Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1981"
Journal Article•
TL;DR: The hypothesis that melatonin inhibits the development of DMBA-induced mammary tumors in the rat while removal of the pineal gland stimulates development of such tumors is supported.
Abstract: The effects of the pineal hormone, melatonin, and of pinealectomy on the incidence of mammary adenocarcinoma in Sprague-Dawley rats treated with 7,12-dimethylbenz(alpha)-anthracene (DMBA) were investigated. Melatonin (2.5 mg/kg), begun on the same day as DMBA (5 mg) treatment and given daily in the afternoon for 90 days, significantly reduced the incidence of mammary tumors from 79% (control) to 20% (treated) (p less than 0.002). Rats pinealectomized at 20 days of age and treated with 7 mg of DMBA at 50 days of age had a higher incidence of tumors (88%) compared to control animals (22%). Fifteen mg of DMBA, which resulted in a higher incidence of tumors, reduced the difference between pinealectomized and control animals. Melatonin only partially reversed the effects of pinealectomy, reducing the incidence from 87% (pinealectomy alone) to 63% (pinealectomy plus melatonin); however, the tumor incidence was still lower (27%) in nonpinealectomized, melatonin-treated animals. Assessment of plasma prolactin, luteinizing hormone, follicle-stimulating hormone, estradiol, and cortisol in DMBA-treated tumor-free and tumor-bearing animals revealed a significantly lower plasma prolactin concentration [27 +/- 5 (S.E.) ng/ml] in melatonin-treated animals as compared to vehicle-treated animals [65 +/- 8 ng/ml]. The concentration of plasma prolactin was less in melatonin-treated, pinealectomized rats (55 +/- 10 ng/ml) as compared to vehicle-treated, pinealectomized animals (101 +/- 13 ng/ml). Other hormones were not affected by melatonin treatment. These data support the hypothesis that melatonin inhibits the development of DMBA-induced mammary tumors in the rat while removal of the pineal gland stimulates development of such tumors. Additionally, these experiments provide evidence that these effects may be mediated by a suppression of plasma prolactin levels.
308 citations
TL;DR: Long-term treatment with the adrenal steroid dehydro-epiandrosterone reduces weight gain without suppressing appetite and inhibits the occurrence of 7,12-dimethylbenz[a]anthracene- and urethan-induced lung tumors in A/J mice.
Abstract: Long-term treatment with the adrenal steroid dehydro-epiandrosterone reduces weight gain without suppressing appetite and inhibits the occurrence of 7,12-dimethylbenz[a]anthracene- and urethan-induced lung tumors in A/J mice.
130 citations
Journal Article•
TL;DR: The increased sensitivity of SENCAR's was apparent regardless of route of administration of initiator or the age or sex of the mice, which suggests that enhanced metabolic activation of hydrocarbon carcinogens by SENCAR mice is unlikely to account for their sensitivity.
Abstract: In order to define factors which determine susceptibility to chemical carcinogenesis, mice sensitive (SENCAR) and resistant (BALB/c) to epidermal carcinogenesis were studied under several treatment conditions for sensitivity to initiation by 7,12-dimethylbenz(a)anthracene or N -methyl- N ′-nitro- N -nitrosoguanidine and promotion by 12- O -tetradecanoylphorbol-13-acetate. In newborns of both strains, topical application of initiator was much less effective than in adults. However, initiation by i.p. injection of 7,12-dimethylbenz(a)anthracene is at least as effective in newborns as in adults, which may indicate that topically applied carcinogen is not delivered effectively to target cells in newborns. Thus, newborn epidermis can respond to 7,12-dimethylbenz(a)anthracene as well as adult epidermis when the initiator is appropriately administered. SENCAR mice are much more sensitive than are BALB/c mice to both initiators, which suggests that enhanced metabolic activation of hydrocarbon carcinogens by SENCAR mice is unlikely to account for their sensitivity. Newborn male SENCAR's developed approximately 50% more papillomas than did females in all groups. BALB/c newborn mice developed so few tumors that a meaningful comparison of sensitivity of males and females could not be made. Thus, the increased sensitivity of SENCAR's was apparent regardless of route of administration of initiator or the age or sex of the mice. SENCAR mice also developed a significant number of papillomas and squamous cell carcinomas with 12- O -tetradecanoylphorbol-13-acetate promotion in the absence of an exogenous initiator. Therefore, the skin of SENCAR mice may contain an initiated population of cells capable of responding to tumor promoters.
110 citations
TL;DR: The results suggest that cultured cell lines derived from different portions of the intestinal tract have similar properties in vitro, but they may have very different responses to chemical carcinogens.
Abstract: Two epithelial cell lines have been established from the duodenum (IEC-17) and the ileum (IEC-18) of outbred germfree Crl:CD(SD)GN rats. They have a very similar morphology and ultrastruture, a normal rat diploid karyotype, comparable growth rates, and a similar set of surface antigens as detected with monoclonal antibodies specific for intestinal epithelial cell surface proteins in vivo. Both cell lines do not grow in soft agar and when injected into syngeneic animals do not form tumors. The toxic effects of benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA) were studied in these two cell lines. The IEC-18 cells were found to be much more sensitive to both chemicals than the IEC-17 cells. In paticular, at concentrations greater than 1 ..mu..g/ml, DMBA completely and irreversibly inhibited cell proliferaion in the IEC-18 cells, whereas it produced a less marked and reversible inhibition in the IEC-17 cells. The metabolism of BP and DMBA to water-soluble products was studied; BP was apparently metabolized at similar rates in the two cell lines, whereas a striking difference was observed with DMBA, which was metabolized at a rate 10-15 times greater in the IEC-18 cells than that in the IEC-17 cells. These results suggest that cultured cell lines derived frommore » different portions of the intestinal tract have similar propertes in vitro, but they may have very different responses to chemical carcinogens.« less
95 citations
TL;DR: The presence of polycyclic aromatic hydrocarbons in petroleum, including BaP, chrysene, and DMBA, significantly enhances the overall embryotoxicity in avian species.
Abstract: Studies with different avian species have revealed that surface applications of microiiter amounts of some crude and fuel oils that coat less than 10% of the egg surface result in considerable reduction in hatching with teratogenicity and stunted growth. Other studies have shown that the embryotoxicity is dependent on the aromatic hydrocarbon content, further suggesting that the toxicity is due to causes other than asphyxia. In the present study the effects of three polycyclic aromatic hydrocarbons identified in petroleum were examined on mallard (Anas platyrhynchos) embryo development. Addition of benzo[a]‐pyrene (BaP), chrysene, or 7,12‐dimethylbenz[a]anthracene (DMBA) to a synthetic petroleum hydrocarbon mixture of known composition and relatively low embryotoxicity resulted in embryotoxicity that was enhanced or equal to that of crude oil when 10 μl was applied externally to eggs at 72 h of development. The order of ability to enhance embryotoxicity was DMBA > BaP > chrysene. The temporal pattern of e...
85 citations
TL;DR: It is demonstrated that supplemental selenium inhibits both chemical-and viral-induced mouse mammary tumorigenesis, and that the development of preneoplastic lesions, an early stage in mammary tumorsigenisation, is very sensitive to seLenium-mediated inhibition.
Abstract: The effect of supplemental selenium on 7,12-dimethylbenz[a] anthracene (DMBA)-induced mammary tumorigenesis was investigated in several mouse strains. Selenium, administered as SeO2 in the drinking water, inhibited mammary tumor formation in DMBA-treated (C57BL x DBA/2f)F1, C3H/StWi and BALB/c female mice. In addition, selenium inhibited the occurrence of DMBA-induced ductal hyperplasias in (C57BL x DBA/2f)F1 and BALB/c mice and mammary tumour virus-induced alveolar hyperplasias in BALB/cfC3H mice. Selenium did not alter the growth of established mammary tumors. These results demonstrate that supplemental selenium inhibits both chemical-and viral-induced mouse mammary tumorigenesis, and secondly, that the development of preneoplastic lesions, an early stage in mammary tumorigenesis, is very sensitive to selenium-mediated inhibition.
82 citations
65 citations
Journal Article•
TL;DR: The data indicate that the primary response to chronic DMBA exposure is a dose-dependent size increase of spontaneous aortic lesions and not the induction of new lesions.
Abstract: The prevalence, size, and patterns of distribution of arterial lesions (plaques) were investigated in cockerels exposed chronically to 7,12-dimethylbenz( a )anthracene (DMBA). Animals, from 5 to 20 weeks of age, received weekly i.m. injections of 5, 10, or 20 mg of DMBA per kg, dissolved in dimethyl sulfoxide. Control animals received weekly injections of dimethyl sulfoxide. All animals were sacrificed at 21 weeks of age. The entire aorta from each animal was cut transversely into 5-mm segments starting at the iliac trifurcation. The cross-sectional area of plaques was determined by light microscopic analysis of sections taken from the face of each segment. Plaque frequency was similar in DMBA-treated and control groups. However, mean plaque cross-sectional area was 7- to 11-fold higher for the treatment groups than for the controls. The distribution of plaque areas in both treated animals and controls was consistent with a log normal distribution. Median cross-sectional area and plaque volume index each increased in a linear fashion with DMBA dose. Small plaques were present in all groups. Large plaques were present only in DMBA-treated animals. Labeling indices of plaques, although low, were 2.3- to 26-fold higher than for underlying medial smooth muscle cells. The data indicate that the primary response to chronic DMBA exposure is a dose-dependent size increase of spontaneous aortic lesions and not the induction of new lesions.
60 citations
TL;DR: The experimental results were consistent with the hypothesis that the early GGT-stained cell populations in hamster buccal pouch mucosa are preneoplastic in nature.
Abstract: The utility of gamma-glutamyl transpeptidase (GGT) was explored as a histochemical marker for chemical carcinogenesis in hamster buccal pouch mucosa. One or both buccal pouches of 18 noninbred male Syrian golden hamsters were treated topically with 0.5% 7,12-dimethylbenz(a)anthracene (DMBA) in mineral oil over 16 weeks to produce numerous epithelial lesions at various stages of neoplastic development. Both buccal pouches of 4 control animals were similarly treated with mineral oil alone. GGT activity was not detectable in untreated pouches or pouches treated with mineral oil alone. With this technique, multiple discrete GGT-stained areas were visible in wholemounts prepared at 1 and 6 weeks after the final application of DMBA. The experimental results were consistent with the hypothesis that the early GGT-stained cell populations are preneoplastic in nature.
57 citations
TL;DR: The results suggest that age and parity not only lower the binding of DMBA to mammary epithelial cell DNA but also increase the efficiency of DNA repair processes, which may explain the lower susceptibility of OV and P rats to DMBA-induced mammary carcinogenesis.
Abstract: The effect of age and parity on the binding of 7,12-dimethybenz[a]anthracene (DMBA) to DNA and the repair of DMBA-damaged DNA have been demonstrated in logarithmic phase and confluent mammary epithelial cell cultures from young virgin (YV), old virgin (OV), and parous (P) noninbred and inbred Sprague-Dawley rats. Over a dose range of 0.1-0.4 micrograms DMBA/ml, DNA binding was 1.5-to 2.0-fold higher in YV cells than in OV or P cells. In addition, a steeper slope of the dose-response curve was obtained with YV cells, suggesting a greater susceptibility of YV cells to DMBA. Excision repair was determined by measuring, in the presence of hydroxyurea and 5-bromodeoxyuridine, tritiated thymidine incorporation into DNA during the repair process. At high doses od DMBA (0.5-2.0 micrograms/ml), excision repair in YV cells was 1.5 times higher than in OV cells and 2 times higher than in P cells. However, with lower DMBA doses (less than 0.5 micrograms/ml) similar levels of repair were obtained in all 3 groups of rats. Since binding to DNA is higher in YV cells at these low DMBA doses, ti is apparent that OV and P cells exhibit a greater DNA repair per unit damage. These results, therefore, suggest that age and parity not only lower the binding of DMBA to mammary epithelial cell DNA but also increase the efficiency of DNA repair processes, which may explain the lower susceptibility of OV and P rats to DMBA-induced mammary carcinogenesis.
50 citations
TL;DR: It is suggested that fat intake does not result in any intrinsic difference in the biochemical action of estrogen, and most (approximately 70%) of the tumors in all 3 dietary groups regressed in response to ovariectomy, which suggested that dietary fat has very little influence on the estrogen dependence of the tumor.
Abstract: The effect of dietary fat on mammary tumor incidence, estrogen-binding capacity as related to the hormone dependency of the tumors, and circulating estrogen levels in Sprague-Dawley rats given an oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) was investigated. Rats were fed diets consisting of 0.5, 5, or 20% corn oil starting at weaning and were administered 5 mg DMBA at 50 days of age. Tumor incidences were 13, 46, and 75% for the groups given 0.5, 5, and 20% fat, respectively, when the experiment was terminated 20-22 weeks later. Serum estradiol, measured at proestrus at 50 days of age and at the end of the experiment, was slightly depressed at both time points in rats fed the 0.5% fat diet but was similar in the other 2 groups. Serum estrone levels were not significantly different at either time point. Estrogen receptor levels in the tumor were the same in the groups given 5 and 20% fat but were lower in the group given 0.5% fat. No difference was detected in the progesterone receptor concentrations. Furthermore, most (approximately 70%) of the tumors in all 3 dietary groups regressed in response to ovariectomy, which suggested that dietary fat has very little influence on the estrogen dependence of the tumor. This observation suggested that fat intake does not result in any intrinsic difference in the biochemical action of estrogen.
TL;DR: The antimutagenic effects of selenium as sodium selenite were investigated using the Ames Salmonella/microsome mutagenicity test and cannot be explained by lethality ofSalmonella typhimurium.
Abstract: The antimutagenic effects of selenium as sodium selenite were investigated using the Ames Salmonella/microsome mutagenicity test. The compounds examined were acridine orange and 7,12-dimethylbenz[ a ]anthracene. Selenium (22 ppm) reduced the number of histidine revertants caused by 20 μg acridine orange and 20 μg 7,12-dimethylbenz[ a ]anthracene by 52 and 74%, respectively. Increasing the quantity of selenium added to the plates further suppressed the mutagenicity of the test compounds. The antimutagenic effects of selenium cannot be explained by lethality of Salmonella typhimurium .
Journal Article•
TL;DR: A study of tumor incidence and tumor growth rates in 7,12-dimethylbenz(a)anthracene-treated female Sprague-Dawley rats fed different types and amounts of dietary fat indicates that the difference in tumor incidence may be a reflection of marked differences in the growth of neoplastic clones to a palpable size within the time frame of the study.
Abstract: A study of tumor incidence and tumor growth rates in 7,12-dimethylbenz( a )anthracene-treated female Sprague-Dawley rats fed different types and amounts of dietary fat indicates that the difference in tumor incidence may be a reflection of marked differences in the growth of neoplastic clones to a palpable size within the time frame of the study. In addition, the observation is made that some antioxidants which inhibit tumor development in animals fed commercial rations are not effective when given in purified diets.
Journal Article•
TL;DR: The 3-methylcholanthrene- and phenobarbital-induced enzymes showed a significantly different regioselectivity toward the metabolism of DMBA or 7-OHM-12-MBA and are attributed to different forms of cytochrome P-450 present in the enzyme preparations.
Abstract: The metabolism of 7,12-[14C]dimethylbenz(a)anthracene ([14C]DMBA) and 7-[7-CH2-3H]hydroxymethyl-12-methylbenz(a)anthracene ([7-CH2-3H]7-OHM-12-BMA) by rat liver nuclei and microsomes was studied by high-performance liquid chromatography. DMBA and 7-OHM-12-MBA are metabolized at methyl group(s) and at the aromatic ring carbons to form trans-dihyrodiols at positions 3, 4, 5, 6, 8, 9, and 10,11 and phenols at positions 2, 3, and 4 by both nuclear and microsomal enzymes. Both nuclear and microsomal monooxygenase enzyme activities were inducible by pretreatment of the animals with phenobarbital or 3-methylcholanthrene. The rates of formation of all metabolites by microsomes were five- to 20-fold higher than those by nuclei in metabolizing DMBA or 7-OHM-12-MBA. The presence of a hydroxyl group at the 7-methyl position of DMBA markedly decreased the rate of metabolism. The rate of total metabolism of 7-OHM-12-MBA was only 20 to 70% of that of DMBA under identical in vitro incubation conditions. The 3-methylcholanthrene- and phenobarbital-induced enzymes showed a significantly different regioselectivity toward the metabolism of DMBA or 7-OHM-12-MBA and are attributed to different forms of cytochrome P-450 present in the enzyme preparations.
TL;DR: Differences in effectiveness of BHT as a tumor inhibitor in the 2 model systems, and thoughts as to a possible mechanism of action with regard to BHT are discussed.
TL;DR: Promotion treatment of 12-O-tetradecanoylphorbol-13-acetate led to an activation of initiated tumor cells in those organs in which a very sensitive, more or less narrowly spaced oncogenic determination period exists.
Abstract: The tumor spectrum and tumor incidence in organs other than the skin were investigated in the 12-O-tetradecanoylphorbol-13-acetate (TPA) treated F 1-generation of 13 groups of NMRI mice which had been initiated by a single intragastric dose of 7,12-dimethylbenz[a]anthracene during days 6, 8, and 10--20 of pregnancy. Promotion by topical application of TPA to the back skin was carried out twice per week 12 weeks after birth over a period of 26 weeks. The forestomach epithelium represented the only organ in which statistically significant 2-stage carcinogenesis could be demonstrated. A promotion effect could be seen in tumors of the Harderian gland, of the liver of male animals and on the development of both benign and malignant tumors of the lung in both sexes. Promotion treatment therefore led to an activation of initiated tumor cells in those organs in which a very sensitive, more or less narrowly spaced oncogenic determination period exists.
Journal Article•
TL;DR: The results suggest that, when mice are exposed to a carcinogen at doses low enough to approach environmental levels, immunization against the carcinogen can provide specific protection.
Abstract: 5-Fluoro-12-methylbenzanthryl-7-acetic acid (5-FMBAAA) is an analog of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) with little or no carcinogenic activity. CD-1 mice immunized with 5-FMBAAA conjugated to bovine serum albumin (BSA) developed serum antibodies capable of binding DMBA. As a means of testing whether this immunization protected against DMBA-induced tumors, a low-dose carcinogenesis model system was developed, entailing the repeated skin application of 25 ng DMBA in dodecane alternating with applications of the tumor promoter, phorbol myristate acetate. Mice immunized with the 5-FMBAAA:BSA conjugate and subsequently exposed to this low-dose regimen for 40 weeks developed significantly fewer skin tumors (0.23 papilloma/mouse) than did unimmunized mice, mice immunized with BSA, or mice immunized with an unconjugated mixture of BSA and 5-FMBAAA (0.47 to 0.54 papilloma/mouse). Immunization did not reduce tumor incidence in mice treated with phorbol myristate acetate alone. The results suggest that, when mice are exposed to a carcinogen at doses low enough to approach environmental levels, immunization against the carcinogen can provide specific protection.
TL;DR: The newborn mouse lung adenoma model has been shown to be a sensitive test for studying the tumorigenicity of bay region diol epoxides and their precursor dihydrodiols, and data indicate that the 3,4-dihydrodiolS of both DMBA and its 7-hydroxymethyl derivative may be proximate carcinogenic metabolites of DMBA in the newborn mouse.
Abstract: The newborn mouse lung adenoma model has been shown to be a sensitive test for studying the tumorigenicity of bay region diol epoxides and their precursor dihydrodiols. When a total dose of 28 nmol of 7,12-dimethylbenz[a]anthracene (DMBA) or its derivatives was injected i.p. into the preweaning mice, it was found that the 3,4-dihydrodiols of both DMBA and 7-hydroxymethyl-12-methylbenz[a]anthracene caused 13.3 and 4.1 times more lung adenomas than DMBA, respectively. The mice treated with the 5,6- and 8,9-dihydrodiols of DMBA, 7-hydroxymethyl-12-methylbenz[a]anthracene and its 5,6- and 8,9- and 10,11-dihydrodiols, 7-methyl-12-hydroxymethylbenz[a]anthracene and 7,12-dihydroxymethylbenz[a]anthracene developed a level of lung adenomas/mouse less than 2-fold higher than that found in the DMSO-treated control group. Liver tumors also developed in some of the mice. The percentage of mice with liver tumors also indicated that the 3,4-dihydrodiols of both DMBA and 7-hydroxymethyl-12-methylbenz[a]anthracene were more tumorigenic than DMBA itself. These data indicate that the 3,4-dihydrodiols of both DMBA and its 7-hydroxymethyl derivative may be proximate carcinogenic metabolites of DMBA in the newborn mouse.
TL;DR: The DMBA mutation frequencies of all 5 wild strains are interpreted as being related to the levels of activating enzymes that metabolize DMBA.
Abstract: 7,12-Dimethylbenz[a]anthracene (DMBA) was tested for the induction of mutations in 5 strains of Drosophila melanogaster. Larvae were fed mixtures containing either 1.0 or 4.0 mM DMBA in darkness. After emergence the males were mated to Base females to test for sex-linked lethals. Canton-S males produced the highest frequency with no significant differences in the induction of lethals by the 2 concentrations. DMBA was slightly mutagenic in Oregon-R males over controls without significant differences between the 2 concentrations. Berlin-K, Lausanne-S and Urbana-S males all produced significantly more mutations at the 4.0-mM than the 1.0-mM concentrations. DMBA produced partial sterility in Canton-S and Urbana-S males. The DMBA mutation frequencies of all 5 wild strains are interpreted as being related to the levels of activating enzymes that metabolize DMBA.
TL;DR: It is indicated that age and parity influence the proliferative status of the cells and their susceptibility to DMBA in vitro, simulating in that way the in vivo situation.
Abstract: Mammary gland epithelial cells from rats of different ages or with different reproductive histories vary in their proliferative properties and susceptibility to dimethylbenz(a)anthracene (DMBA) carcinogenesis in vivo. The present study was carried out to determine whether these differences are maintained under in vitro conditions. Primary cultures of mammary gland epithelial cells of young virgin, old virgin, and parous rats were treated with various doses of DMBA. Growth rates, DNA synthesis, and dose-response curves were determined; the toxicity of DMBA was measured by its effect on cell growth. Cell morphology was studied by transmission and scanning electron microscopy. Epithelial cells from the mammary gland of young virgin rats adapted rapidly to the culture conditions, behaving as if the cells were in the logarithmic phase of growth prior to plating. Mammary gland epithelial cells from old virgin and parous rats required a lag period prior to cell growth during which the proliferating cells adapted to the culture conditions. Cells from each group had comparable doubling times, and DNA synthesis peaked approximately 1 d after initiation of growth in culture. The numbers of proliferating cells decreased with increasing age and parity of the donor. Mammary gland epithelial cells of young virgin rats were more susceptible to both low and high doses of DMBA than those of old virgin and parous rats when the carcinogen was added either 24 h after plating or at the peak of DNA synthesis. These results indicate that age and parity influence the proliferative status of the cells and their susceptibility to DMBA in vitro, simulating in that way the in vivo situation.
TL;DR: Hydrolysates of DNA that had been isolated from mouse skin treated with 3H-labelled 7,12-dimethylbenz[a]anthracene (DMBA) were subjected to chromatography and the fluorescence spectra were consistent with the idea that the metabolic activation of DMBA in mouse skin occurs through the formation of 'bayregion' diol-epoxides in the 1,2,3,4-ring.
Abstract: Hydrolysates of DNA that had been isolated from mouse skin treated with 3H-labelled 7,12-dimethylbenz[a]anthracene (DMBA) were subjected to chromatography on Sephadex LH20 columns and 3H-labelled products that eluted in the region expected for nucleoside-hydrocarbon adducts were purified further by high pressure liquid chromatography (h.p.l.c.). The fluorescence spectra of three major products that were resolved by this method were determined using photoncounting spectrophotofluorimetry. The fluorescence spectra of all three products were anthracene-like and similar to the spectra of nucleoside-hydrocarbon adducts obtained from DNA that was incubated with 3,4-dihydro-3,4-dihydroxy-7,12-dimethylbenz[a]anthracene 1,2-oxide (DMBA-3,4-diol 1,2-oxide). This is consistent with the idea that the metabolic activation of DMBA in mouse skin occurs through the formation of 'bayregion' diol-epoxides in the 1,2,3,4-ring.
TL;DR: Ovariectomy appeared to be less effective in producing sustained control growth in DMBA-induced mammary tumors in rats exposed prenatally to diethylstilbestrol.
Abstract: The effects of ovariectomy on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were investigated after rats ahd been exposed prenatally to diethylstilbestrol (DES). Pregnant rats were inoculated with either DES (total dose: 1.2 micrograms) in sesame oil or with the vehicle alone on days 10 and 13 of gestation. Female offspring were given 2 gastric intubations of DMBA (10 mg each) 1 week apart beginning at 50 plus or minus 1 days of age. When the average diameter of a mammary tumor exceeded 2 cm, the animal was ovariectomized. The initial response of most tumors in both the DES-exposed and control groups to ovariectomy was size regression. The growth of 7 tumors that arose soon after DMBA treatment in each group was studied for 12-20 weeks after ovariectomy. Whereas only 1 tumor from the control group resumed active growth after the initial regression period, 6 tumors in the DES-exposed group overcame the initial effects of ovariectomy and began to grow again. Thus ovariectomy appeared to be less effective in producing sustained control growth in DMBA-induced mammary tumors in rats exposed prenatally to DES.
TL;DR: Modifications of the ribose moiety and of the guanine residue at the C-8 position in the cellular RNA by a metabolite of a polycyclic hydrocarbon are shown for the first time.
Abstract: The interaction of guanosine with 7,12-dimethylbenz[a]anthracene (DMBA) 5,6-oxide under alkaline conditions resulted in the formation of six derivatives. These six compounds were cochromatographed with nucleosides obtained by hydrolysis of RNA isolated from rat liver cells treated with [3H]DMBA. The cochromatography showed that three of these adducts were formed in cellular RNA. The three products constituted less than 5% of the total nucleoside-DMBA adducts as shown by chromatography on Sephadex LH-20 and high-pressure liquid chromatography. In one of them, the 2'-hydroxy group of the ribose moiety of guanosine was linked to the C-5, and in the second, to the C-6 position of the DMBA 5,6-oxide residue. In the third derivative, the C-8 position of guanosine was linked to the C-5 of the DMBA 5,6-oxide moiety. These results show, for the first time, modifications of the ribose moiety and of the guanine residue at the C-8 position in the cellular RNA by a metabolite of a polycyclic hydrocarbon.
Journal Article•
TL;DR: Although the demethylated antiestrogens have a 20- to 50-fold enhanced affinity for the mammary tumor estrogen receptor in vitro as compared to their parent compound in vivo, both forms are equally potent antitumor and antiuterotrophic agents.
Abstract: This study compares the antitumor activities of the nonsteroidal antiestrogens α-{ p -[2-(1-pyrrolidino)ethoxy]phenyl}-4-methoxy-α′-nitrostilbene (CI628) and cis -{3-[ p -(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol} (U23,469) with their demethylated metabolite forms in the dimethylbenz( a )anthracene-induced rat mammary tumor system. Since these demethylated forms are generated during the action of the parent antiestrogens in vivo and are selectively accumulated in the nuclear estrogen receptor fraction in preference to the parent compound, we investigated whether direct administration of the metabolites might prove more effective than administration of the parent antiestrogens in eliciting tumor regression. We have therefore compared the potencies of the parent antiestrogens and their demethylated forms α-{ p -[2-(1-pyrrolidino)ethoxy]phenyl}-4-hydroxy-α′-nitrostilbene (CI628M) and cis -{3-[ p -(1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthyl)-phenoxy]-1,2-propanediol} (U23,469M) in stimulating the regression of established dimethylbenz( a )anthracene-induced mammary tumors; and we have monitored the effects of these antiestrogens on estrogen receptors and the enzyme peroxidase as a specific marker for estrogen action in mammary tumors and in uteri of tumor-bearing animals. In mammary tumor cytosol in vitro , the antiestrogens competed with [ 3 H]estradiol for binding to estrogen receptor with affinities of 113% (CI628M), 5% (CI628), 31% (U23,469M), and 0.6% (U23,469), where the affinity of estradiol is considered to be 100%. However, all four antiestrogens were equally effective as antagonists of tumor growth in vivo . Administration of 25 or 100 µg daily of either parent (CI628 and U23,469) or the demethylated (CI628M and U23,469M) antiestrogens was able to elicit the regression of the majority of dimethylbenz( a )anthracene tumors, while low doses (2.5 µg/day) of any of these four compounds had no effect on tumor growth. The 25- and 100-µg doses of antiestrogens markedly reduced tumor cytoplasmic estrogen receptor levels, but they failed to elevate significantly tumor peroxidase activity. Uterine weights were significantly decreased below the diestrus controls following treatment with 25- or 100-µg daily dosages of the antiestrogens; and these treatments resulted in the nuclear localization of approximately 80% of total estrogen receptors. Uterine peroxidase activity, which was high in diestrus control females, was dramatically reduced to 5 to 25% by the intermediate- or high-dose levels of the antiestrogens. These results indicate that, although the demethylated antiestrogens have a 20- to 50-fold enhanced affinity for the mammary tumor estrogen receptor in vitro as compared to their parent compound in vivo , where the parent compounds are rapidly converted to the demethylated metabolites, both forms are equally potent antitumor and antiuterotrophic agents. These high-affinity antiestrogens should be excellent ligands for experiments designed to elucidate the mechanism of antiestrogen action in breast cancer.
TL;DR: The long-term topical administration of 7,12-dimethylbenz(a)anthracene to the skin of male and female animals treated with Mastomys induced a broad spectrum of benign and malignant tumors in all animals treated.
Abstract: The long-term (34 weeks) topical administration of 7,12-dimethylbenz(a)anthracene (DMBA) to the skin of male and femaleMastomys induced a broad spectrum of benign and malignant tumors in all animals treated. In a two-stage carcinogenesis experiment with topical initiation with DMBA and topical promotion with TPA, 50% of the animals developed both benign and malignant skin tumors. In general, benign tumors occurred between weeks 15 and 25, whereas malignant tumors were seen 40 weeks after initiation. In contrast to the situation in Mus musculus, the benign tumors consisted mainly of keratoacanthomas instead of fibroepitheliomas. In the non-initiated, TPA-treated, control group four benign and four malignant tumors were seen, whereas animals of the DMBA-initiated, acetonetreated control group were free of tumors. The promotion of virus transformed cells with TPA is discussed.
TL;DR: It was observed that the earlier the pregnancy was terminated, the greater was the incidence of mammary tumors, which would indicate that the inhibitory effect of pregnancy is related to changes occurring during the later half of gestation.
Abstract: The relationship between mammary cell proliferation during pregnancy and susceptibility to 7,12-dimethylbenz(a)anthracene (DMBA) was examined. DMBA was administered intravenously to Sprague-Dawley rats on the 5th, 10th or 15th day of pregnancy. [3H]thymidine labelling index (LI) of the mammary cells at the time of treatment with the carcinogen was determined and found to be higher in the pregnant rats than in age-matched virgin controls. In spite of the high proliferative index of the mammary cells, significant inhibition of tumorigenesis occurred in the pregnancy rats allowed to complete pregnancy and parturition following treatment with DMBA. However, when pregnancy was terminated by cesarian section shortly after treatment with DMBA, there was a significantly higher tumor incidence as compared to the "full-term" rats. It was observed that the earlier the pregnancy was terminated, the greater was the incidence of mammary tumors. This would indicate that the inhibitory effect of pregnancy is related to changes occurring during the later half of gestation. The differentiation of mammary cells for milk synthesis as pregnancy progresses is postulated to be a major reason for the observed refractoriness of the mammary cells to DMBA at that time.
TL;DR: Hypercholesterolemia of dietary origin appears to enhance slightly chemical carcinogenesis in this model of diet-induced changes in serum cholesterol levels and their relationship to mammary carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene.
TL;DR: Using the in vivo DNA damage alkaline elution assay, a satisfactory correlation with carcinogenicity in the same target organ has been previously shown for a variety of chemical agents, and this work was intended to enlarge the exploration of the predictivity of this test.
Abstract: Using the in vivo DNA damage alkaline elution assay, a satisfactory correlation with carcinogenicity in the same target organ has been previously shown for a variety of chemical agents. This work was intended to enlarge the exploration of the predictivity of this test. Benzo[a]pyrene (BP) was found negative for damage to liver DNA of mice and rats, and 7,12-dimethylbenz[a]anthracene (DMBA) negative for damage to liver and bone marrow DNA of mice and slightly positive for damage to mammary gland DNA of young female rats. The results were found to be correlated with the extension of DNA arlyation in target organs in similar experimental conditions. From carcinogenicity data reported in the Survey of Compounds Which Have Been Tested for Carcinogenic Activity (vols. 1961-1973) BP and DMBA were both found to be essentially negative as liver carcinogens; however, DMBA was a potent carcinogen in inducing mammary tumors.
01 Apr 1981
TL;DR: The development of mammary dysplasia (mastopathia cystica) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in neonatally androgenized female rats was dependent on estrogens, and cystic-type mammary Dysplasia developed in rats with a relative or absolute excess of estrogens.
Abstract: The development of mammary dysplasia (mastopathia cystica) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in neonatally androgenized female rats was dependent on estrogens, and cystic-type mammary dysplasia developed in rats with a relative or absolute excess of estrogens. At 2 days of age, 137 female rats were neonatally androgenized by single subcutaneous injections of 1.25 mg testosterone propionate (TP). At 50 days of age, all rats were given 20 mg DMBA by gastric intubation. About one-half of the TP rats were ovariectomized at 78 days of age. Rats in test groups were given daily intramuscular injections of 10 micrograms 17 beta-estradiol (E) or 4 mg progesterone (P) for 228 days starting from 78 days after birth. In all TP rats, corpora lutea were absent in the ovaries. the incidence of mammary dysplasia in TP rats was 89.7%. Ovariectomy (OVEX) of TP rats induced a significant and marked decrease in the incidence of mammary dysplasia (3.7%). In TP rats with OVEX, a high incidence of mammary dysplasia was found in those given E (95.7%) but not in those given P (0%). The incidences of cystic-type mammary dysplasia in TP rats, TP rats with E, TP rats with OVEX and E and TP rats with P were 65.5, 86.7, 91.3 and 0%, respectively.
TL;DR: The data show that application of monodispersed mammary cells inoculated into the subscapular fat pad of isologous female rats in the study of mammary cell physiology and carcinogenesis would be very useful.