Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1977"

Predominant role of prolactin in stimulating the growth of 7, 12-dimethylbenz(a)anthracene-induced rat mammary tumor.

Abstract: Summary The effect of prolactin in supporting the growth of 7,12-dimethylbenz(a)anthracene-induced mammary tumor in adult female Sprague-Dawley rats was investigated when estrogen receptors were blocked by the nonsteroidal antiestrogen, Tamoxifen, ICI 46,474 Following an oophorectomy-induced remission, perphenazine, which stimulates endogenous prolactin release, was able to restore tumor growth whether or not Tamoxifen was added A second course of perphenazine treatment, instituted after the tumors were allowed to shrink, was again effective in stimulating tumor growth After a regression in tumor size induced by oophorectomy and daily administration of Tamoxifen, perphenazine was able to restore original tumor size despite continued treatment with Tamoxifen In intact rats, after regression was obtained by daily administration of Tamoxifen and the prolactin inhibitor, lergotrile mesylate, perphenazine induced tumor growth when the latter was discontinued, even though Tamoxifen was continued for 50 days Estrogen receptors measured at the time of maximum stimulation by perphenazine were undetectable On the other hand, estradiol did not stimulate tumor growth when serum prolactin was depressed to undetectable levels by lergotrile These results indicate that prolactin supports the growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumor and that estrogen receptors are not required under these conditions

Control of hormone receptor levels and growth of 7,12-dimethylbenz(a)anthracene-induced mammary tumors by estrogens, progesterone and prolactin.

Abstract: The effect of various hormone treatments was investigated on the growth and hormone receptor levels of hormone-dependent (those which regressed after ovariectomy) dimethylbenz- (a)anthracene (DMBA)-induced mammary tumors in the rat. Hormone binding measured in die tumors which remained 5½ weeks after ovariectomy was low for estradiol-17β (E2) (0.6 ± 0.2 pmol/g tissue), R 5020 (0.9 ± 0.4 pmol/g tissue) and prolactin (PRL) (0.9 ± 0.4% of specific binding). In non-castrated animals, binding values were 2.9 ± 0.4 pmol/g tissue, 13.7 ± 2.0 pmol/g tissue and 3.2 ± 0.3% for E2, R 5020 and PRL, respectively. Administration of progesterone (P) alone (0.5 mg/day) for three weeks to castrated animals had no effect on tumor size or hormone binding. Treatment with E2 (0.5 μg/day) for the same period of time increased tumor size and hormone binding: E2, 3.0 ± 0.7 pmol/g tissue; R 5020, 14.8 ± 3.3 pmol/g tissue; PRL, 2.4 ± 0.6%. At a daily dose of 2 mg, PRL alone increased tumor size slightly while honnone binding remai...

Increased in Vitro Growth Capacity of Tracheal Epithelium Exposed in Vivo to 7,12-Dimethylbenz(a)anthracene

Abstract: Heterotopic tracheal transplants of rats were exposed in vivo to 150 or 640 microng of 7, 12-dimethylbenz(a)anthracene (DMBA) delivered over 2 weeks, and the epithelium was studied in vitro in an attempt to identify changes in growth behavior during early phases of neoplastic development Explants were made from the exposed tracheas, as well as from a series of controls, and the rate of epithelial outgrowth from the explants was measured Secondly, the capacity of the outgrowths to survive as primary cultures and their ability to survive multiple in vitro passages were studied During the initial planting, the rate of outgrowth was by far the greatest from the explants preexposed to 150 microng DMBA Outgrowth from explants preexposed to 640 microng DMBA was sparse during the first planting but increased markedly during repeated planting when insulin- and hydrocortisone-supplemented medium was used Establishment of outgrowth during repeated planting of carcinogen-exposed tracheal pieces was clearly hormone dependent Control explants did not exhibit this hormone dependency Primary cultures could be established from only three of six explants preexposed to 150 microng DMBA These explants had been initiated in insulin- and hydrocortisone-supplemented medium The primary cultures were successfully subcultured Primary cultures were also established from five of five explants preexposed to 640 microng DMBA and cultured in hormone-supplemented medium At least one cell line was obtained from each of the explants To establish and maintain primary cultures from control tracheas required an enriched medium containing amino acid supplements, sodium pyruvate, and putrescine, as well as the hormone supplements However, such cultures could not be subcultured The primary cultures from the carcinogen-exposed explants and the subsequently developed cell lines all exhibited morphological characteristics of keratinizing squamous epithelium These characteristics include: epithelioid cell morphology, multilayering and sloughing of orangeophilic squamous cells, and the presence of keratohyalin granules These experiments demonstrate a markedly increased in vitro growth capacity of tracheal epithelium after a short in vivo exposure to carcinogen

3-methylcholanthrene And 7,12-dimethylbenz[a]anthracene in mouse skin.

Abstract: The metabolic activation of the polycyclic hydrocarbons benzo [a] pyrene and 7-methylbenz [a] anthracene in mouse skin appears to involve the formation of vicinal diol-epoxides [l] that react with nucleic acids in this tissue [2-51. This mechanism of activation may be a general one for this class of chemical carcinogens and efforts are now being made to extend the hypothesis to include other hydrocarbons. The examination, using photon-counting spectrofluorimetry, of nucleic acids isolated from tis’sues treated in vivo with polycyclic hydrocarbons, has already proved to be of value in identifying the sites of activation in benzo [a] pyrene [2] and in 7-methylbenz [a] anthracene [4,6] . In this paper we present data from fluorescence studies obtained with the potent carcinogens 3-methylcholanthrene (I) and 7,12-dimethylbenz[a] anthracene (II). These data show that the hydrocarbon moieties, bound to the DNA of mouse skin treated in vivo with either of the parent hydrocarbons, have spectral characteristics consistent with the retention of a substituted anthracene nucleus in

Metabolism of Benzo[a]pyrene and 7,12-Dimethylbenz[a]anthracene in Cultured Human Bronchus and Pancreatic Duct

Abstract: Summary The metabolism of two carcinogenic polynuclear aromatic hydrocarbons, benzo[ a ]pyrene (BP) and 7,12-dimethylbenz[ a ]anthracene, was studied in explants of human pancreatic duct and bronchus cultured in a chemically defined medium. In cultured human bronchial mucosa, activity of aryl hydrocarbon hydroxylase was inducible by both benz[ a ]anthracene and BP. Prior exposure of the bronchial explants to benz[ a ]anthracene altered the qualitative features of the metabolite profile of BP as analyzed by high-pressure liquid chromatography. The metabolite profiles of BP produced by normal-appearing bronchi from patients with lung cancer were also compared with those from patients without lung cancer. The profiles were similar except for an observed higher percentage of organic solvent-extractable metabolites formed by bronchi from the noncancer patients that eluted from the column as a single peak. This peak cochromatographed with both the 9,10-diol and a triol of BP. 7,12-Dimethylbenz[ a ]anthracene was bound to the DNA of cultured human bronchial cells at higher levels than was BP. Binding of 7,12-dimethylbenz[ a ]anthracene to DNA in human pancreatic duct was consistently less than that in cultured bronchi in the 5 patients studied. Human pancreatic duct and bronchus have the capacity to activate polynuclear aromatic hydrocarbons into metabolic intermediates that bind to DNA and, presumably, into ultimate carcinogens.

Antagonism of development and growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors by the antiestrogen U 23,469 and effects on estrogen and progesterone receptors.

Abstract: This study analyzes the effectiveness of a nonsteroidal antiestrogen, cis -(3-[ p -(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol (U 23,469) previously shown to be potent in antagonizing estrogeninduced uterine growth, in preventing the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors and in eliciting the regression of established tumors; the study also attempts to elucidate the mechanisms of the tumor antagonism of U 23,469. Virgin female Sprague-Dawley rats that receive DMBA at 47 to 50 days of age and then receive U 23,469 (250 µg s.c. in 0.15 m NaCl daily) have a greatly reduced number of mammary tumors and a markedly decreased tumor area. Treatment with U 23,469 for increasing time periods (3, 6, or 12 weeks) beginning 2 weeks after DMBA results in a progressive decrease in tumor size and number and a progressive delay in onset of tumor appearance. U 23,469 treatment beginning 1 week after DMBA or given prior to DMBA is even more effective. The time course of tumor regression (3 months after DMBA) by U 23,469 or ovariectomy is similar, with 50% regression in ca. 2 weeks, and both elicit regression of almost all tumors (>90%). After ovariectomy, cytosol progesterone receptor levels are greatly diminished in tumors and uteri, while cytosol estrogen receptor (ER) levels are high; in both tissues little ( ca. one–third) of ER is in the nucleus. During U 23,469 treatment, cytosol ER content is very low in regressing tumor and uterus and over 90% of ER is in the nucleus; cytosol progesterone receptor is slightly depressed in the uterus but is at the untreated level in mammary tumor. These receptor studies suggest that the effectiveness of this antiestrogen in antagonizing mammary tumor development and growth may reside in its ability markedly to perturb the distribution of ER, maintaining over 90% of ER in the nucleus with concomitant low levels of cytoplasmic ER, a situation that may render the mammary tissue insensitive to the animal's own endogenous estrogens.

Metabolism of 7,12-dimethylbenz[a]anthracene in mouse skin homogenates analyzed with high-pressure liquid chromatography.

Abstract: The metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) in epidermal homogenates from 3-methylcholanthrene-pretreated mice was analyzed with high-pressure liquid chromatography. Metabolism was undetectable in the absence of pretreatment. Specific activities in epidermal homogenates from pretreated mice were found to be approximately 100 to 1000 times lower than those observed in comparable incubations containing hepatic microsomes from MC-pretreated rats. The major metabolite formed was identified as 7-hydroxymethyl-12-methylbenz[a]anthracene. Each of the known hydroxymethyl metabolites also was present in detectable quantities. The K-region diol was not measurably present in incubations with mouse skin homogenates or rat liver microsomes from MC-pretreated animals. 7,8-Benzoflavone, 5,6-benzoflavone, and 17-beta-estradiol were found to be potent inhibitors of the metabolic transformation of DMBA by epidermal homogenates in vitro, whereas butylated hydroxytoluene and 1,1,1-trichloro-2,3-propene oxide had little effect on or enhanced metabolite formation from DMBA in vitro.

Quantitative exposure of grafted rat tracheas to 7, 12-dimethylbenz(a)anthracene.

Abstract: A method was developed for continuously exposing tracheal epithelium to measured amounts of carcinogen. Beeswax was the vehicle for sustained release of carcinogen, and tracheas transplanted to s.c. sites were target tissues. In the experiment reported here, transplanted rat tracheas were exposed to a potent carcinogen, 7,12-dimethylbenz(a)anthracene (DMBA). The rate of release of DMBA from the beeswax carrier within the tracheal lumen approached first order when the initial concentration of carcinogen was high (3200 to 325 µg in a 24.45-mg pellet). With lower concentrations, where the carcinogen was dissolved in the beeswax, initial release was rapid, and most of the carcinogen was delivered within 4 weeks. At high DMBA dose levels, the entire tracheal epithelium was uniformly replaced by keratinizing squamous metaplasia after 1 week of exposure, and after 2 months, when from 280 to 910 µg DMBA had been delivered, all transplants had developed invasive squamous carcinomas. Sarcomas also developed in 19% of the transplants. At lower dose levels the epithelial reactions were more varied, and tumor development was more protracted. The lowest DMBA dose presently known to induce carcinomas in this experimental model is 40 µg, which is in the dose range used for tumor initiation in skin carcinogenesis studies in mice.

Inhibition of the Tumor-initiating Ability of the Potent Carcinogen 7,12-Dimethylbenz(a)anthracene by the Weak Tumor Initiator 1,2,3,4-Dibenzanthracene

Abstract: Aryl hydrocarbon hydroxylase (AHH) in mouse epidermis was inducible by topical application of several tumor-initiating polycyclic aromatic hydrocarbons. The weak tumor initiator 1,2,3,4-dibenazanthracene (1,2,3,4-DBA), at dose level of 200 nmoles, increased AHH activity more than 10-fold over that of the acetone controls at 12 hr after treatment. Administration of the same quantity of the potent initiator 7,12-dimethylbenz( a )anthracene (DMBA) increased AHH activity approximately 4-fold over that of the control at 12 hr after treatment. Simultaneous treatment with 200 or 100 nmoles of DMBA and 1,2,3,4-DBA resulted in AHH activity that was 546 and 732% that of the controls, respectively, 12 hr after treatment; this was less AHH activity than was observed when 1,2,3,4-DBA was administered alone. Doses of 20 nmoles or more of 1,2,3,4-DBA, when given at about the same time as DMBA, effectively inhibited DMBA initiation of skin tumors in a two-stage system of tumorigenesis. The results suggest that the weak initiator 1,2,3,4-DBA may program the epidermal AHH system to metabolize the strong carcinogen DMBA to noncarcinogenic intermediate(s).

Potent Inhibitory Effect of a New Antiestrogen (RU 16117) on the Growth of 7,12-Dimethylbenz[a]anthracene-lnduced Rat Mammary Tumors

Abstract: The new antiestrogen RU 16117 at doses of 8 or 24 mcg daily had been shown to completely prevent the development of rat mammary cancer when given from the day after 712-dimethylbenz(a)anthracene (DMBA) administration. This study was undertaken to investigate the effect of this compound on the growth of DMBA-induced tumors which had already developed in Sprague-Dawley rats. The effect was compared with that of castration. Levels of receptors for 17beta-estradiol (E2) progesterone and prolactin (PRL) were correlated with the response. At about 3 months after DMBA administration animals with palpable tumors were selected. The rats were then treated daily for 4 weeks with .1 .5 2.5 or 12.5 mcg E2 or with 2 8 or 24 mcg RU 16117 injected in .1 ml of 1% gelatin in .9% NaCl. Controls were injected with the vehicle alone. For comparison a group of rats were ovariectomized. After 4 weeks treatment rats were killed blood collected and a cytosol was prepared from tumor tissues. Binding assays and radioimmunoassays were done. 8 and 24 mcg doses of RU 16117 led to 45 and 65% inhibition of tumor number respectively and tumor size was markedly reduced. Lower doses had less effect. Ovariectomy had an effect similar to that of 24 mcg RU 16117. E2 doses did not change the number or size of tumors. Decreased levels of receptors for E2 progesterone and PRL were found in the tumors remaining after ovariectomy. The 24 mcg dose of RU 16117 had a similar effect on levels of E2 and PRL receptors. It was considered likely that RU 16117 exerts its inhibitory activity at both the hypothalamic-pituitary and tumor levels.

Comparative effects of a series of prolactin inhibitors, 17beta-estradiol and 2alpha-methyldihydrotestosterone propionate, on growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas.

Abstract: Summary Eight ergot alkaloids and ergoline derivatives, effective prolactin inhibitors, were tested for activity against DMBA-induced rat mammary carcinomas. Compounds were administered daily, 5 times/week for 4 weeks, and rats were observed for an additional 4 weeks. Groups treated with androgen and estrogen were used as positive controls. Those ergot compounds and ergolines that proved to be highly effective in reducing tumor size or in inducing regression of tumors to nonpalpability were Deprenon (d-6-methyl-8-ergolin-1-ylacetic acid amide) and ergocryptine; effective to an intermediate degree were Dironyl [ N -(d-6-methyl-8-isoergolin-1-yl)- N ′, N ′-diethylurea], ergocornine, and Lysenyl [ N -(d-6-methyl-8-isoergolenyl)- N ′, N ′-diethylurea]; and effective to a minimal degree were Lergotrile (2-chloro-6-methylergoline-8β-acetonitrile), CB-154, and 6605-VUFB (d-6-methyl-8-cyanomethylergolin-1). Remission of many individual carcinomas was brief, and duration of complete regression (all tumors in the rat were nonpalpable) was less than 10 weeks.

Effect of Age of Non-Skin Tissues on Susceptibility of Skin Grafts to 7,12-Dimethylbenz[a]anthracene (DMBA) Carcinogenesis in BALB/c Mice, and Effect of Age of Skin Graft on Susceptibility of Surrounding Recipient Skin to DMBA

Abstract: The influence of age-dependent alterations in non-skin tissues on chemical carcinogen-induced skin papilloma development was studied by treatment with 7,12-dimethylbenz[alpha]anthracene (DMBA) of 4-month-old skin grafts sewed onto 4- and 20-month-old syngeneic recipients. Skin of 4- and 20-month-old BALB/c female mice differed in susceptibility to DMBA carcinogenesis, but the 4-month-old grafts showed the same papilloma incidence independent of the age of the recipient mice. In a different experiment, the influence of age of skin grafts on papilloma development on DMBA-treated recipient skin was studied. Fourteen- and 26-month-old skin grafts were carried by 14-month-old recipients. Grafts of those two ages are known to differ in susceptibility to DMBA carcinogenesis, but no effect of the grafts on papilloma development on DMBA-treated recipients was detectable. It was concluded that certain age-dependent differences in skin susceptibility to chemical carcinogens are solely a reflection of alterations in the skin at the site of carcinogen treatment.

Autoradiographic localization of Prolactin Receptors in 7,12-Dimethylbenz[ a]anthracene-Induced Rat Mammary Carcinoma

Abstract: In this investigation prolactin receptor sites were localized by autoradiography in 712-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors from rats. Tumors were removed when they reached the size of 2 X 4 cm and sliced to a thickness of .5 mm. Sections cut from the slices were incubated for 3 hours in medium 199 (1% bovine serum albumin 5 mM CaC12 5mM HEPES buffer) at pH 7.4 and 400000 counts/minute of iodine-125-ovine prolactin in the presence or absence of 1 mcg of unlabeled prolactin. After further preparation and storage for 4 months in a light-tight box slides were developed fixed and stained and then photographed. All tumors were labeled by iodine-125-ovine prolactin. Prolactin receptors were associated with only half the total cells. Specific prolactin binding was confined to tumor cells and nonspecific binding was present in alveolar spaces and connective tissue. In some tumors prolactin recepotrs were found in all tummor cells whereas in other tumors half of the cells did not contain any receptors or very few. Reproductions of autoradiographs illustrate findings. Results suggest that variations in receptor content of the tumors may be caused by 2 distinct populations of cells. 1 type contains many receptors and the other very fewreceptor sites or none at all.

Effects of depot injections of retinyl palmitate on 7,12-dimethylbenz[a]anthracene-induced preneoplastic changes in rat skin.

Abstract: The preneoplastic skin changes usually induced by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) to adult rat skin did not appear when animals were treated locally with depot im injections of high doses of retinyl palmitate (RP) prior to exposure to the carcinogen. The epidermal histology after RP-DMBA treatment was similar to that seen in areas exposed to RP alone. Keratinization was inhibited but there was no cellular atypia, evidence of cell injury, or mucous metaplasia. Other features were hyperplasia with acanthosis and thickened stratum granulosum, parakeratosis, intercellular edema, and loss of hair overlying the injection site. Ultrastructurally, the epidermal cells contained conspicuously fewer tonofibrils and increased dense chromatin, when compared to control cells. Skin changes observed following treatment of littermates with DMBA alone included the appearance of giant tumor cells, dyskeratotic cells, nuclear hyperchromatism, increased nucleocytoplasmic ratio, and pleomorphic nuclei and nucleoli. oss of desmosomes, increased tonofibrils, and defects in the basement membrane with epithelial projections into the dermis were also seen. These preneoplastic changes did not regress when application with DMBA was discontinued after 6 weeks; exposure to the carcinogen for longer than 6 weeks resulted in an exacerbation of the abnormal state. RP had profound effects on rat epidermis that interfered with the effects of a potent skin carcinogen. The mechanisms underlying the phenomenon have not been defined. The use of depot injections of the vitamin which avoids both systemic toxicity and the local irritation seen with topical exposure could serve as a model in which the anticarcinogenesis properties of retinoids could be explored.

Metabolism and Cytotoxicity of 7,12-Dimethylbenz[a] anthracene by Hamster, Rat and Rabbit Embryo Cell Cultures

Abstract: 1. The metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) by rat, hamster and rabbit fibroblasts has been studied and compared with the metabolism of the hydrocarbon by liver homogenates. The metabolism of DMBA by cell cultures and by liver homogenates was very similar. The ethyl acetate-soluble metabolites identified included dihydrodiols, phenols and hydroxymethyl derivatives. Other more polar metabolites and unidentified water-soluble metabolites were also formed.2. High yields of phenols and other more polar metabolites, which may be tetrahydrotetrols, were produced by rabbit fibroblasts.3. Kinetic studies showed that the metabolic activity of rabbit fibroblasts was high but that the conversion of DMBA into water-soluble metabolites was lower than with hamster and rat fibroblasts.4. 7,12-Dimethylbenz[a]anthracene-induced cytotoxicity was inversely related to the conversion of metabolized DMBA to water-soluble derivatives.

The Effect of Ovariectomy, Tamoxifen and the Combination Adriamycin and 5-FU on 7,12-Dimethylbenz(a)anthracene Induced Mammary Cancer of the Rat

Abstract: This study was carried out in order to compare the therapeutic effect of ovariectomy, of the antiestrogen tamoxifen and of the combination adriamycin and 5-fluorouracil (5-FU) in 7,12-dimethylbenz (a) anthracene (DMBA) induced premenopausal mammary cancer. 74 rats were randomized to receive (A) ovariectomy, (B) tamoxifen 14 mg/m2, day 1–21, per os, (C) Tamoxifen 2,1 mg/m2, day 1–21, per os, (D) combination chemotherapy of adriamycin and 5-FU and (E) no therapy. 72 rats were evaluable. Ovariectomy was the most effective treatment resulting in five (36 %) complete and seven (50 %) partial remissions out of 14. Tamoxifen (B) yielded one (7 %) partial remission and seven (47 %) no changes out of 13 treated rats. Median tumor size was 0.5 g after ovariectomy and 3.9 g after tamoxifen (B) respectively. The level of significance was p

Effect of 7,12-dimethylbenz(a)anthracene on the binding of aminoacyl transfer RNA in rat liver.

Abstract: Summary Homogenates of the liver of female rats obtained 2 or 7 days or 3 months after the i.v. injection of 7,12-dimethylbenz(a)anthracene were used to prepare ribosomes and postmicrosomal supernatant fractions and to prepare 0.5 m KCl salt wash fractions of the 40 S ribosomal subunits. The activity of the ribosomes was unchanged by 7,12-dimethylbenz(a)anthracene. The activity of the supernatant preparation, which contained limiting amounts of Elongation Factor 1 relative to Elongation Factor 2, in peptide synthesis was significantly increased 2 days but not 7 days after the injection. Evidence was obtained that this increase was due to increased activity in binding phenylalanyl transfer RNA. The factor-dependent binding of methionyl transfer RNA fMet to control rat liver ribosomes was also markedly increased 2 days but not 7 days after the injection. The liver of animals that bore mammary tumors 3 months after 7,12-dimethylbenz(a)anthracene injection also showed an increase in binding both of the aminoacyl transfer RNA species. The results are discussed in relation to the induction of liver drug-metabolizing enzymes and to liver regeneration.

Prolactin Binding to 7,12-Dimethylbenz(a)anthracene-induced Mammary Tumors and Liver in Diabetic Rats

Abstract: Growth rates of 7,12-dimethylbenz( a )anthracene-induced mammary tumors and the specific 125I-labeled prolactin binding to membrane fractions prepared from livers and tumors were studied in rats made diabetic by streptozotocin injection. Growth was inhibited in a majority of tumors, and prolactin binding was reduced in both tumors and livers from diabetic animals. Prolactin binding to individual tumors varied over a wide range in both intact and diabetic animals. Scatchard analysis of binding data revealed that the apparent affinity of prolactin binding to liver and tumor membranes was similar (Ka ∼ 3.0 × 109 m-1) and was not affected by diabetes. We suggest that the reduction in prolactin binding to tumors may render these tissues less responsive to prolactin and thereby explain, at least in part, the observed inhibition of tumor growth in diabetic rats. However, some tumors in diabetic animals regressed despite relatively high levels of prolactin binding activity. Therefore, additional factors most certainly play important roles in the mechanism(s) by which the growth of 7,12-dimethylbenz( a )-anthracene-induced tumors is impaired in the diabetic rat.

Protective effect of chloramphenicol and dextramycin against the adrenocorticolytic action of 7,12-dimethylbenz(a)anthracene

Abstract: The effect of chloramphenicol (CA) and dextramycin (DM) on the adrenocorticolytic action of 7,12-dimethylbenz(a)anthracene (DMBA) was studied in rats. Administration of CA in doses of 0.1–1.0 mg/g and of DM in doses of 0.05–1.0 mg/g 1.5 h before the carcinogen was shown to prevent the development of adrenal necrosis completely. If smaller doses of CA and DM were given, and also if they were given 48 h before the carcinogen or 1.5 h after it, the protective effect was partially preserved. If CA and DM were given 3, 6, or 24 h after DMBA the toxic action of the carcinogen was unchanged.

Mammary tumor and leukemia in male Sprague-Dawley rats evoked by a series of intragastric administration of 7,12-dimethylbenz(a)anthracene.

Abstract: A series of administration of 7,12-dimethylbenz[a]anthracene given at biweekly intervals by gastric intubation of juvenile male rats of the Sprague-Dawley strain elicited considerable number of mammary carcinomas, leukemias, and ear duct tumors. The evoked leukemia shared two main types; 51.6% of erythroblastic stem cell and 48.4% of myelogenous.

Metabolism of 7,12,-dimethylbenz(a)anthracene by normal and regenerating rat livers.

Abstract: The in vitro metabolisms of [14C]7,12-dimethylbenz(a)anthracene (DMBA) by post-mitochondrial supernates and microsomes from intact and regenerating rat livers were compared. Both cell fractions from regenerating livers at 48, 72, and 96 h after partial hepatectomy metabolized less [14C]DMBA than similar fractions from intact livers. Prior in vivo treatment with DMBA enhanced metabolism by the cell fractions from both groups, but specific activities of cell fractions from regenerating livers were always about 60% or less of those from intact livers. Thin-layer chromatographic analysis of metabolites formed in incubations using either cell fraction failed to reveal distinct differences between ether-soluble or water-soluble products of similar fractions from intact and regenerating livers. However, highly reproducible differences were found between chromatograms of water-soluble metabolites formed by microsomes and post-mitochondrial supernates in both intact and regenerating livers. Extrapolations from these studies indicate large differences in the metabolic capacity of intact and regenerating livers when expressed on a whole-liver basis, but it is suggested that there may be additional factors contributing to the increased retention of DMBA by regenerating livers.

Synthesis of potential metabolites of 7,12-dimethylbenz[a]anthracene

Abstract: More and more experimental evidence is accumulating that the carcinogenic polycyclic aromatic hydrocarbons do not exert their carcinogenicity per se, but that they must be activated metabolically in the host organism, and that one or several of the produced metabolites are the ultimate carcinogens (2, 3, 7). Information relevant to the process of chemical carcinogenesis may be derived from these metabolites if they are available in sufficient quantities for experimental work. We now wish to report synthesis of 9-hydroxyand lO-hydroxy-7,12-dimethylbenz[a]anthracenes, potential metabolites of 7,12-dimethylbenz [ a] anthracene. Reaction of 4-methoxyphthalic anhydride (6) with l-naphthylmagnesium bromide afforded a mixture of the isomeric acids 1 and 2 in 54% yield. They were separated by fractionated crystallization from benzene or glacial acetic acid. The proportion 2-( l-naphthoyl)-5-methoxybenzoic acid (1) to 2-( 1naphtholy)-4-methoxybenzoic acid (2) was 1:4.5. The structure of the acids was proved by decarboxylation of 1 to l-methoxybenzoylnaphthalene (4 , 5) prepared independently from anisocyanide and l-naphthylmagnesium bromide. 2-[ l-Hydroxy-1(l-naphthyl)ethyl]-5-methoxybenzoic acid lactone (3) was prepared from 1 with methylmagnesium bromide. Reduction of 3 with zinc and aqueous alkali gave 2-[ l-(l-naphthyl)ethyl]-5methoxybenzoic acid (5). Cyclization of 5 with anhydrous HF led to 9-methoxy-l2-methylbenz[a]anthr-7-one (7). 9-Methoxy7,12-dimethylbenz[a]anthracene (9) was obtained from 7 with methylmagnesium bromide and treatment of the crude reaction product with ptoluenesulfonic acid. 9 was demethylated with thioethoxide ion in dimethylformamide ( 7) to 9a which was not isolated but acetylated directly to 9b. By the same sequence of reactions, 2, through the intermediates 4, 6, and 8, was transformed into lO-methoxy-7,12-dimethylbenz[ alanthracene (10). Demethylation of 10 gave crude loa, acetylated to lob.

Inhibition by neonatal hypothalamic estrogen implantation of carcinogen-induced mammary tumorigenesis in female rats.

Abstract: The effect of estrogen treatment of neonatal female rats on mammary tumors induced by 712-dimethybenz(a)anthracene (DMBA) was investigated. 5-day-old animals were given intrahypothalamic micropellet implants containing .4 mcg estradiol-paraffin mixture or paraffin vehicle alone (sham-operated controls). Nonoperated animals served as intact controls. DMBA was administered intragastrically at 45 days of age. The animals were sacrificed 3 weeks after the appearance of the 1st mammary tumor or 16 weeks after administration of DMBA. Implantation of the estradiol-pariffin micropellets in the anterior to middle part of the hypothalamus produced persistent vaginal estrus while animals implanted in the middle to posterior part of the hypothalamus showed regular cyclic changes. The appearance of mammary tumors was delayed in rats implanted in the anterior to middle part of the hypothalamus in comparison with sham-operated and intact controls. Since the age of vaginal opening and the mammary rating of all 3 groups was the same it is concluded that the hypothalamus of estradiol-paraffin implanted rats is altered by the estrogen while the mammary glands showed little effect. This would indicate that the delay or suppression of mammary tumorigenesis in rats treated with DMBA by estradiol is primarily the result of irreversible changes in the hypothalamo-pituitary-gonadal axis.