0.32 ng/ml (8.12±0.83 nM) MPA causes a maximal or near-maximal 60% inhibition of tumor growth measured 56 days later. Such data suggest that controlled-release formulations giving constant and low blood levels of MPA could be used for the treatment of breast cancer in women. Such a low concentration of MPA should avoid the side effects observed with the high doses of the compound.
TL;DR: It is concluded that the depletion of LC from carcinogen-treated skin is due to the increased LC migration and not carcinogens-induced cell death.
TL;DR: It is concluded from experiments with immature PMSG-treated rats, that DMBA mono-oxygenase activity is localized in follicular granulosa (and/or theca) cells, and is recovered in a population of cells harvested at a higher density on the Percoll gradient.
TL;DR: The data suggest that DMBA-induced ovarian cancer in rats is a good experimental model for human ovarian cancer, and that Mn-SOD is also a good marker for disease in the animal model.
Abstract: Manganese superoxide dismutase (Mn-SOD) is strongly expressed in human ovarian cancer, and the serum level of the enzyme is a useful marker for the diagnosis and monitoring of human ovarian cancer. In the present study we found that Mn-SOD was highly expressed in primary and transplanted ovarian cancers in rats induced by 7,12-dimethylbenz[a]anthracene (DMBA), as judged by enzyme-linked immunosorbent assay as well as by Northern blot analysis. The serum levels of Mn-SOD in the tumor-bearing rats were also higher than those in control rats. The antibody strongly reacted with rat ovarian carcinoma tissues. These data suggest that DMBA-induced ovarian cancer in rats is a good experimental model for human ovarian cancer, and that Mn-SOD is also a good marker for disease in the animal model.
Journal Article•
TL;DR: The DNA adduct concentrations formed were comparable to both in vitro and in vivo experiments with both mammals and fishes, indicating that relatively small, "environmentally realistic" doses of PAH have the ability to bind significantly to critical cellular macromolecules of young fish in vivo.
Abstract: Juvenile rainbow trout were exposed via two intramuscular injections to either 14C-DMBA for 24 hr or 14C-BaP for 48 hr, after which the livers were removed for DNA extraction and analysis. In the fish exposed to 14C-BaP, 0.2 ng was bound to the DNA, representing 0.5% of the total liver PAH-derived radioactivity and 2.38% of the administered dose. Liver DNA and RNA were found to contain 0.5% of the administered dose, respectively. Liver analysis of rainbow trout exposed to 14C-DMBA demonstrated that 0.4 ng and 0.3 ng were bound to the DNA and RNA, respectively. This represents 1.0% and 0.6% of the liver DMBA burden, respectively. The DNA adduct concentrations formed were comparable to both in vitro and in vivo experiments with both mammals and fishes, indicating that relatively small, "environmentally realistic" doses of PAH have the ability to bind significantly to critical cellular macromolecules of young fish in vivo.
TL;DR: Since the spleen has previously been found to be less sensitive to DNA fragmentation induced by DMBA than the PPs, these results suggest that covalent binding may not be the primary determinant of lymphotoxicity in these organs.
TL;DR: It is reasonable to conclude that beta-carotene-mediated modification of adducts is associated with the inhibition of a syn-adduct, which is derived from further metabolism of a 7-OHM-12-MBA intermediate.
01 Jan 1992
TL;DR: The results suggest that estrogen stimulates the production of t-PA but not u-PA and that this estrogen dependency oft-PA is limited to malignant DMBA-mammary tumor cells.
Abstract: The hormonal regulation of two plasminogen activators, tissue-type plasminogen activator (t-PA) and urokinase (u-PA), was studied both in 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinoma and in DMBA-induced rat mammary dysplasia. t-PA activity in DMBA-mammary carcinoma was decreased markedly by oophorectomy and recovered upon estradiol administration to reach the maximum level at 12 hr. In contrast to its effect on DMBA-mammary carcinoma, estradiol had no effect on t-PA activity in DMBA-mammary dysplasia. Furthermore, DMBA-mammary carcinoma cells in primary culture displayed similar estrogen-dependency in production of t-PA, while t-PA production in DMBA-mammary dysplasia cells was not under the control of estradiol in vitro. Moreover, estrogen-stimulated production of u-PA activity was not observed in DMBA-mammary carcinoma cells or DMBA-mammary dysplasia cells both in vivo and in vitro. Taken together, these results suggest that estrogen stimulates the production of t-PA but not u-PA and that this estrogen dependency of t-PA is limited to malignant DMBA-mammary tumor cells.
TL;DR: The present result demonstrated that the simple and rapid AO supravital staining method is a valuable and easier method for obtaining dose- and time-response data for quantification of micronucleus induction by chemicals.
Abstract: Micronucleus assays using mouse peripheral blood stained vitally on acridine orange (AO)-coated slides were evaluated at two laboratories with 7,12-dimethylbenz[a]anthracene (DMBA) and compared with the standard bone marrow assay. DMBA was administered by single intraperitoneal injection to CD-1 mice at doses ranging from 5 to 80 mg/kg, then 5 microliters of peripheral blood was sampled from a tail vein at 24, 48, 72, 96, and 120 h after treatment. Similar incidences of micronucleated young erythrocytes were observed in peripheral blood reticulocytes and bone marrow polychromatic erythrocytes. The dose response of micronucleated reticulocytes was delayed compared to that of micronucleated polychromatic erythrocytes. The dose-response curves after treatment with DMBA differed depending on the sampling times, which revealed the difficulty of obtaining accurate dose-response relations in the micronucleus assay. The present result demonstrated that the simple and rapid AO supravital staining method is a valuable and easier method for obtaining dose- and time-response data for quantification of micronucleus induction by chemicals.
TL;DR: Investigation of the stimulatory effect of a high-fat diet on tumorigenesis, tumor proliferation and cell kinetics of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in Sprague-Dawley rats found that switching from aHighfat diet to a low-fat diets may improve the prognosis of breast cancer.
Abstract: We investigated the stimulatory effect of a high-fat diet on tumorigenesis, tumor proliferation and cell kinetics of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in Sprague-Dawley rats, and sought to determine whether switching the animals from a high-fat diet to a low-fat diet would suppress tumor proliferation and cell kinetics. The high-fat diet significantly stimulated tumorigenesis, tumor proliferation and cell kinetics. After the animals were switched from the high-fat diet to the low-fat diet, however, tumor growth decreased, the BrdUrd labeling indices of tumors significantly decreased, and the potential doubling times of tumors significantly increased. Therefore, switching from a high-fat diet to a low-fat diet may improve the prognosis of breast cancer.
TL;DR: Results suggest DMBA induces a repair process that limits its own effectiveness--a process that can be sustained by other PAHs.
Abstract: The combined action of 7,12-dimethylbenz[a]anthracene (DMBA) and alpha-naphthoflavone (alpha NF) on the survival and neoplastic transformation of C3H10T1/2 mouse embryo fibroblasts has been examined and correlated with DNA adduct formation and removal. When a 24 h DMBA treatment of asynchronously growing cells was followed for the next 24 h by a treatment with alpha NF + DMBA, both killing and transformation per viable cell were abrogated to a large extent. In some instances, transformation was completely abrogated--i.e. reduced to control frequencies--even at nontoxic concentrations of DMBA, indicating that changes in survival were not the reason for the reduction in transformation. Even at toxic concentrations of DMBA, post-treatment with alpha-NF + DMBA resulted in 10-fold reductions in transformation frequency. 3-Methylcholanthrene (3MC) also reversed DMBA cytotoxicity but with a dependence on 3MC concentration that was qualitatively different from that for alpha NF. The abrogation of cell killing occurred at lower molar ratios of alpha NF:DMBA than the abrogation of transformation; less than or equimolar concentrations resulted in maximal abrogation of killing, but about equal concentrations were required to abrogate transformation. Although the preceding findings suggest that different mechanisms may be involved in these endpoints, taken together they suggest that second treatments make apparent the repair of lesions due to a first treatment with DMBA alone. To test this hypothesis, the formation and removal of DMBA-DNA adducts were measured. Adducts were not removed when the second treatment was growth medium alone, but enhanced removal was observed when second treatments consisted of DMBA alone or DMBA plus one of several other polycyclic aromatic hydrocarbons (PAHs). Relative to killing and neoplastic transformation, these results suggest DMBA induces a repair process that limits its own effectiveness--a process that can be sustained by other PAHs.
TL;DR: Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7, 12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative.
Abstract: Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative of 7,12-DMBA: 7-methylbenz[a]anthracene (MBA)-12-CH 2 -C8dG (13%), 7-MBA-12-CH 2 -N7Gua (55%), 12-MBA-7-CH 2 -N7Gua (12%), 7-MBA-12-CH 2 -C8Gua (10%), and 7,12-(CH 2 OH) 2 -BA (10%). The first three are primary products of the electrochemical reaction, whereas the last two are secondary products