Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1975"
Journal Article•
TL;DR: Dehydroepiandrosterone, an adrenal steroid that has been reported to be produced in subnormal amounts and found in lower plasma concentrations in women with benign and malignant breast tumors, protects cultured rat liver epithelial-like cells against a flatoxin B1-induced cytotoxicity and protects hamster embryonic fibroblasts against aflatoxin B 1- and 7,12-dimethylbenz(a)anthracene-induced transformation.
Abstract: Dehydroepiandrosterone, an adrenal steroid that has been reported to be produced in subnormal amounts and found in lower plasma concentrations in women with benign and malignant breast tumors, protects cultured rat liver epithelial-like cells against aflatoxin B1-induced cytotoxicity and protects hamster embryonic fibroblasts against aflatoxin B1- and 7,12-dimethylbenz(a)anthracene-induced transformation. Related androgenic steroids show significantly less protective effect. Dehydroepiandrosterone also inhibits the rate of conversion of [3H]-7,12-dimethylbenz(a)anthracene to water-soluble metabolites by rat liver epithelial-like cells, suggesting that the steroid probably exerts its protective effect by inhibiting carcinogen activation.
68 citations
Journal Article•
TL;DR: The results give good supporting evidence that estrogen plays a primary role in tumor growth and the interactions of prolactin and estrogen at tumor sites are necessary for regulatory events related to tumor growth.
Abstract: Summary Hormonal influences on dimethylbenz(a)anthracene-induced tumor growth were investigated in detail by endocrine ablation and replacement of hormones. The majority of tumors regressed following ablation and most of them were reactivated by subsequent administrations of estrogen (0.1 to 5 µg) or prolactin (2 mg). Increasing numbers of tumors, however, were not stimulated by prolactin when administration was delayed, and a basal level of estradiol (0.01 µg) in addition to prolactin was required for reactivation of tumors. Nafoxidine hydrochloride, a competitor of estrogen at the receptor sites, arrested growth of a large portion of dimethylbenz(a)anthracene-induced tumors in intact animals but failed to retard growth of prolactin-stimulated tumors. On withdrawal of prolactin-nafoxidine, rapid regression of tumor occurred and readministration of prolactin failed to activate most of the tumors for as long as 28 days. Our results give good supporting evidence that estrogen plays a primary role in tumor growth. The interactions of prolactin and estrogen at tumor sites are necessary for regulatory events related to tumor growth.
62 citations
TL;DR: The hypothesis that there may exist a prolactin regulatory mechanism of estrogen action at the tumor site is supported, as both estrogen and prolact in situ in modulating hormonal receptor binding capacities may contribute to the overall stimulatory effect of these two hormones on DMBA-tumors.
Abstract: In order to test the in vivo effect of prolactin on estrogen receptor (ER) binding capacity in tumors induced by 7,12 dimethylbenz(a)anthrancene (DMBA-tumor), growth of the tumors from changes in prolactin and estrogen levels was compared retrospectively with cytoplasmic ER levels. It was demonstrated that some tumors required prolactin, some needed prolactin-estrogen during their growth period anda small number were not influenced by hormonal milieu. ER was present in hormonally dependent tumors but was low or absent in hormonaly-independent tumors. Deletion of hormones by endocrine ablation in the host rat resulted in tumor regression loss of ER. Replenishment of ER and subsequent tumor growth were accomplished by injection of prolactin or prolactin-estrogen in endocrine ablated rats but were not achieved in rats bearing tumors exposed to prolactin-nafoxidine. Our results demonstrate that both estrogen and prolactin were essential for growth of hormonally dependent DMBA-tumors. Tumor growth was also prevented when cytoplasmic ER was not replenished , indicating that ER may be an indispensable prerequisite for growth. Prolactin, independently of or cooperatively with estrogen, stimulated ER binding capacity. These results support the hypothesis that there may exist a prolactin regulatory mechanism of estrogen action at the tumor site. The interactions of estrogen and prolactin in situ in modulating hormonal receptor binding capacities may contribute to the overall stimulatory effect of these two hormones on DMBA-tumors.
57 citations
Journal Article•
TL;DR: Growth of induced tumors was inhibited by feeding rats an arginine-enriched diet containing 5% L-arginine in addition to the necessary components for rats, including 15% milk casein, which significantly reduced both the rate of tumor induction and the number of tumors induced per rat.
Abstract: The effect of L-arginine on growth of rat mammary tumors induced by 7,12-dimethylbenz(a)anthracene was studied. Growth of induced tumors was inhibited by feeding rats an arginine-enriched diet containing 5% L-arginine in addition to the necessary components for rats, including 15% milk casein. The diet significantly reduced both the rate of tumor induction and the number of tumors induced per rat. Histological examination showed that the tumors induced were more benign in rats fed the arginine-enriched diet than in those fed the control diet. A possible mechanism of the inhibitory effect of L-agrinine id discussed.
53 citations
TL;DR: DDT may inhibit DMBA-induced mammary tumors and leukemia by stimulating hepatic metabolism and excretion of DMBA so that less carcinogen is available to peripheral tissues by inhibiting the same enzyme systems induced by DDT.
Abstract: Female Sprague-Dawley rats, 36 days old, were pretreated for 2 weeks either with 100 ppm 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) or 250 ppm S-(1,2-dicarbeth-oxyethyl)OO-dimethyldithiophosphate (Malathion) in the diet. From day 50 they were given, via stomach tube, 21 consecutive daily doses of 0.714 mg 7,12-dimethylbenz[a]anthracene (DMBA). Pesticide diets and observation of the animals for mammary tumors continued until necropsy, 230 days after the start of DMBA administration. DDT-treated rats had a significantly lower mammary tumor incidence, prolonged tumor latency period, and fewer tumors per rat than did the control group. Animals given Malathion (an organophosphate pesticide) had a higher mammary tumor incidence, shortened latency period, more tumors per rat, and more actively growing tumors than did the control group (DMBA only). Leukemia incidence in rats surviving to necropsy (230 days after the start of DMBA administration) was 11/20 for control, 2/29 for DDT, and 8/12 for Malathion-treated rats. Leukemia was primarily myelogenous. DDT may inhibit DMBA-induced mammary tumors and leukemia by stimulating hepatic metabolism and excretion of DMBA so that less carcinogen is available to peripheral tissues. Malathion may potentiate DMBA induction of mammary tumors and leukemia by inhibiting the same enzyme systems induced by DDT.
44 citations
TL;DR: The epoxide hydratase inhibitor 1,2-epoxy-3, 3,3,3-trichloropropane was found to eliminate all dihydrodiol formation and markedly inhibit the formation of several dimethylbenzanthracene metabolites.
Abstract: High pressure liquid chromatography has enabled quantitative analysis of the in vitro metabolism of 7,12-dimethylbenz[a]anthracene, 7-methyl-12-hydroxymethylbenz[a]anthracene, 7-hydroxymethyl-12-methylbenz[a]anthracene, and 7,12-dihydroxymethylbenz[a]anthracene by 3-methylcholanthrene-induced and control rat liver microsomes. The following previously unrecognized metabolites have been tentatively identified: 5,6-dihydro-5,6-dihydroxy-7-methyl-12-hydroxymethylbenz[a]anthracene, 3-hydroxy-7,12-dihydrodihydroxymethylbenz[a]anthracene, 4-hydroxy-7,12-dihydrodihydroxymethylbenz[a]anthracene, and 8,9-dihydro-8,9-dihydroxy-7,12-dihydroxymethylbenz[a]anthracene. The epoxide hydratase inhibitor 1,2-epoxy-3,3,3-trichloropropane was found to eliminate all dihydrodiol formation and markedly inhibit the formation of several dimethylbenzanthracene metabolites. It is proposed that the tentatively identified 3-hydroxy and 4-hydroxy derivatives are formed by an enzymatic mechanism that does not involve epoxides as intermediates. The metabolic pathways of 7,12-dimethylbenz[a]anthracene in hepatic microsomal enzymes are proposed.
42 citations
TL;DR: A very good inverse correlation was found between the potential life span of a species and the apparent capacity of its cultured fibroblasts to activate DMBA.
36 citations
Journal Article•
TL;DR: Serial sections of mammary glands from female Sprague-Dawley rats were examined at different intervals after rats were treated with 7,12-dimethylbenz[a]anthracene (CMBA), and all mammary tumors were adenocarcinomas of ductal origin.
Abstract: Serial sections of mammary glands from female Sprague-Dawley rats were examined at different intervals after rats were treated with 7,12-dimethylbenz[a]anthracene (CMBA). DMBA was given either by intravenous (iv) injection or by local application. Lesions with histologic characteristics typical of mammary adenocarcinomas were observed in the mammary glands as early as 20 days after DMBA treatment, when no other lesions were detectable. Whereas hyperplastic alveolar nodules in the mammary glands began to appear 35 days after iv injection of DMBA, they were never observed after local application of the carcinogen. All mammary tumors were adenocarcinomas of ductal origin.
33 citations
Journal Article•
TL;DR: It is demonstrated that certain 7,12-dimethylbenz(a)anthracene-induced tumors, which continue to grow after ovariectomy of the host, contained significant amounts of 17beta-(3H)estradiol bound to cytoplasmic as well as nuclear components.
Abstract: Experiments were undertaken with 7,12-dimethylbenz(a)anthracene-induced mammary tumors of the rat to determine whether ovarian-dependent and ovarian-independent tumors could be distinguished on the basis of differences in the estrogen binding capacity of the tumors in vitro and in vivo . Our results confirm reports showing that ovarian-dependent tumors undergo interaction between 17β-[3H]estradiol and specific estrogen binding components both in vivo and in vitro , as described for other estrogen target tissues. However, our results also demonstrated that certain 7,12-dimethylbenz(a)anthracene-induced tumors, which continued to grow after ovariectomy of the host, contained significant amounts of 17β-[3H]estradiol bound to cytoplasmic as well as nuclear components. The sedimentation properties of these components were indistinguishable from those of either ovarian-dependent 7,12-dimethylbenz(a)anthracene-induced tumors or rat uterus. The cytoplasmic binding components of both classes of tumors exhibited similar specificities for estrogens. There did not appear to be an absolute correlation between estrogen-binding capacity of a tumor and its growth response to ovariectomy.
33 citations
TL;DR: The presence of ER in DMBA‐tumors was demonstrated by the use of dextran‐charcoal assay, sephadex chromatography, sucrose gradient sedimentation, and organ culture techniques, and prolactin‐insulin significantly stimulated ER binding capacity, as compared with control without Prolactin.
Abstract: The presence of ER in DMBA-tumors was demonstrated by the use of dextran-charcoal assay, sephadex chromatography, sucrose gradient sedimentation, and organ culture techniques. It was found that tumors have binding sites ranging from 10-13 to 10-15 moles/mg protein, and a dissociation constant of ER 10-9 to 10-10 M. In experiments with tumor explants, prolactin-insulin significantly stimulated ER binding capacity, as compared with control without prolactin. This stimulation was tissue-specific and inhibited by progesterone. Insulin had a synergistic effect on prolactin stimulation of ER. Our results presents a plausible explanation for tumor responses to these hormones in vivo. This interaction of prolactin, estrogen, and progesterone may be a common phenomenon for all estrogen-responsive tissues.
29 citations
Journal Article•
TL;DR: Although most of the ergoline derivatives depressed serum prolactin concentrations in rats, only a few had pronounced effects against the dimethylbenz[a]anthracene-induced mammary carcinoma in rats.
Abstract: Summary The ability of a series of 8β-carboxamido ergolines, 8-formamido ergolines, and 8-methyl ergolines to cause regressions of established dimethylbenz[a]anthracene-induced mammary carcinomas was compared to some ergot alkaloids. Although most of the ergoline derivatives depressed serum prolactin concentrations in rats, only a few had pronounced effects against the dimethylbenz[a]anthracene-induced mammary carcinoma in rats. Some derivatives from each of the three groups of substituted ergolines gave comparable activities against the dimethylbenz[a]anthracene-induced mammary carcinoma.
TL;DR: The feeding of phenobarbital concurrently with the application of DMBA delayed the appearance of papillomas initially, but the suppression of the ultimate tumor yield was variable, and appeared to be dependent on the dose of the carcinogen and the age-dependent toxicity response of the mice.
TL;DR: Differences were observed in the fatty acid composition of tumor and mammary gland lipid, particularly the concentrations of polyunsaturated fatty acids which were generally much higher in the tumor lipids.
Abstract: The lipid class and fatty acid composition profiles of mammary glands of female rats fed a nutritionally adequate diet are compared to those of tumors induced in the mammary glands by intravenous injection of dimethylbenz(a)anthracene of animals fed the same diet. Ca. 95% of the lipids of the mammary glands of the control group of animals consisted of triglycerides; glycolipids and phospholipids were present in only minor amounts. In contrast, the lipids of the mammary tumors contained much lower amounts of neutral lipids and higher concentrations of phospholipids. The glycolipid fraction was a minor component of both tissues but differed greatly in composition. The composition of the phospholipid and neutral lipid fractions, particularly the latter, of the mammary tumors also differed from that of the mammary glands of the control animals. The neutral lipids of the tumor tissues contained elevated levels of free fatty acids and cholesterol and much lower concentrations of triglyceride compared to the mammary gland lipids. Differences also were observed in the fatty acid composition of tumor and mammary gland lipid. The greatest differences occurred in the concentrations of polyunsaturated fatty acids which were generally much higher in the tumor lipids.
TL;DR: There are indications that the additional DMBA application accelerated the destruction of the oocytes, which might result in a more rapid intrasplenic tumour induction.
Abstract: A single intravenous injection of 100 mg/kg body weight (b.w.) of 7, 12 dimethylbenz(a)anthracene (DMBA) induces a high percentage of ovarian granulosa cell tumours in C3H mice. After implantation of ovarian tissue into the spleen of gonadectomized female C3H mice similar tumours were found, resulting from an over-stimulation by pituitary gonadotrophins. In the present study the tumour development in intrasplenic ovarian tissue was observed after an additional single intravenous application of 100 mg/kg b.w. DMBA. It was found that the induction of granulosa cell tumours did not seem to be affected by the carcinogen injection whether 12 weeks before or 12 weeks after ovarian tissue was implanted into the spleen. The morphology of these neoplasms corresponds to the DMBA induced granulosa cell tumours in orthotopic ovaries. A direct carcinogenic effect of DMBA on ovarian cells in mice could not be demonstrated but there are indications that the additional DMBA application accelerated the destruction of the oocytes, which might result in a more rapid intrasplenic tumour induction.
TL;DR: The peroxidase and estradiol-metabolizing activities of mammary tumors induced by 7,12-dimethylbenz(a)anthracene were determined in fresh and stored tissue and it is suggested that the amount of peroxide present might reflect the ability of tumor cells to differentiate in response to hormonal stimulation and be indicative of the degree of tumor progression.
TL;DR: Preliminary experiments demonstrated that liver microsomes isolated from DMBA treated partially hepatectomized animals metabolized less DMBA in vitro than did microsome isolated fromDMBA treated intact animals, suggesting the greater persistence of unmetabolized DMBA may be related to the greater carcinogenicity of this compound for regenerating, as compared with intact, rat liver.
Abstract: The hepatic subcellular distribution, binding and persistence of 3H-7,12-dimethylbenz(a)anthracene were compared in partially hepatectomized rats and in intact controls. By 2 weeks after injection, intact liver homogenates contained only 9% of the total radioactivity present 4 h after injection; regenerated liver contained 60% in spite of a tripling in liver mass during this time. Cell fractions isolated from regenerated liver had 9-59 fold greater hexane extractable specific activities than those from intact liver. The radioactivity present in hexane extracts co-chromatographed with a 3H-7,12-dimethylbenz(a)anthracene standard. Preliminary experiments demonstrated that liver microsomes isolated from DMBA treated partially hepatectomized animals metabolized less DMBA in vitro than did microsomes isolated from DMBA treated intact animals. The greater persistence of unmetabolized DMBA may be related to the greater carcinogenicity of this compound for regenerating, as compared with intact, rat liver.
Journal Article•
TL;DR: Results indicated that this might be due to a difference in the amounts of 7,12-dimethylbenz(a)anthracene and actinomycin D bound to the mammary glands.
Abstract: The inhibitory effect of actinomycin D on the induction of tumors by in vitro exposure of mammary glands to 7,12-dimethylbenz(a)anthracene was studied. When actinomycin D was given i.p. 24 hr before excision of the mammary glands, the induction of tumors by in vitro exposure of the glands to 7,12-dimethylbenz(a)anthracene was significantly decreased. On the other hand, when actinomycin D was administered 24 hr after excision, it had no effect on the induction of tumors.
In vitro exposure of excised glands to 7,12-dimethylbenz-(a)anthracene and actinomycin D significantly decreased tumor induction. However, the order of exposure to 7,12-dimethylbenz(a)anthracene and actinomycin D influenced the inhibitory effect of actinomycin D on tumor induction. Results indicated that this might be due to a difference in the amounts of 7,12-dimethylbenz(a)anthracene and actinomycin D bound to the mammary glands.
01 Jan 1975
Journal Article•
TL;DR: In this article, the distribution of the bleomycin A2 suspended in sesame oil (oil Bleo Suspension) in rat organs and tumors after the intramuscular administration was investigated by bioassay, the effect of intratumor administration of the suspension on the growth of rat mammary carcinoma induced by 7, 12-dimethylbenz (a) anthracene was also studied.
Abstract: Distribution of the bleomycin A2 suspended in sesame oil (Oil Bleo Suspension) in rat organs and tumors after the intramuscular administration was investigated by bioassay, the effect of intratumor administration of the suspension on the growth of rat mammary carcinoma induced by 7, 12-dimethylbenz (a) anthracene was also studied. The oil suspension showed a protracted concentration in either tumor or organ tissues, but showed similar inhibitory effects on rat mammary carcinoma to those by regular bleomycin solution. Further studies should be performed on the effect of bleomycin A, in sesami oil on mammary carcinoma.
TL;DR: It is suggested that malignant transformation of the epithelial cells may occur within the first 4-6 days, after which there appears to be a loss of normal synthetic control of nuclear DNA, RNA, and cytosol protein.
Abstract: The effects of 7,12-dimethylbenz[a]anthracene (DMBA) on levels of four mammary epithelial cell macromolecules were investigated at various times between 1 and 14 days after Sprague-Dawley virgin female rats were fed the carcinogen. Whereas the level of nuclear protein remained relatively constant throughout this period, comparison with normal controls revealed that significant reductions in nuclear RNA and cytosol protein levels occurred in cells from DMBA-treated animals 24 hours after carcinogen treatment; levels were lowest within the first 3 days. Cytosol protein and nuclear RNA values then increased progressively, reaching normal levels between 4 and 6 days; they were elevated 122% (+/-6 SD) and 41% (+/-5), respectively, above controls by the 14th day. DNA levels remained within normal limits up to the 4th day, after which they gradually increased to 36% (+/-5) above normal by the 14th day. All four macromolecules in neoplastic epithelial cells derived from three mammary adenocarcinomas approximately 135 days after DMBA was fed to rats showed increases similar to, though more pronounced than, those seen in mammary epithelial cells 14 days after carcinogen administration, which suggested that early changes in these macromolecules, especially in RNA and cytosol protein, may be related to DMBA mammary carcinogenesis. The data further suggested that malignant transformation of the epithelial cells may occur within the first 4-6 days, after which there appears to be a loss of normal synthetic control of nuclear DNA, RNA, and cytosol protein.
Journal Article•
TL;DR: IVA is one of the most powerful inhibitors of the acute toxicity of DMBA and has the simplest aliphatic structure and the smallest molecule among protectors of the adrenals against hydrocarbon-induced damage; its mechanism of action awaits further elucidation.
Abstract: Isopropylvaleramide (IVA) and allylisopropylacetamide (AIA) inhibit hemorrhagic adrenocortical necrosis and mortality caused by 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats. Unlike their effect on hepatic microsomal cytochrome P-450, the anti-DMBA action of these compounds does not depend on the presence of the reactive allyl group in the molecule. Similarly, related barbiturates, regardless of whether they contain, like AIA, an allyl group and consequently destroy cytochrome P-450 (secobarbital and aprobarbital) or have, like IVA, saturated side chains and therefore do not effect the microsomal hemoprotein (pentobarbital and phenobarbital), proved ineffective in preventing both adrenal damage and death caused by DMBA. Hence, the protective action of IVA and AIA cannot be attributed to the destruction of the microsomal enzyme system responsible for the activation of DMBA. The toxicity of another carcinogen, dimethylnitrosamine, which also requires metabolic activation by microsomal enzymes, is not influenced by either IVA or AIA. IVA, which counteracts the adrenocorticolytic action of DMBA when given prior to, simultaneously with, or even after this carcinogen, has no discernible effect on hydrocarbon metabolism in vivo or in vitro. IVA is one of the most powerful inhibitors of the acute toxicity of DMBA. It has the simplest aliphatic structure and the smallest molecule among protectors of the adrenals against hydrocarbon-induced damage; its mechanism of action awaits further elucidation.
TL;DR: The effect of two metabolites of 7,12-dimethylbenz(a)anthracene and 7,8-benzoflavone—an inhibitor of DMBA metabolism—on the dynamics of its fluorescence in the skin of living mice was studied.
Abstract: The effect of two metabolites of 7,12-dimethylbenz(a)anthracene (DMBA)—7-hydroxymethyl-12-methylbenz(a)anthracene and 7,12-dihydroxymethylbenz(a)anthracene—on the dynamics of its fluorescence in the skin of living mice was studied. The first metabolite did not change the dynamics of DMBA fluorescence whereas the second, if applied to the skin in equimolar proportions with DMBA, delayed its fluorescence. A similar effect was obtained with 7,8-benzoflavone—an inhibitor of DMBA metabolism.