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9,10-Dimethyl-1,2-benzanthracene is oxygenated by rat liver microsomal cytochrome P-450 oxygenase to its 9,10-epidioxide. This transannular 1,4-peroxide is converted further into the diol by the microsomal preparation and NADPH. These two products constitute the majority of the metabolites found under the conditions described.
The antigenic activity of rat submandibular gland carcinoma induced by 9,10 dimethyl-1,2 benzanthracene (DMBA) has been evaluated using rabbit antisera to normal submandibular gland extract and to extracts of the induced tumors. Extracts of all tumors and premalignant lesions show reduction in the concentration of several of the intrinsic antigens of the normal submandibular gland when they were evaluated by immunodiffusion and immunoelectrophoresis. Although all the induced tumors, including those used for antisera preparation, are well-differentiated epidermoid carcinoma, a considerable variation is present in the antigenic pattern of each tumor. When antisera to several tumors, absorbed with rat serum and kidney extract, were used in studying extracts of all induced tumors, antigenic bands were observed. The number of these bands varies from three to five. All the induced carcinomas share the presence of two of these bands in the alpha and beta-globulin region, the remaining bands differ from one tumor to another.
After incubation of [4-14C]progesterone with cell-free homogenates of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced mammary tumor of rats, 20 alpha-hydroxy-4-pregnen-3-one, 5 alpha-pregnane-3,20-dione, 20 alpha-hydroxy-5 alpha-pregnan-3-one, 3 alpha-hydroxy-5 alpha-pregnan-20-one, and 5 alpha-pregnane-3 alpha, 20 alpha-diol were identified as the metabolites. In normal mammary tissue, however, 4-pregnene-3 alpha-diol was isolated in addition to 5 alpha-reduced, and 3 alpha- and 20 alpha-hydroxy metabolites. When radioactive testosterone was employed as a substrate, 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha, 17 beta-diol were obtained as the metabolites of the mammary tumor. In the normal mammary gland, only 4-andorstene 3 alpha, 17 beta-diol was formed as its metabolite. Although the enzyme activities relevant to the metabolism varied among the tumor examined, the activity of 20 alpha-hydroxysteroid dehydrogenase in the mammary tumor was significantly lower than that in the normal mammary gland, whereas the activity of 5 alpha-reductase was higher in some of the mammary tumors than in the normal gland. The 5 alpha-reductase activity in the normal mammary gland was mostly localized in the crude microsomal fraction, whereas the same enzyme activity in the tumor was detected in all the organelle fractions. The activities of 20 alpha-hydroxysteroid dehydrogenase and NADPH-linked 3 alpha-hydroxysteroid dehydrogenase were found mainly in the cytosol fractions of the tumor and the normal tissue. The NADH-linked 3 alpha-hydroxysteroid dehydrogenase activity was detected only in the cytosol fraction of the normal mammary gland, but in the tumor studied, the activity of this enzyme was detected in all the subcellular fractions examined.
The purpose of this study was to determine whether or not endogenous mammary peroxidase can serve as a cytochemical marker to distinguish ovarian hormone-dependent from ovarian hormone independent mammary tumors. Spontaneous mammary tumors arising in virgin C3H and GR mice (hormone independent tumors) and hormone-dependent mammary tumors arising during pregnancy in GR mice were examined. None of these tumors contained mammary peroxidase. Mammary tumors induced in Sprague-Dawley rats with methylnitrousourea (MNU) and dimethylbenzanthracene (DMBA) were also examined. These tumors included hormone-dependent and hormone independent ones. Several of the DMBA-induced hormone-dependent tumors contained a few peroxidase-positive cells, but the hormone independent tumors were negative. All of the MNU-induced tumors examined were negative for mammary peroxidase. Twenty human breast tumors (malignant and non-malignant) removed from women at surgery, were also negative for mammary peroxidase. Our results indicate that endogenous mammary peroxidase cannot be used to distinguish hormone-dependent from hormone independent mammary tumors.
Two highly purified rat casein mRNA fractions were used as templates to synthesize complementary DNA (cDNA) hybridization probes using RNA-directed DNA polymerase isolated from avian myeloblastosis virus. Both of the probes selectively hybridized to RNA isolated from lactating mammary tissue, but not to poly(adenylic acid)-containing rat liver RNA. An analysis of the kinetics of hybridization of the cDNA derived from the 15S casein mRNA (cDNA12S) with their individual mRNA templates indicated that greater than 90% hybridization occurred over a R0t range of one and one-half logs with R0t 1/2 values of 0.0023 and 0.0032 mol s l.-1, respectively. Compared with the total RNA isolated from lactating mammary tissue, these values represented a 166- and 245-fold purification, respectively, of these individual mRNA fractions. Using the 15S casein mRNA as a template, two probes of different lengths and specific activities were synthesized. The deoxyribonucleotide and mRNA concentrations and the temperature of incubation were optimized to obtain either a high specific activity cDNA probe, 330 nucleotides long, which represented approximately 25% of the mRNA or a lower specific activity preparation containing some complete cDNA copies, 1300 nucleotides in length. The Tm of the longer cDNA15S-15S mRNA hybrid was 88.5 degrees C, while that of the short cDNA15S-RNA hybrid was 82.5 degrees C. Following this initial characterization, the cDNA15S probe was utilized for three separate determinations: (1) Analysis of the sequence divergence between mouse and rat casein mRNAs. It was observed that the rate of hybridization of heterologous rat cDNA15S-mouse casein mRNA was only 20% that of the homologous rat cDNA15S-rat casein mRNA hybridization. The resulting heterologous hybrid displayed approximately 17% mismatching compared with the homologous hybrid. (2) Determination of the gene dosage for casein mRNA in normal and malignant mammary cells. In this study, an analysis of the kinetics of hybridization of the high specific activity cDNA15S probe with an excess of DNA isolated from lactating mammary tissue, carcinogen-induced mammary tumors, or rat liver indicated that casein mRNA was transcribed from the nonlification or deletion was observed during tumor formation or the process of mammary differentiation. (3) Quantitation of casein mRNA sequences during normal mammary gland development. RNA excess hybridizations were performed using RNA extracted from either pregnant, lactating, or regressed rat mammary tissue. The concentration of casein mRNA molecules/alveolar cell was found to increase 12-fold from 5 days of pregnancy until 8 days of lactation and then declined to approximately 2% of the maximal level of 79 000 molecules/cell by 7 days after weaning. A coordinate increase was observed in casein mRNA sequences detected by cDNA hybridization and mRNA activity measured in a cell-free translation assay.
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When mouse MLg cells were treated with 3-methylcholanthrene or 7,12-dimethylbenz[alpha]anthracene in the presence of microsomal enzymes and NADPH after 5-iododeoxyuridine (IUDR) treatment, the induction rate of the endogenous C-type virus was increased fivefold to sixfold in comparison with the culture treated with IUDR only. In this reaction, both the microsomal enzymes and NADPH were indispensable. 7,8-Benzoflavone, an inhibitor of the metabolism of hydrocarbons in hamster embryo cultures, inhibited the reaction. For detecting the enhancing activity, the concentration of IUDR for the pretreatment, the concentration of the test products, and the duration of the treatment with the products were important factors. In screening 30 polycyclic hydrocarbons, we were unable to detect a correlation between the in vivo carcinogenicity in the skin and the enhancing activity in the conditions tested.
Hyperimmune rabbit antiserum to an early, nonstructural herpes simplex virus type 2 (HSV-2)-induced polypeptide (VP143) reacted in immunofluorescence tests with a variety of cell lines transformed by HSV-2. Cytoplasmic fluorescence was observed in 10 to 50% of HSV-2-transformed cells, whereas no fluorescence was observed in cells transformed by other oncogenic DNA viruses or by a chemical carcinogen. VP143-specific reactivity could be absorbed from anti-VP143 serum with HSV-2-transformed cells but not with cells transformed by other agents. When HSV-2-transformed cells were synchronized in mitosis and examined at various times postmitosis for VP143-specific fluorescence, the expression of VP143 was shown to be cell cycle dependent.
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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.
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In gonadectomized and totally or partially criptorchid rats, subcutaneous inoculation of 0,5 mg of DMBA often determines the development of sarcomas at variable, sometimes marked, distances from the site of inoculation. The phenomenon is exhibited maximally in rats subjected to unilateral cryptorchidism or to unilateral gonadectomy; in minimal measure in those subjected to bilateral gonadectomy. It is not exhibited in the intact animals. The Authors, though presenting several hypotheses, are not able to furnish a satisfactory explanation of the phenomenon.
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.
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