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Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1982"


Journal Article
TL;DR: H-1 which, it has already been shown, invokes a resistance to the incidence of spontaneous and adenovirus-induced neoplasms in hamsters also produces a suppression of a carcinogen-induced tumor in these animals; this suggests that the H-1-induced barrier to successful oncogenesis by these diverse agents has a common mechanism which, present experiments indicate, is not related to a positive or negative H- 1 serology.
Abstract: Hamsters, given injections s.c. at birth of H-1 parvovirus and 1 month later given a single injection of 7,12-dimethylbenz(a)anthracene, had a 38% tumor incidence compared with a 95% incidence in animals receiving 7,12-dimethylbenz(a)anthracene alone. Thus, H-1 which, it has already been shown, invokes a resistance to the incidence of spontaneous and adenovirus-induced neoplasms in hamsters also produces a suppression of a carcinogen-induced tumor in these animals; this suggests that the H-1-induced barrier to successful oncogenesis by these diverse agents has a common mechanism which, present experiments indicate, is not related to a positive or negative H-1 serology. The pathology of the 7,12-dimethylbenz(a)anthracene-induced tumors was similar for both control and H-1-infected hamsters. Although all but one of the primary neoplasms were anaplastic fibrosarcomas as reported previously by others, 25% of the affected females had, in addition, mammary adenocarcinomas, an extremely rare tumor in hamsters.

64 citations


Journal Article
TL;DR: The clonal nature of the GGT-stained plaques for their apparent ability to persist in an occult form for several weeks or months lend further support to the hypothesis that these carcinogen-altered cell populations may be potential precursors for the development of squamous epithelial neoplasia.
Abstract: Individual γ-glutamyl transpeptidase (GGT)-stained cells and cell doublets were rapidly induced in the epithelium of hamster buccal pouch treated with biweekly topical applications of 0.5% 7,12-dimethylbenz(a)anthracene (DMBA) in mineral oil. The cells were detected histochemically in whole mounts of pouch epithelium harvested as early as 3 days after the first application of this carcinogen. During 3 consecutive weeks of DMBA treatment, progressively larger GGT-stained epithelial cell populations (plaques) up to 0.5 mm in diameter were encountered. Similar GGT-stained lesions were not detected in whole mounts of untreated epithelium and were rarely seen in GGT-stained whole mounts prepared from mineral oil-treated pouch epithelium. In an experiment designed to assess the stability of the GGT-staining pattern, very few plaques could be detected 12 weeks after a 3-week regimen of six DMBA applications. However, data are presented suggesting that a brief series of three DMBA applications reinduced GGT histochemical activity in occult intraepithelial plaques, which had lost enzyme activity but had persisted over an 11-week treatment-free interval. The clonal nature of the GGT-stained plaques and their apparent ability to persist in an occult form for several weeks or months lend further support to the hypothesis that these carcinogenaltered cell populations may be potential precursors for the development of squamous epithelial neoplasia.

61 citations


Journal ArticleDOI
TL;DR: This study shows for the first time that DMBA is carcinogenic to fish, by repeated short-term exposures to an aqueous suspension of 5 ppm 7,12-dimethylbenz[a]anthracene.

61 citations


Journal Article
TL;DR: The dietary concentrations of selenium shown to inhibit the early stage(s) of cancer induction in this system were both significantly lower and fed for a shorter time interval than that which was previously reported.
Abstract: The inhibitory activity of short-term feeding of one of four concentrations of dietary selenium against the induction of mammary gland carcinomas by 7,12-dimethylbenz(a)anthracene (DMBA) was studied in female Sprague-Dawley rats When 28 days old, the animals were placed on a Torula yeast diet formulation which contained, by analysis, either 005, 015, 105, or 206 microgram of selenium, as sodium selenite, per g of diet Mammary cancer was induced by a single po administration of either 75 or 150 mg DMBA at 50 days of age The animals were maintained on the above diets until 14 days after carcinogen treatment at which time all animals were transferred to a chow diet containing 021 microgram of selenium per g of diet The study was terminated 120 days after DMBA administration The concentrations of selenium in the liver and mammary tissue measured at the time of DMBA treatment increased with increasing levels of dietary selenium (p less than 005) At the low dose of DMBA, there was a trend towards reduction in the number of cancers with increased amounts of selenium, but the only significant difference occurred between groups fed the next to lowest and the highest level of selenium At the high dose of DMBA, the number of observed cancers showed a strong dose effect (p less than 005) In addition, tumor load was significantly reduced in selenium-supplemented rats (p less than 005), and there was a significant delay (p less than 005) in the time to appearance of the cancers of animals receiving the highest level of selenium when compared with those receiving the lowest level The dietary concentrations of selenium shown to inhibit the early stage(s) of cancer induction in this system were both significantly lower and fed for a shorter time interval than that which was previously reported

43 citations


Journal Article
TL;DR: The results indicate that mammary tumor regression induced by 4-OHA is mainly the result of the inhibition of aromatization, although other activities of the compound may also contribute.
Abstract: Aromatase inhibitor, 4-hydroxyandrostene-3,17-dione (4-OHA), is a highly effective treatment in rats with 7,12-dimethylbenz(a) anthracene-induced hormone-dependent mammary tumors. Over 90% of tumors regress to less than one-half of their original size, and a high proportion regress completely. Treatment of rats with other inhibitors, 4-acetoxyandrostene-3,17-dione and 1,4,6-androstatriene-3,17-dione produce similar results. In comparison with other aromatase inhibitors, the compounds reduced ovarian estrogen secretion in the rat to the same extent as aminoglutethimide, whereas Teslac was without effect. The latter two compounds caused little and no regression of DMBA-induced mammary tumors, respectively. Our recent studies with 4-OHA, 4-acetoxyandrostene-3,17-dione, and 1,4,6-androstatriene-3,17-dione indicate that they interact with aromatase by a two-component mechanism, a rapid competitive inhibition, and a slower enzyme inactivation. Treatment of rats with 4-OHA also caused greater than 80% loss of ovarian aromatase activity in vivo and a reduction in ovarian estrogen secretion, which are maintained for at least 48 hr after injection. Although 4-OHA is cleared rapidly in vivo, the above results suggest that the compound has a sustained effect. Thus, when 7,12-dimethylbenz(a)anthracene-induced tumor-bearing rats were treated with 4-OHA injections on alternate weeks, tumor regression continued to occur during weeks without treatment. The overall regression was similar to that with continuous treatment. 4-OHA is also effective and similar to ovariectomy in rats with hormone-dependent metastatic mammary tumors produced by nitrosomethylurea. Our results indicate that mammary tumor regression induced by 4-OHA is mainly the result of the inhibition of aromatization, although other activities of the compound may also contribute.

37 citations


Journal ArticleDOI
TL;DR: Results indicate that metabolism of DMBA at positions 1, 3, 2- and 4- is important for biological activity and that for certain derivatives (i.e., 1,2,3,4-H4-DMBA), alternate pathways of metabolic activation may also be important.
Abstract: We have determined the skin tumor-initiating activity in SENCAR mice of two A-ring derivatives of 7,12-dimethylbenz[a]anthracene (DMBA) 4-Fluoro-7,12-dimethylbenz[a]anthracene at a dose of 200 nmol per mouse exhibited weak activity, producing 06 papillopmas per mouse; doses of 10 and 20 nmol per mouse had no activity A derivative of DMBA with the A-ring reduced, 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene (1,2,3,4,-H-DMBA), had substantial tumor-initiating activity when compared with the parent hydrocarbon In one experiment, doses of 10 and 100 nmol per mouse gave rise to 16 and 95 papillomas per mouse, respectively; similar results were obtained in 3 additional experiments Although the tumor-initiating activity of 1,2,3,4,-H4-DMBA was approximately one-tenth that of DMBA, this derivative was slightly (17%) more active than benzo[a]pyrene 1,2,3,4-H4-DMBA was tested for the ability to induce mutations to 6-thioguanine-resistance in Chinese hamster V79 cells In the absence of feeder cells capable of metabolizing polycyclic hydrocarbons, it was not mutagenic However, in a cell-mediated mutation assay with secondary hamster embryo cells as activators, this derivative produced mutations in a dose-dependent manner and was approximately one-tenth as active as DMBA These results indicate that metabolism of DMBA at positions 1-, 3-, 2- and 4- is important for biological activity and that for certain derivatives (ie, 1,2,3,4-H4-DMBA), alternate pathways of metabolic activation may also be important

36 citations


Journal ArticleDOI
TL;DR: In this article, the influence of selenium on transformation of mammary cells, induced by 7,12-dimethylbenz[a]anthracene (DMBA), was assessed in organ culture of the whole mammary glands from BALBc female mice.

30 citations


Journal Article
TL;DR: The loss of hormone-regulated differentiated function in these tumors, which maintained hormone-dependent growth, suggests the presence of a defective regulatory mechanism beyond the level of the hormone-receptor-complex.
Abstract: In the hormonally responsive 7,12-dimethylbenz( a )anthracene (DMBA)- or N -nitrosomethylurea (NMU)-induced mammary carcinomas, regulatory mechanisms have been altered such that these tumors retain their hormonal dependence for growth but possess only a limited ability to synthesize the mammary gland-specific milk proteins Quantitation of casein mRNA levels revealed that very low levels of casein messenger RNA (mRNA) were expressed in both the DMBA- and NMU-induced tumors growing in virgin animals (01 to 04% of the maximally induced 8-day-lactating mammary gland) Growth of DMBA-induced tumors in pregnant rats and the treatment of NMU-induced tumor-bearing animals with thioproperazine indicated that the tumor casein mRNA levels were hormone inducible (34- and 21- fold for the DMBA- and NMU-induced tumors, respectively) However, casein mRNA levels were still only 1 to 2% of those found in the normal mammary gland under the same hormonal environment Localization of the casein-synthesizing cells in the DMBA-induced tumors by peroxidase-antiperoxidase staining and a specific casein antiserum indicated that, in both control and hormone-treated tumors, the vast majority of cells (>95%) were unable to synthesize casein The hormonal induction of casein mRNA sequences could be correlated with an increase in the number of cells synthesizing casein, which appeared as small clusters of cells throughout the tumors Therefore, the loss of hormone-regulated differentiated function in these tumors, which maintained hormone-dependent growth, suggests the presence of a defective regulatory mechanism beyond the level of the hormone-receptor complex

29 citations



Journal ArticleDOI
TL;DR: The influence of dietary selenium on the mutagenic activation of 7,12-dimethylbenz[ a ]anthracene (DMBA) by rat liver S9 was studied using the Ames test as mentioned in this paper.
Abstract: The influence of dietary selenium on the mutagenic activation of 7,12-dimethylbenz[ a ]anthracene (DMBA) by rat liver S9 was studied using the Ames test. Rats received supplemental selenium, as sodium selenite, in the drinking water or in the diet. All rats additionally received 0, 20, 50, 100, or 500 mg Aroclor 1254 per kg body weight. Revertant counts decreased 72 and 31% at the 20- and 100-mg/kg induction levels, respectively, with S9 preparations from rats given selenium supplementation, compared to controls. No significant effect of selenium on S9 preparations was observed in rats treated with 500 mg/kg Aroclor. Preparations of S9 from rats receiving 2.5 ppm Se in their diet produced 46, 84 and 70% less revertants than controls at the 20-, 50- and 100-mg/kg induction levels. Increasing the selenium concentration in the diet to 5 ppm reduced the revertant counts by 71, 68 and 65%, at the 20-, 50- and 100-mg/kg induction level of Aroclor, respectively. Dietary selenium supplementation was shown to decrease the mutagenic activation of DMBA by liver microsomes. These studies indicate that in vivo selenium supplementation may reduce susceptibility to the action of various carcinogens.

27 citations


Journal ArticleDOI
TL;DR: Investigation of the induction of mammary tumors in virgin female inbred BALB/c mice after administration of 7,12-dimethylbenz[a]anthracene (DMBA) over a wide range of doses indicated that in the low dose range induction of Mammary tumors was the predominant effect of DMBA exposure, whereas at moderate to high doses the toxic and carcinogenic effects ofDMBA on other tissues significantly influenced the final incidence of mammaries.
Abstract: The induction of mammary tumors in virgin female inbred BALB/c mice after administration of 7,12-dimethylbenz[a]anthracene (DMBA) over a wide range of doses was studied. Mice were exposed at 12 weeks of age to single or multiple doses of DMBA ranging from 0.0025 to 12.0 mg by gastric intubation and were checked regularly for mammary tumors. The experiment was terminated when the mice were 800 days of age. In the dose range of 0.0025--0.125 mg DMBA, the incidence of mammary tumors was dose-dependent. At higher doses, the mammary tumor incidence became less dose-dependent and was nearly independent of doses above the 0.25-mg level. Analysis of the data for the rate of appearance of mammary tumors with age of the animals and for the age at death of non-mammary tumor-bearing animals indicated that in the low dose range induction of mammary tumors was the predominant effect of DMBA exposure, whereas at moderate to high doses the toxic and carcinogenic effects of DMBA on other tissues significantly influenced the final incidence of mammary tumors. Greater than 90% of the tumors that resulted from administration of low doses of DMBA were adenocarcinomas. In contrast, adenocarcinomas and adenoacanthomas were found in approximately equal proportions following administration of high doses of DMBA.

Journal ArticleDOI
TL;DR: DFMO has clear antitumoral activity against the rat mammary tumour induced by DMBA, manifested principally as a decreased rate of tumour appearance but meaningful effects on tumour growth are observed if the drug is administered during early tumour development or in combination with cyclophosphamide.
Abstract: 1. The effects of DL-alpha-difluoromethylornithine (RMI 71782; DFMO) on the tumours induced in female rats by a single oral administration of 20 mg 7,12-dimethyl-benz[a]anthracene (DMBA) have been investigated. 2. Treatment with DFMO (2% aqueous solution as sole drinking fluid) starting 30 days after administration of DMBA resulted in markedly fewer animals with tumours and greater than 90% reduction in the total number of tumours. 3. In rats bearing at least one palpable tumour, treatment with DFMO (2% in the drinking water) slowed significantly the rate of appearance of new tumours but affected to only a minimal extent the growth of existing tumours. Tumour ornithine decarboxylase activities and putrescine concentrations were reduced by treatment with DFMO; the activity of S-adenosyl-L-methionine decarboxylase was increased and the concentration of spermine either remained unchanged or increased depending on the length of treatment. 4. Cyclophosphamide, 100 mg/kg, injected once then repeated after 10 days, altered neither the rate of appearance of new tumours nor the growth of the existing tumours. Combined treatment with DFMO plus cyclophosphamide resulted in regression of the majority of tumours existing at the start of treatment and a marked reduction in the rate of appearance of new tumours. 5. In conclusion, DFMO has clear antitumoral activity against the rat mammary tumour induced by DMBA. The effects are manifested principally as a decreased rate of tumour appearance but meaningful effects on tumour growth are observed if the drug is administered during early tumour development or in combination with cyclophosphamide.

Journal ArticleDOI
TL;DR: The results indicate that analog II and tamoxifen were equally effective in reducing the growth of established DMBA-induced rat mammary tumors and that analogue II produced a greater reduction in the occurrence of new tumors during the 7-week treatment period.

Journal ArticleDOI
TL;DR: While the medium containing insulin, prolactin, growth hormone, estrogen and progesterone was highly conducive to DMBA transformation, 4-HPR inhibition of transformation was limited to only 21% and the antagonistic action of estrogen was noticeably more pronounced.

Journal ArticleDOI
TL;DR: Evidence is presented that the first evidence of monohydroxymethyl-DMBA-deoxyribonucleoside adducts being formed after the administration of DMBA per se are formed.
Abstract: The polycyclic aromatic hydrocarbon, 7,12-dimethyl benz[a] anthracene (DMBA) is a potent carcinogen to the female Sprague-Dawley rat, and when administered under conditions that have been shown to produce cancer, resulted in extensive formation of hydrocarbon-deoxyribonucleoside adducts. Sephadex LH-20 and reverse-phase h.p.l.c. and spectrofluorometric analysis of these adducts demonstrate that at least one adducts results from the binding of 7, 12-dimethylbenz [a] anthracene-1,2,3,4-tetrahydro-3,4,-dihydroxy-1,2,-oxide. In these experiments, employing i.p. administration of the hydrocarbon, a second more polar adduct was observed. Evidence is presented that this adduct results from the formation of a monohydroxymethyl-methyl-benz [a] anthracene-A-ring-diol-epoxide. While both of the monohydroxymethyl-DMBA metabolites have been shown to bind cellular DNA following their administration this is the first evidence of monohydroxymethyl-DMBA-deoxyribonucleoside adducts being formed after the administration of DMBA per se. The evidence suggests that this more polar adduct is a 7-hydroxymethyl-12-methylbenz[a]anthracene-deoxyribonucleoside adduct.

Journal Article
TL;DR: Findings show that MM are hormone independent but, like hormone-dependent female tumors, contain ER and estrogen-dependent PR.
Abstract: Biological characteristics and estrogen (ER) and progesterone (PR) receptors were studied in male mammary carcinomas induced by 7,12-dimethylbenz(a)anthracene (DMBA) in male inbred Sprague-Dawley rats (MM). DMBA-induced carcinomas in females (MF) were used as controls. In 36 of 44 female rats given 20 mg DMBA once by gastric intubation at 50 days of age, MF with microscopic characteristics of cystic papillary adenocarcinoma developed 124 ± 49 (S.D.) days after challenge. In all of the 42 male rats given 10 mg DMBA at 14-day intervals for 14 weeks starting from 28 days of age, MM with microscopic characteristics of medullary adenocarcinoma developed 106 ± 21 days after the first intubation of DMBA. The growth of primary MM was unaffected by orchiectomy or estrogen. Eighty to 100% of the MM transplanted in the four groups could grow in intact female rats, ovariectomized female rats, intact male rats, and castrated male rats, while the transplanted MF could grow only in intact female rats. The histology of MM was unchanged in primary and transplanted tumors under various hormonal conditions. ER were present in almost all of the hormone-independent primary and transplanted MM, although the levels for cytosol ER in MM were significantly lower than those in MF. Injection of 10 µg 17β-estradiol induced marked synthesis of PR in primary and transplanted MM, even 24 and 48 hr after the 17β-estradiol injection. These findings show that MM are hormone independent but, like hormone-dependent female tumors, contain ER and estrogen-dependent PR.

Journal ArticleDOI
TL;DR: Ethyldiazoacetate (EDA), a substance which has been shown to induce skin tumors when administered i.v. to rats, was tested with regard to its initiating capacity and led to a skin tumor spectrum comparable to that produced by DMBA-TPA, however, the survival time of the EDA- TPA treated animals was significantly higher than those exposed to DMBA -TPA.
Abstract: In contrast to a previous report by Shubik and in accordance with a pilot study from our laboratory with female rats, the 2-stage skin carcinogenesis experiment could be successfully accomplished in male Sprague-Dawley rats. Male animals of this species are better suited for this long-term experiment since, under the conditions used, females are very sensitive to mammary gland tumor formation and show a drastically reduced survival time. A broad spectrum of tumors of epidermal origin could be induced by topical initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetra-decanoyl-phorbol-13-acetate (TPA) as promoter. The tumors were not only localized in the interfollicular epidermis but to a large extent also in the epidermal appendages. More importantly, the DMBA - TPA treatment led to the development of a variety of tumors of the connective tissue and the angiofibrous matrix. The incidence of these tumors was almost comparable to that found for epidermal tumors. In some animals we observed up to 12 histologically different tumors. Compared to the mouse, the tumor incidence in organs other than the skin was definitely lower. Ethyldiazoacetate (EDA), a substance which has been shown to induce skin tumors when administered i.v. to rats, was tested with regard to its initiating capacity. The combination EDA-TPA led to a skin tumor spectrum comparable to that produced by DMBA-TPA. However, the survival time of the EDA-TPA treated animals was significantly higher than those exposed to DMBA-TPA. EDA, therefore, seems to be a suitable alternative to DMBA for systemic initiation of skin tumors.

Journal ArticleDOI
TL;DR: Tumors grouped by growth status irrespective of hormone status showed an inverse relationship between PGE2 content and growth response, andHaloperidol treatment promoted tumor growth even after ovariectomy and returned tumor P GE2 values to control levels.
Abstract: Prostaglandin content in 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors was correlated with growth responses to alterations in endogenous estrogen and prolactin. Prostaglandin E2 (PGE2) content varied inversely with tumor latency. Ovariectomy of tumor-bearing Sprague-Dawley rats resulted in regression of tumors in 90% of the castrated rats. PGE2 content in tumors from ovariectomized rats was elevated twofold (P less than 0.05) compared to PGE2 content in tumors from intact controls. Haloperidol treatment promoted tumor growth even after ovariectomy and returned tumor PGE2 values to control levels. Tumors grouped by growth status irrespective of hormone status showed an inverse relationship between PGE2 content and growth response.

Journal ArticleDOI
TL;DR: Among the azo dyes investigated, Sudan III was most efficient in protecting against DMBA-induced CA, and Polychlorinated biphenyl and phenobarbital, inducers of drug-metabolizing enzymes, also suppressed DMBA -induced CA.
Abstract: Noninbred Long-Evans rats fed Sudan III at 24 hours before they were given an injection of 7,12-dimethylbenz[a]anthracene (DMBA) displayed prominently suppressed DMBA-induced chromosome aberrations (CA) in their bone marrow cells. Rats fed Sudan III simultaneously with the DMBA injection showed no suppressed CA effect. The suppressive effect of Sudan III on DMBA-induced CA paralleled the dose rate of Sudan III when given in the range between 1 and 10 mg Sudan III/kg body weight; higher doses produced no additional suppression. The capacity of various Sudan III-related chemicals to prevent DMBA-induced CA paralleled their capacity to prevent DMBA-induced adrenal apoplexy and mammary cancer. Among the azo dyes investigated, Sudan III was most efficient in protecting against DMBA-induced CA. Polychlorinated biphenyl and phenobarbital, inducers of drug-metabolizing enzymes, also suppressed DMBA-induced CA.

Journal ArticleDOI
TL;DR: The present studies support the anticarcinogenic potential of selenium and indicate that form and concentration are important factors in this trace element's efficacy.
Abstract: The antimutagenic effect of selenium as sodium selenite, sodium selenate, selenium dioxide, and seleno-methionine was studied in the AmesSalmonella/microsome mutagenicity test using 7,12-dimethylbenz(a)anthracene (DMBA) and some of its metabolites. Selenium (20 ppm) as sodium selenite reduced the number of histidine revertants on plates containing up to 100 μg DMBA/plate. Increasing concentrations of selenium as sodium selenite, sodium selenate, and selenium dioxide up to 40 ppm Se progressively decreased the number of revertants caused by 50 μg DMBA. DMBA and its metabolites 7-hydroxymethyl-12-methylbenz(a)anthracene, 12-hydroxymethyl-7-methylbenz(a)anthracene, and 3-hydroxy-7,12-dimethylbenz(a)anthracene were mutagenic forSalmonella typhimurium TA100 in the presence of an S-9 mixture. Selenium supplementation as Na2SeO3 reduced the number of revertants induced by these metabolites to background levels. The antimutagenic effect of inorganic selenium compounds cannot be explained by toxicity of selenium as determined by viability tests withSalmonella typhimurium TA100. Selenium supplementation in all forms examined, except sodium selenate, decreased the rate of spontaneous reversion. Selenium as sodium selenate was slightly mutagenic at concentrations of 4 ppm or less. Higher concentration of Na2SeO4 inhibited the mutagenicity of DMBA. The present studies support the anticarcinogenic potential of selenium and indicate that form and concentration are important factors in this trace element's efficacy.

Journal ArticleDOI
TL;DR: Although [14C]DMH was absorbed more rapidly from the intestinal lumina of guinea pigs than from those of rats, the rat accumulated more of the carcinogen in the intestinal mucosa and liver than the mouse.
Abstract: The specific effects of bile acids as cocarcinogens were investigated. Absorptions of [14C]7,12-dimethylbenz[a]anthracene, [14C]dimethylhydrazine ([14C]DMH), and [3H]inulin from loops of colons from outbred Sprague-Dawley rats and Hartley guinea pigs were determined. In each animal absorption of one carcinogen and inulin was studied in one control loop and in an experimental loop containing either deoxycholic acid (DOC) or chenodeoxycholic acid (CDOC). DOC had a more pronounced effect on increasing loss of carcinogen from the intestinal lumen than did CDOC. This role of bile acids was consistent with their known effect of increasing intestinal permeability. Less carcinogen remained in the colon mucosa when DOC was present in the intestinal lumen. Although [14C]DMH was absorbed more rapidly from the intestinal lumina of guinea pigs than from those of rats, the rat accumulated more of the carcinogen in the intestinal mucosa and liver.

Journal Article
TL;DR: It is hypothesized that the promoting effect of dietary fat on dimethylbenz(a)anthracene-induced mammary tumorigenesis is mediated via the immune system, although a role for the endocrine system still cannot be ruled out.
Abstract: The interaction of dietary fat and the thymus in the induction of mammary tumors by dimethylbenz(a)anthracene has been examined in female Sprague-Dawley rats. In these experiments, rats fed diets of 0.5% (low fat), 5% (normal fat), or 20% (high fat) corn oil from weaning (21 days of age) were thymectomized or sham thymectomized at 35 days of age and were given 5 mg of dimethylbenz(a)anthracene at 55 days of age. Thymectomy exerted a protective effect in rats fed low and normal fat diets, and this was not reversed by Thymosin Fraction V. In high fat-fed rats, tumorigenesis was increased compared to the low fat groups, and in addition, the protective effect of thymectomy was absent. This differential effect of thymectomy could not be explained on the basis of changes in prolactin concentration, since prolactin levels were decreased in all dietary groups. Neither diet nor thymectomy affected corticosterone levels or the estrus cycle of mature rats. Peripheral blood lymphocytes were, however, decreased by both thymectomy and increasing the fat content of the diet. It is hypothesized that the promoting effect of dietary fat on dimethylbenz(a)anthracene-induced mammary tumorigenesis is mediated via the immune system, although a role for the endocrine system still cannot be ruled out.

01 Oct 1982
TL;DR: The primary target of DMBA-induced immunosuppression was considered to be on antigen-presenting macrophages rather than on T cells, and the suppression of development of hapten-primed B cells may be a secondary phenomenon induced by the suppressed helper T cell activities.
Abstract: The cellular mechanism of immunosuppression induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied by using both in vivo and in vitro assay systems. When the effect of DMBA on antibody responses was studied by the use of an adoptive cell transfer system of primed cells with second antigen in X-irradiated recipient mice, the development of both hapten-primed B cells and carrier-primed helper T cells induced by thymus dependent hapten-carrier conjugate was found to be markedly suppressed in DMBA-treated mice. When the B cell activity in DMBA-treated mice was directly assessed using thymus-independent hapten-carrier conjugate, anti-hapten antibody response was not suppressed at all. Since the development of hapten-primed B cells to thymus-dependent carrier requires the presence of carrier-primed helper T cells, DMBA treatment seems to affect primarily T cells but not B cells, and the suppression of development of hapten-primed B cells may be a secondary phenomenon induced by the suppressed helper T cell activities. Since the development of helper T cell activities requires antigen presentation by macrophages, it was determined which type of T cells or macrophages was the primary target of DMBA-induced immunosuppression. Antigen-primed T cells from DMBA-treated mice did not proliferate as well on stimulation with secondary antigen in vitro. Furthermore, antigen-pulsed macrophages from DMBA-treated mice did not fully activate T cells from normal mice. Thus, the primary target of DMBA-induced immunosuppression was considered to be on antigen-presenting macrophages rather than on T cells.

01 Aug 1982
TL;DR: Biweekly intragastric intubations of 7,12-dimethylbenz[a]anthracene (DMBA) rapidly induce mammary carcinoma in high yield in gonadectomized female and male rats, which are ovary-independent, though they contain estrogen receptors (ER).
Abstract: Biweekly intragastric intubations of 7,12-dimethylbenz[a]anthracene (DMBA) rapidly induce mammary carcinoma in high yield in gonadectomized female and male rats. These tumors are ovary-independent, though they contain estrogen receptors (ER). In 84.4% of 32 female rats and in 100% of 35 male rats which were gonadectomized at 27 days of age and given 10 mg of DMBA 8 times at 14-day intervals starting from 28 days of age, mammary carcinoma developed 102.4 +/- 28.1 (SD) and 107.2 +/- 25.5 (SD) days, respectively, after the first intubation of DMBA. More than 55% (55 approximately 83%) of seed tumors taken from 18 tumors induced in ovariectomized rats and 18 tumors induced in orchiectomized rats could grow in intact and ovariectomized females and intact and castrated males. Cytosol ER were found in all of 10 tumors induced in gonadectomized male and female rats.

Journal ArticleDOI
TL;DR: While repeated 20-R X-rays during and following DMBA applications enhance DMBA carcinogenesis, identical X-ray exposures prior to and during DMBA Applications appear either to slightly inhibit or to have no appreciable effect on DM BA carcinogenesis.
Abstract: peated Low-Level X Radiation in Hamster Cheek Pouch Carcinogenesis: Dependence on the Relative Timing of DMBA and Radiation Treatments. Radiat. Res. 90, 155-164 (1982). Low-level X radiation was shown to enhance Syrian hamster cheek pouch carcinogenesis by 7,12-dimethylbenz(a)anthracene (DMBA) when radiation was administered concurrently with and following DMBA applications. We studied the effects of altering the timing of radiation and DMBA applications on this enhancement. DMBA in mineral oil was applied twice weekly for 10 weeks and 20 R head and neck X radiation once weekly for 17 weeks. In duplicate studies, animals received radiation, DMBA, or DMBA plus X radiation. In the DMBA plus X-ray group, there were 9 weeks of preirradiation and 7 weeks of concurrent treatments. Radiation alone did not result in any histologically detectable changes. In one study, preirradiation may have reduced the carcinogenic activity of DMBA, while in the second study there were no significant differences in tumor incidences between X radiation plus DMBA and DMBA only groups. Thus, while repeated 20-R X-ray exposures during and following DMBA applications enhance DMBA carcinogenesis, identical X-ray exposures prior to and during DMBA applications appear either to slightly inhibit or to have no appreciable effect on DMBA carcinogenesis.

Journal ArticleDOI
TL;DR: The data suggest that DMBA treatment can inhibit the production but not the antivirus activity of murine gamma IFN, and DMBA was either added to target cells before the addition of exogenous Gamma IFN or mixed together with exogenous gammaIFN.
Abstract: Spleens were removed from Swiss Webster mice, and cultures of spleen cells were prepared. Gamma (ty pe II immune) interferon (IFN) production was induced in these cells by addition of the purified protein form of phytohemagglutinin (PHA-P) to the cultures. When 7,12-dimethylbenz[a]anthracene (DMBA) was added to the cultures either before or after addition of PHA-P, the production of gamma IFN was inhibited. The degree of inhibition was greater when the cells were treated with DMBA before addition of PHA-P. In experiments to determine the effects of DMBA on the antivirus activity of previously prepared gamma IFN preparations, DMBA was either added to target cells before the addition of exogenous gamma IFN or mixed together with exogenous gamma IFN. In both cases. the antivirus activity of this exogenous gamma IFN was not affected. These data suggest that DMBA treatment can inhibit the production but not the antivirus activity of murine gamma IFN.

Journal ArticleDOI
TL;DR: In this paper, the estrogen receptor affinities of meso and (+/-)-N,N'-dialkyl-1,2-bis(2,6-dichloro-4-hydroxypheny)ethylenediamines (2) are described.
Abstract: The syntheses and estrogen receptor affinities of meso- and (+/-)-N,N'-dialkyl-1,2-bis(2,6-dichloro-4-hydroxypheny)ethylenediamines (2) are described. They show high binding affinities in both diastereomeric forms but with a preference for the meso isomer, reaching a RBA value of 8.6 (meso-2b; 17 beta-estradiol = 100). Both stereoisomers of 2b exhibit a strong inhibitory effect on the 7,12-dimethylbenz[alpha]anthracene (DMBA) induced hormone-dependent mammary carcinoma of the Sprague-Dawley rat, reducing the tumor area by 74 (meso-2b) and 24% [(+/-)-2b], respectively, after 4 weeks administration of 6 x 6 (mg/kg)/week. The high uterotrophic potency makes a mode of action likely which corresponds to the effect of high doses of estrogens.

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TL;DR: The study provides a first mechanistic concept for melanoma initiation by DMBA and shows that metabolic activation of DMBA is prerequisite to initiation and has a similar molecular basis as in other target cells ofDMBA, the essential pathway including the cytochrome P-448-dependent monooxygenase system.
Abstract: Initiation of dermal melanocytes by 7,12-dimethylbenz[a]-anthracene (DMBA) in the dorsal skin of Syrian golden hamsters was investigated for its sensitivity to inhibition by 7,8-benzoflavone (BF). Initiation was carried out by a single intragastric application of DMBA (50 mg/kg body weight) and melanoma development pursued with or without subsequent promotion through repeated topical administration of 12-O-tetradecanoylphorbol-13-acetate (40 nmol/animal, 3 X weekly). A single intragastric application of BF (200 mg/kg body weight) 2 h prior to DMBA resulted in a suppression of melanoma yields by approximately 70%. Further, there were indications that BF generally causes a decrease of melanoma rates and an increase of survival rates. The study provides a first mechanistic concept for melanoma initiation by DMBA. It shows that metabolic activation of DMBA (i) is prerequisite to initiation and (ii) has a similar molecular basis as in other target cells of DMBA, the essential pathway including the cytochrome P-448-dependent monooxygenase system.

Journal ArticleDOI
TL;DR: If treatment with RA is delayed until 6 months after carcinogen administration, the protective effect of RA can still be observed although its effectiveness is less dramatic than when it is administered earlier.
Abstract: Prolonged exposure to retinyl acetate (RA) in the diet inhibits the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary cancers in rats. The effectiveness of RA was examined when given 6 months after the administration of DMBA. Non-inbred female Sprague-Dawley rats with DMBA-induced mammary tumors were divided into 3 groups and treated for 4 weeks as follows: Group 1 served as controls, group 2 was ovariectomized, and group 3 received 328 mg RA/kg diet. Ovariectomy (OVX) markedly reduced both the number and size of the tumors. RA administration failed to induce any significant regression in tumor number but significantly retarded tumor growth when compared to tumor growth in group 1 controls. The levels of estradiol, progestin, and prolactin (PRL) receptors were significantly reduced after OVX, whereas only the levels of PRL receptors declined significantly after RA administration. Circulating progesterone concentrations were not affected in the RA-treated group but the plasma PRL level was significantly increased. The present studies show that if treatment with RA is delayed until 6 months after carcinogen administration, the protective effect of RA can still be observed although its effectiveness is less dramatic than when it is administered earlier.

Journal ArticleDOI
TL;DR: Chronic administration of IPR after the instillation of DMBA caused a high death rate but no statistically significant change in the incidence of salivary gland tumors, irrespective of whether NMU was given at the peak of stimulated DNA synthesis or without pretreatment with IPR.
Abstract: The effect of isoproterenol (IPR) (20 mg/kg, twice per wk) on mammary gland tumors induced by N-nitroso-N-methylurea (NMU) (40 or 77 mg/kg, iv) was studied. Within 18 weeks 50--60% of the noninbred female Sprague-Dawley rats that received a single injection of NMU developed carcinomas of the mammary gland. In addition, a malignant lymphoma was observed. There was no change in the incidence of tumors if NMU was administered at the time that DNA synthesis was stimulated in the submandibular glands by two injections of IPR (160 mg/kg, ip) given 24 hours apart. Tumors of unequivocal salivary gland origin were not observed, irrespective of whether NMU was given at the peak of stimulated DNA synthesis or without pretreatment with IPR. However, in 10% of the tumor-bearing rats, tumors were found in the neck region. These tumors could be separated from the salivary glands by dissection and were of mammary gland origin. Chronic treatment with IPR caused marked enlargements of the parotid and submandibular glands with hypertrophy of the acinar cells and degeneration of the duct system. Such a treatment caused a high death rate but no change in the incidence of the tumors. The effect of chronic IPR treatment (10 mg/kg twice per wk or 5 mg/kg three times per wk) on submandibular gland tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) was also studied. With the intraglandular injection of 100 or 200 micrograms of DMBA, the incidences of squamous cell carcinomas in the glands were 6.8 and 38.6%, respectively. Chronic administration of IPR after the instillation of DMBA caused a high death rate but no statistically significant change in the incidence of salivary gland tumors.