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Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1997"


Journal Article
TL;DR: The data show that the endogenous TGF-β system has tumor suppressor activity in the mammary gland and lung, suggesting a role for endogenous T GF-βs in regulating development or maintenance of mammary alveoli.
Abstract: To test the hypothesis that the transforming growth factor-β (TGF-β) system has tumor suppressor activity in the mammary gland, we have generated transgenic mice overexpressing a dominant-negative mutant form of the type II TGF-β receptor, under the control of the mouse mammary tumor virus-long terminal repeat. High-level expression of the transgene was observed in the mammary and salivary glands, with lower expression in the lung, spleen, and testis. Older nulliparous transgenic mice (9–17 months) showed a marked increase in the incidence and degree of lobulo-alveolar side-branching in the mammary glands when compared to wild-type littermates (24.8% of glands examined histologically versus 14.4%; P = 0.004), suggesting a role for endogenous TGF-βs in regulating development or maintenance of mammary alveoli. Spontaneous tumorigenesis was unchanged in the transgenic mice. However, following initiation with the carcinogen 7,12-dimethylbenz[a]anthracene, the transgenic group showed a significant increase in the incidence and multiplicity of mammary tumors when compared with wild-type littermates (40% incidence in transgenic mice versus 22% for wild-type, with 4 of 25 transgenics developing multiple mammary tumors versus 0 of 27 wild-type; P = 0.03). An early increase in the incidence of lung tumors was also observed in transgenic mice, but no difference between genotype groups was seen in the incidence of tumors in tissues in which the transgene is not expressed. The data show that the endogenous TGF-β system has tumor suppressor activity in the mammary gland and lung.

195 citations


Journal ArticleDOI
TL;DR: A relatively non-toxic group of AhR agonists which exhibit potent antitumorigenic activity in the DMBA-induced rat mammary tumor model represent a new class of indirect-acting antiestrogens which have potential for clinical treatment of mammary cancer.

79 citations


Journal ArticleDOI
TL;DR: The results indicate that GTCs are not effective at inhibiting progression of rat mammary carcinogenesis, but Polyphenon E may exert a weak inhibitory effect on the early promotion stage.

67 citations


Journal ArticleDOI
TL;DR: It was found that telomerase activity expressed in neoplastic and preneoplastic lesions of hamster buccal pouch epithelium after DMBA treatment correlated with the histopathological degree of malignancy.
Abstract: The modifying effects of dietary exposure to two natural products, protocatechuic acid (PCA) and costunolide during the development of neoplasms in oral carcinogenesis initiated with 7,12-dimethylbenz[a]anthracene (DMBA) were investigated in male Syrian golden hamsters. All hamsters except those in the test chemical alone and control groups received DMBA (0.5%) in mineral oil to the right buccal pouch 3 times per week for 4 or 6 weeks. At 13 weeks of age, the groups exposed to DMBA were fed diet containing PCA or costunolide at a dose of 0.2 g/kg diet (200 ppm) for 17 weeks. The other groups consisted of hamsters given mineral oil alone for 6 weeks, or given 200 ppm PCA or costunolide alone, or untreated. All animals were necropsied at the termination of the experiment (week 24). PCA or costunolide significantly decreased the tumor burden (P < 0.001-P < 0.05) and the extent of dysplastic areas (%) (P < 0.001-P < 0.05). PCA significantly decreased the mean number of AgNORs/nucleus (P < 0.05). The BrdUrd-labeling index was reduced by dietary administration of test compounds, though not significantly. These results suggest that PCA and costunolide inhibited hamster buccal pouch carcinogenesis and such inhibition may be related to suppression of cell proliferation in the buccal mucosa. It was also found that telomerase activity expressed in neoplastic and preneoplastic lesions of hamster buccal pouch epithelium after DMBA treatment correlated with the histopathological degree of malignancy.

65 citations


Journal ArticleDOI
TL;DR: The results indicate that whereas GTC may inhibit mammary carcinogenesis in the post-initiation stage, the effect is weak and not dose-dependent.

54 citations


Journal ArticleDOI
TL;DR: Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH and Imperatorin at a dose of 400 nmol dramatically decreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA.
Abstract: Several naturally occurring coumarins previously found to be potent inhibitors of mouse hepatic ethoxyresorufin-O-deethylase (EROD) and/or pentoxyresorufin-O-dealkylase (PROD) were examined for their effects on formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) DNA adducts in mouse epidermis, as well as, their effects on skin tumor initiation by these polycyclic aromatic hydrocarbons (PAH). Bergamottin, a potent inhibitor of hepatic EROD, given topically 5 min prior to an initiating dose of B[a]P, significantly decreased total covalent binding of B[a]P to DNA in a dose-dependent manner 24 h after treatment. A dose of 400 nmol bergamottin reduced covalent binding of B[a]P by 72%. Coriandrin, at a dose of 400 nmol also significantly reduced total covalent binding of B[a]P by 59%. In addition, formation of the major (+)anti-B[a]P-diol epoxide-N2-dGuo adduct was selectively reduced by both of these coumarins. In contrast, bergamottin and coriandrin did not significantly decrease covalent binding of DMBA to epidermal DNA at doses of either 400 nmol or 800 nmol. Imperatorin and isopimpinellin, which are more potent inhibitors of hepatic PROD activity, significantly reduced overall binding of DMBA to epidermal DNA by 67% and 52%, respectively, when applied at doses of 400 nmol. These two coumarins also inhibited B[a]P-DNA adduct formation at similar doses but to a lesser extent. Imperatorin at a dose of 400 nmol dramatically decreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA. Bergamottin was a potent inhibitor of tumor initiation by B[a]P while coriandrin was less effective in this regard. Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH. At dose levels higher than those effective against DMBA, imperatorin also inhibited tumor initiation by B[a]P. The results demonstrate that several naturally occurring coumarins possess the ability to block DNA adduct formation and tumor initiation by PAHs such as B[a]P and DMBA. The mechanism for reduced DNA adduct formation and tumor initiation appears to involve inhibition of the P450s involved in the metabolic activation of these hydrocarbons. Finally, the differential effects of certain coumarins on B[a]P vs DMBA DNA adduct formation and tumor initiation may be useful for dissecting the role of specific cytochromes P450 in their metabolic activation.

54 citations


Journal ArticleDOI
TL;DR: The results implicate programmed cell death as a mechanism underlying DMBA-mediated immunosuppression and suggest that preB cell death is influenced by local interactions with AhR+ bone marrow stromal cells.

46 citations


Journal ArticleDOI
TL;DR: It is demonstrated that certain naturally occurring coumarins inhibited metabolic activation of B[a]P and DMBA in cultured mouse keratinocytes and specifically inhibited the formation of DNA adducts derived from the anti diol-epoxide diastereomers from either hydrocarbon.
Abstract: Several naturally occurring coumarins to which humans are routinely exposed have been previously found to be potent inhibitors and inactivators of cytochrome P450 (P450) 1A1-mediated monooxygenase in both murine hepatic microsomes and in a reconstituted system using purified human P450 1A1 [Cai et al. (1993) Chem. Res. Toxicol., 6, 872-879 and Cai et al. (1996) Chem. Res. Toxicol., 9, 729-736]. In the present study, several of these coumarins were investigated for their inhibitory effects on the metabolism and metabolic activation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in cultured mouse keratinocytes. Initial analysis of B[a]P metabolism in cultured keratinocytes showed that imperatorin, isoimperatorin, coriandrin, and bergamottin, at concentrations of 2 nM equal with B[a]P, reduced the formation of water-soluble metabolites of B[a]P by 33% to 57%. Bergamottin and coriandrin were the most potent inhibitors of the compounds examined. HPLC analysis of organic solvent-soluble metabolites of B[a]P indicated that all the coumarins tested significantly reduced the formation of individual B[a]P metabolites (including phenols, diols and tetraols). However, the greatest effect was on the formation of B[a]P tetraols. Additional experiments determined the ability of selected coumarins to block covalent binding of B[a]P and DMBA to DNA in keratinocytes. Bergamottin preferentially inhibited the binding of B[a]P to DNA by 56%, while coriandrin preferentially inhibited the binding of DMBA to DNA by 48%. Notably, analysis of individual DNA adducts formed from B[a]P and DMBA indicated that both bergamottin and coriandrin specifically inhibited the formation of anti diol-epoxide DNA adducts derived from both hydrocarbons. The preferential inhibitory effect of bergamottin and coriandrin on the formation of anti diol-epoxide adducts derived from DMBA was further confirmed by separation of anti- and syn-diol-epoxide-DNA adducts using immobilized boronate chromatography. The current study demonstrates that certain naturally occurring coumarins inhibited metabolic activation of B[a]P and DMBA in cultured mouse keratinocytes and specifically inhibited the formation of DNA adducts derived from the anti diol-epoxide diastereomers from either hydrocarbon. The current data also suggest that certain naturally occurring coumarins may possess anticarcinogenic activity toward polycyclic aromatic hydrocarbons.

43 citations


Journal ArticleDOI
TL;DR: These low dose models of lymphomagenesis and mammary carcinogenesis should prove useful for tests of chemopreventive agents that target the initiation phase of carcinogenesis.
Abstract: Existing models of mouse mammary carcinogenesis induced by the model polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) typically use a small number of bolus doses applied intragastrically. In contrast to this, typical human exposures to carcinogens are thought to be at lower doses and to occur with chronic or sporadic timing. When the classical dosage (1 mg DMBA given once a week for 6 weeks) was split into five daily doses of 200 microg given intragastrically to female SENCAR mice each week for 6 weeks, toxicity was high and the major tumor type seen was lymphoma. Lowering the dose to 60 microg/day gave less toxicity, a 75% incidence of lymphoma and a 30% incidence of mammary carcinoma. However, 20 microg DMBA given five times per week for 6 weeks resulted in a 65-70% incidence of mammary carcinoma within approximately 50 weeks. This represents a 50-fold lower daily dosage of DMBA than that used in the classical model. DNA was prepared from 10 mammary adenocarcinomas and 10 lymphomas and exons 1 and 2 of the H-ras1, K-ras and N-ras genes were sequenced using PCR techniques. Mutations altering codons 12 or 61 of one of the ras family genes were found in 4/10 mammary carcinomas and 5/10 lymphomas. Three mammary tumors exhibited codon 61 mutations, one in each of the genes studied, and a fourth tumor contained a codon 12 mutation in the K-ras gene. Among the lymphomas, two mutations in codon 12 of K-ras, one mutation in codon 61 of K-ras and two mutations in codon 61 of N-ras were also found. Each of the mutations could be interpreted as a G-->T or A-->T transversion. It is suggested that the high incidence of lymphoma at the higher, repetitive doses may be related to immunotoxicity. These low dose models of lymphomagenesis and mammary carcinogenesis should prove useful for tests of chemopreventive agents that target the initiation phase of carcinogenesis.

43 citations


Journal ArticleDOI
TL;DR: Depurinating adducts of BP with guanine were identified in rat mammary glands treated with BP and the major stable adduct, formed via the diol epoxide pathway, accounted for over 64% of all the stableAdducts.
Abstract: Both 7,12-dimethylbenz[a]anthracene (DMBA) and benzo[a]pyrene (BP) are carcinogenic in the rat mammary gland. The depurinating and stable adducts of DMBA and BP formed in vitro and in mouse skin were previously identified and quantitated. Identification and quantitation of the depurinating and stable DNA adducts of DMBA and identification of the depurinating adducts of BP formed in rat mammary glands in the 24 h after intramammillary injection of DMBA or BP are reported in this paper. The depurinating adducts of DMBA, which constitute 52% of all adducts detected, are DMBA bound at the 12-methyl group to the N-7 of adenine (Ade) or guanine (Gua), namely, 7-methylbenz[a]anthracene (MBA)-12-CH2-N7Ade (39%) and 7-MBA-12-CH2-N7Gua (13%). All of the stable adducts were formed from the diol epoxide(s) of DMBA. Depurinating adducts of BP with guanine, namely, 8-(BP-6-yl)guanine (BP-6-C8Gua) and BP-6-N7Gua, were identified in rat mammary glands treated with BP. The major stable adduct, formed via the diol epoxide ...

42 citations


Journal Article
TL;DR: The data indicate a seasonal variation in the development and growth of DMBA-induced breast cancer in Sprague-Dawley rats, and one possible explanation for this phenomenon may be the seasonal variations in pineal melatonin production and immune function previously reported in rodents under constant environmental conditions.
Abstract: There is good evidence in some species, including rats, that circannual rhythms are innate and can occur even under constant environmental conditions. Such circannual rhythms, e.g. in hormone levels and immune system function, may influence tumourigenesis. This prompted us to study 7,12-dimethylbenz[a]anthracene(DMBA)-induced mammary carcinogenesis at different seasons of the year in female Sprague-Dawley rats under constant environmental conditions (photoperiod, temperature, air humidity, food). DMBA was administered orally at a dose of 5 mg per rat at the first day of the experiment and then at weekly intervals up to a total dose of 20 mg per rat. Rats were palpated once weekly for the presence of mammary tumours. After 13 weeks, they were necropsied for examination of the number and size of mammary tumours. Age-matched groups of 36-99 rats were used per experiment. When the experiment was performed twice within 2 years during the same season (spring/summer), tumour incidence (56 and 61%) and tumour burden were almost equal, indicating that data obtained in this way were reproducible. However, the same experiment performed in autumn yielded a significantly lower tumour incidence (34%) and tumour burden. When the experiment was started during winter, tumour incidence was similar to the spring/summer groups, but tumour burden was lower. The data indicate a seasonal variation in the development and growth of DMBA-induced breast cancer in Sprague-Dawley rats. One possible explanation for this phenomenon may be the seasonal variation in pineal melatonin production and immune function previously reported in rodents under constant environmental conditions.

Journal ArticleDOI
TL;DR: It is found that different ploidy effects were induced in four Chinese hamster-derived cell lines treated through two cell cycles with polycyclic aromatic hydrocarbons in the absence of a metabolic activation system, and the V79-MZ and V79 cell lines might be good systems for detecting aneuploidogens.
Abstract: We found that different ploidy effects were induced in four Chinese hamster-derived cell lines (V79-MZ, V79, CHL and CHO-K1) treated through two cell cycles with polycyclic aromatic hydrocarbons in the absence of a metabolic activation system. 5-Bromodeoxyuridine was used to investigate cell cycle delay and sister chromatid exchanges (SCE) induced by the chemicals. Benzo[a]pyrene (BP) induced aneuploidy at 2.5-10 micrograms/ml in V79-MZ cells. 7,12-Dimethylbenz[a]anthracene (DMBA) induced polyploidy at 3.125-6.25 and 6.25-1.25 micrograms/ml in V79-MZ and V79 cells respectively. Higher concentrations caused cell cycle delay and, therefore, did not affect ploidy. BP and DMBA did not induce a significant increase in SCE frequency at the above doses. 3-Methylcholanthrene tested up to its solubility limit (10 micrograms/ml) did not induce numerical aberrations in any cell line. The clastogen mitomycin C, tested up to 0.01 microgram/ml, did not produce numerical aberrations but did significantly increase SCE frequency in all cell lines. The spindle poison colchicine, tested up to 0.1 microgram/ml, induced ploidy changes in the four cell lines that showed different sensitivities. Four cell lines showed no arylhydrocarbon hydroxylase activity, and V79-MZ, but not the other cells lines, showed high glutathione S-transferase activity. Aneuploidy induction by BP and polyploidy induction by DMBA in the absence of S9 mix in vitro have not been described before, and the finding might be due to the effect on tubulin. Due to their specificity and high sensitivity, the V79-MZ and V79 cell lines might be good systems for detecting aneuploidogens.

Journal ArticleDOI
TL;DR: It is indicated that BBP acts as a blocking agent toward DMBA-induced rat mammary DNA adduct formation and mammary carcinogenesis, and this effect partly may be due to increased metabolism of BBP in the liver.
Abstract: Although the risk for cancer is multifactorial, a substantial portion of cancer incidence rates is related to environmental factors, including diet and environmental chemicals. The magnitude of the contribution to cancer of the breast from exposure to environmental chemicals remains unclear. The phthalate ester plasticizers are abundantly-produced industrial chemicals that have become widely-dispersed environmental pollutants. The present studies were conducted to determine the effect of the phthalate ester, benzyl butyl phthalate (BBP) on mammary gland carcinogenesis induced in the female rat by the polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA). Exposure to BBP (i.p. injection) at 100 and 500 mg/kg doses for 5 days resulted in a significant 72 and 92% inhibition, respectively, in the in vivo formation of mammary DMBA-DNA adducts, compared to controls. Treatment with BBP (i.g. intubation) for 7 days resulted in a significant (48%) inhibition in mammary DMBA-DNA adduct formation only for those animals receiving the 500 mg/kg dose, compared to controls. Administration of BBP (i.g.) at 500 mg/kg for 7 days also was associated with a significant 8.5-fold increase in the liver activity of 7-ethoxyresorufin-O-deethylase. No change in liver glutathione-S-transferase activity was observed for animals treated with both BBP (i.g.) doses. Treatment with BBP (i.g.) at 250 and 500 mg/kg doses for 7 days prior to DMBA administration resulted in a significant 37% decrease in mammary tumor incidence for both doses, compared to controls. The number of mammary adenocarcinomas per rat was significantly inhibited by 60 and 70% for rats exposed to BBP at the 250 and 500 mg/kg doses, respectively, compared to controls. Therefore, the present studies indicate that BBP acts as a blocking agent toward DMBA-induced rat mammary DNA adduct formation and mammary carcinogenesis. This effect partly may be due to increased metabolism of BBP in the liver. These results underscore the need to further examine the effect of BBP and other phthalates on the various stages of mammary carcinogenesis, as well as on the metabolism of mammary carcinogens.

Journal ArticleDOI
TL;DR: It is shown that cells with a high expression level of WT1 tended to develop into leukemia and that WT1 contributed to leukemogenesis in the late stage, suggesting that the expression ofWT1 plays an important role in cell proliferation and in maintaining the viability of some leukemia cells.
Abstract: The Wilms'-tumor gene WT1 may have a different function from a tumor-suppressor gene in some leukemias. Using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat leukemia system, we examined whether WT1 expression was involved during leukemogenesis, since this model enabled us to analyze cells altered by DMBA at various stages of leukemogenesis. By the semi-quantitative reverse-transcriptase polymerase chain reaction(RT-PCR) method, WT1 expression was detected in 15 (71%) of 21 DMBA-induced erythroblastic leukemias. Among 15 WT1-expressing leukemias, GATA-1, which is an erythroid-specific transcription factor and might regulate WT1 expression, was also expressed in 13 cases (p < 0.05). On the other hand, WT1 expression was not detected in any normal or early pre-leukemic rats and was detected in 1 of 8 rats in late pre-leukemic stages. These results showed that cells with a high expression level of WT1 tended to develop into leukemia and that WT1 contributed to leukemogenesis in the late stage, suggesting that the expression of WT1 plays an important role in cell proliferation and in maintaining the viability of some leukemia cells. Int. J. Cancer 72:696–699, 1997. © 1997 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: The significantly increased binding of DBP to the mammary epithelial DNA over BP and DMBA is in concordance with its known higher mutagenicity and tumorigenicity.
Abstract: Dibenzo[a,l]pyrene (DBP) has recently emerged as a potent environmental carcinogen having greater carcinogenicity in the rat mammary epithelial glands than 7,12-dimethylbenz[a]anthracene (DMBA), previously considered to be the most potent mammary carcinogen and benzo[a]pyrene (BP), a ubiquitous environmental carcinogen. Previous studies on the tumor-initiating potential of DBP, DMBA, and BP demonstrated that DBP was 2.5 times more potent in inducing the tumors in mouse skin and rat mammary glands than DMBA; BP was a weak mammary carcinogen in these animals. The present study was designed to investigate if the significantly increased mammary carcinogenicity of DBP over DMBA and BP was related to increased DNA adduction at the target site. Female Sprague–Dawley rats were treated by intramammillary injection with an equimolar dose of 0.25 μmol/gland of DBP, DMBA, and BP at the 3rd, 4th and 5th mammary glands on both sides. 32P-Postlabeling analysis of mammary epithelial DNA of rats treated with DBP produced two major (nos. 3 and 6) and at least 5 minor adducts. DMBA treatment resulted in one major and 4 minor DNA adducts while BP produced one major and two minor adducts. Quantitation of the adduct radioactivity revealed that DNA adduction was 6- and 9-fold greater in DBP-treated animals than in BP- and DMBA-treated animals, respectively. The adduct levels per 109 nucleotides in mammary epithelial cells for DBP, BP and DMBA were in the following descending order: 1828±378, 300±45 and 207±72, respectively. Tissue distribution of DNA adducts in non-target organs following DBP treatment showed similar adduct pattern as found in the mammary epithelial cells except the liver, which resulted in 4 additional adduct spots; vehicle-treated tissue DNA processed in parallel did not show any detectable adducts. DMBA- and BP–DNA adduct patterns in various tissues were similar to that found in mammary epithelial cells, however, significant quantitative differences were found; BP–DNA adducts were undetectable in the pancreas and bladder. Quantitation of adduct radioactivity showed a 15- to 60-fold lower DBP-DNA adduction in these tissues than the levels found in the mammary tissue; similarly 5–20 and 30–100 times lower DNA adduction was found following treatment with DMBA and BP, respectively. The significantly increased binding of DBP to the mammary epithelial DNA over BP and DMBA is in concordance with its known higher mutagenicity and tumorigenicity.

Journal ArticleDOI
01 Mar 1997-Leukemia
TL;DR: It is shown that HL-60 R has a global defect in its ability to be induced to differentiate by a variety of pathways, not merely the retinoid pathway, and several putative differentiation agents may have anti-cancer activities, even though they do not induce differentiation of the cancer cells.
Abstract: All-trans retinoic acid (RA) induces granulocytic differentiation of acute promyelocytic leukemia cells both in vivo and in vitro. In the HL-60 wild-type (WT) early promyelocytic leukemia cell line, granulocytic differentiation appears to be directly mediated by the nuclear receptor RARα. An HL-60 subline resistant to RA (HL-60 R) contains a point mutation which results in a truncation of 52 amino acids at the COOH end of RARα. Cross-talk between differentiation, clonal inhibition of growth and apoptosis was studied using HL-60 WT, HL-60 R, and HL-60 R infected by a retroviral vector containing RARα (LX) as targets, which were cultured with various retinoids, vitamin D3 analogs, HMBA, or DMSO. None of these compounds induced significant differentiation of HL-60 R and HL-60 LX, but they did induce differentiation of HL-60 WT. In contrast, retinoids inhibited the clonal proliferation of HL-60 WT, HL-60 R, and HL-60 LX. Vitamin D3 analogs including KH1060 stimulated the clonal growth of HL-60 R; but they inhibited clonal growth of HL-60 WT and LX. Levels of Bcl-2 strongly decreased in HL-60 WT and LX after treatment by retinoids, while no change in expression occurred in HL-60 R. Neither KH 1060 nor 9-cis RA induced apoptosis of HL-60 R, but these agents did induce apoptosis in HL-60 LX WT. Taken together, we showed that HL-60 R has a global defect in its ability to be induced to differentiate by a variety of pathways, not merely the retinoid pathway. Furthermore, our HL-60 models showed that inhibition of proliferation and induction of apoptosis and differentiation can be dissociated. Clinically, these results suggest that several putative differentiation agents may have anti-cancer (antiproliferative) activities, even though they do not induce differentiation of the cancer cells.

Journal ArticleDOI
TL;DR: It is shown that iron overload acts as a mild tumor promoter in mouse skin and oxidative stress generated by iron overload plays an important role in the augmentation of cutaneous tumorigenesis.
Abstract: SummaryIron overload is known to occur in West European and American populations due to the consumption of an iron-rich diet. There are also genetic disorders which lead to body iron overload. It has been shown that iron overload predisposes humans to an increased risk of cancer. In experimental animals, iron overload is known to enhance intestinal, colon, hepatic, pulmonary and mammary carcinogenesis. However, the mechanism by which iron overload enhances chemically-induced carcinogenesis is not known. In this study, we show that iron overload acts as a mild tumor promoter in mouse skin. Female albino swiss mice were given 1 mg iron/mouse parenterally for 2 weeks to induce iron overload. These animals showed a three-fold increase in cutaneous iron concentration as compared to normal mice. Tumors were initiated by topically applying 7,12-dimethylbenz(a)anthracene (DMBA). Appearance of the first tumor (latency period), percent tumor incidence and number of tumors/mouse were recorded. When compared to the c...

Journal ArticleDOI
TL;DR: Results suggest that LOH related to loss of the wild‐type N‐ras allele reproducibly occurs in leukemias with the N‐ra mutation, and it is likely that theN‐ras mutation is induced early, and cells that have lost the wild-type N-ras allele seem to develop into leukemia.
Abstract: The 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat leukemia model enables scientists to analyze cells altered by carcinogens at various stages of leukemogenesis. We have reported that a consistent type of point mutation. A-->T transversion at the second base in codon 61 of the N-ras gene, was present in this leukemia and that this mutation appeared in bone marrow cells as early as 48 h after a single dose of DMBA. In addition, two leukemia cell lines with the N-ras mutation had no wild-type N-ras allele. Therefore, we examined whether these alterations were essential to the DMBA-induced leukemias. In the study reported here, we confirmed the occurrence of this N-ras mutation in 18 (86%) of 21 primary leukemias and loss of the N-ras wild-type allele in 12 (67%) of 18 leukemias with the mutated N-ras. By using microsatellite markers on chromosome 2, loss of heterozygosity (LOH) at the N-ras locus was observed in eight leukemias, all of which were shown to have lost the wild-type N-ras allele by mutant-allele-specific amplification. These results suggest that LOH related to loss of the wild-type N-ras allele reproducibly occurs in leukemias with the N-ras mutation. Considering the timing of the N-ras mutation and LOH, it is likely that the N-ras mutation is induced early, and cells that have lost the wild-type N-ras allele seem to develop into leukemia. We believe that this system provides a suitable model for studying a series of genetic alterations from the earliest stage of carcinogenesis that cannot be approached in human malignancies.

Journal ArticleDOI
TL;DR: Non-specific cytotoxicity in oyster toadfish has been shown to be substantially more sensitive to DMBA than non-specific phagocytosis.

Journal ArticleDOI
TL;DR: The effect of a peptide prepared from corn gluten meal by proteolysis with alkaline protease on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor progression were investigated in female Sprague-Dawley rats and total number and total weight of tumors were greater in the CAS group compared with 5-CP, 10-CP or AA groups.

Journal ArticleDOI
TL;DR: The results suggest that the BNF-inducible trout P450 (CYP1A), not the constitutive P450s, is the major catalyst for the biotransformation of DMBA to metabolites that bind to macromolecules.

Journal ArticleDOI
TL;DR: An in vitro transformation procedure that involved the treatment of normal hamster oral mucosal keratinocytes (NHKs) with DMBA was established to enhance the ability to define the genetic and molecular changes related to chemical carcinogenesis and oral malignant transformation.

Journal ArticleDOI
TL;DR: In this article, the trans-3,4-dihydrodiol metabolites of 9- and 10-fluoro-7,12-dimethylbenz[a]anthracene, -7-methylbenz [a]-anthracenes, and -12-methyl benz[a], were described as putative carcinogenic metabolites that undergo activation by the P-450 microsomal enzymes to ultimate carcinogenic anti- and syn-diol epoxide metabolites that bind to nucleic acids in vivo.

Journal ArticleDOI
TL;DR: 7,12-dimethylbenz(a)anthracene (DMBA) causes necrosis in endocrine organs and metabolism in follicles and corpora lutea from porcine ovaries was demonstrated not only in the microsomal but also in the mitochondrial fraction, in contrast to what has been found in the rat ovary.

Journal Article
TL;DR: A prolonged effect of exogenous M, demonstrated by prevention of increase in TG in the thymus and of irradiated animals caused by administration of DMBA, was observed, which is needed to explain the relationship between the beneficial effect of M on metabolic changes and its presumable oncostatic effect in rats.
Abstract: Metabolic profile is an important biological marker of neoplastic processes not only in the tumor itself but also in the host organism. The neurohormone melatonin has been implicated in experiments as an oncostatic agent. Female Wistar:Han SPF rats (Velaz, Prague, Czech Republic) were irradiated continuously for 15 days using a daily gamma rays dose of 96 mGy. At the end of exposure one group of rats was administered 5 mg/kg b.w. of dimethylbenz/a/anthracene (DMBA) intragastrically. During the period of exposure to ionizing radiation a part of the animals was supplied with melatonin (M) at a concentration of 20 microliters/ml in drinking water. Selected parameters of lipid and carbohydrate metabolisms and levels of selected hormones were determined 2, 30 and 100 days post-irradiation. The irradiation itself caused only small changes in tissue lipids. The application of a single low dose (subthreshold from the point of view of induction of mammary tumors) of DMBA caused more pronounced changes in nonirradiated animals; of the changes observed an increase in lipids in the liver, triacylglycerols (TG) in the thymus and decrease in myocardial glycogen predominated. The intake (by drinking) of exogenous M prevented the biochemical pattern of fatty liver in animals administered DMBA in both groups, irradiated and nonirradiated. A prolonged effect of exogenous M, demonstrated by prevention of increase in TG in the thymus and of irradiated animals caused by administration of DMBA, was observed. The mechanism of metabolic effect of M is not known. Additional experiments are needed to explain the relationship between the beneficial effect of M on metabolic changes and its presumable oncostatic effect in rats.

Journal ArticleDOI
TL;DR: The results suggest that prolactin (PRL) increasesthe incidence of adenocarcinoma in the DMBA-induced mammarytumor model, and DHEA especially decreases the incidence ofAdenocARCinoma.
Abstract: The present study was performed to investigate theeffects of dehydroepiandrosterone (DHEA) compared with those ofsex steroid hormones on the mammary tumor inducedby local injection of 7, 12-dimethylbenz(a)anthracene (DMBA) inhyperprolactinemic female rats. Under sustained hyperprolactinemia induced bypimozide (PMZ) from day 21, DMBA was injectedlocally into the mammary glandular tissues on day73. Rats were divided into 5 groups asfollows; steroid free (DP group), 17 β-estradiol (DP+ E2 group), testosterone (DP + T group),progesterone (DP + Prog group), or dehydroepiandrosterone (DP+ DHA group). The growth pattern and histologicalclassification of the tumor in these 5 groupsand rats treated only with DMBA (D group)were examined. All of the tumors grew toa size of 10 mm in diameter andafter retaining the size for a certain duration,increased the size rapidly again (onset of rapidtumor growth). The period from the day ofDMBA administration to that of onset of therapid tumor growth in DP group was shorterthan in D group, and the period inDP + DHA was longer than DP groupand longest in steroid-treated groups. The incidence ofadenocarcinoma was 2 tumors/16 animals in D group,9/11 in DP group, 5/11 in DP +Prog group, 2/7 in DP + E2 group,2/8 in DP + T group, and 0/10in DP + DHA group. The incidence ofadenocarcinoma in each steroid group except in DP+ Prog group was lower than in DPgroup. These results suggest that prolactin (PRL) increasesthe incidence of adenocarcinoma in the DMBA-induced mammarytumor model, and DHEA especially decreases the incidenceof adenocarcinoma.

Journal ArticleDOI
TL;DR: Topical application of chemically extracted oil and naturally extracted oil (C.O. and N.O.) highly prevented the appearance of skin tumors in experimental animals and significantly increased the rate of mice survival as compared to that of animals of group 1.
Abstract: The effect of topical application of black seed oil on 7,12-dimethylbenz(a)anthracene (DMBA)-induced skin tumors in BALB/c mice was investigated. Topical application of chemically extracted oil (C.O.) and naturally extracted oil (N.O.) highly prevented the appearance of skin tumors in experimental animals. Skin tumors (papillomas and carcinomas) were initiated by application of 300 mu g DMBA (on days 1,8) followed by applying 0.5 mg croton oil, biweekly until the end of the experiment (25 weeks). The application of N.O. completely prevented the appearance of skin tumors in mice of group 3 versus a tumor incidence of 78.9% in animals of group 1 (carcinogenic control) (cc). Painting the skin of mice with C.O. (group 2) significantly reduced the tumor incidence to 14.2%. Moreover, a significant decrease was observed in number of mice bearing tumors, and number of tumors per mouse in group 2. Multiplicity was also decreased but insignificantly in the same group. The treatment with C.O. and N.O. insignificantly increased the rate of mice survival as compared to that of animals of group 1.

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TL;DR: The DMBA-DNA binding assay was utilized to evaluate the chemopreventive potential of positional isomers of XSC (o, m- and p-XSC) applied at selenium doses of 5 and 15 ppm and found the latter appears to be slightly more effective than its sulfur analog p- XTC.
Abstract: As shown earlier p-XSC inhibits DMBA-induced mammary cancer in female CD rats. This inhibition is due, in part, to inhibition of DMBA-DNA adduct formation in the target organ. We have now utilized the DMBA-DNA binding assay to evaluate the chemopreventive potential of positional isomers of XSC (o-, m- and p-XSC) applied at selenium doses of 5 and 15 ppm; p-XTC, the sulfur analog of p-XSC, was used at an equimolar dose to determine whether selenium is required for the observed inhibitory effect. Selenium and sulfur compounds were administered in a semipurified high-fat diet (23.5% corn oil). Rats were fed for 1 week prior to oral administration of a single dose of [H-3]DMBA (5 mg/rat); animals were sacrificed 24 h later, DNA was isolated from mammary fat pads and levels of total binding were determined. All agents produced a dose-dependent inhibition of DMBA-DNA binding in the mammary tissues. The inhibition at 5, respectively 15 ppm Se in the form of XSC isomers and at 30 mu M, respectively 90 mu M in the form of p-XTC was: o-XSC (27%, 42%); m-XSC (32%, 47%); p-XSC (22%, 29%); and p-XTC (10%, 20%); only inhibition by dietary o-XSC and m-XSC at 15 ppm Se reached statistical significance (p<0.05). Thus, o-XSC and m-XSC equally inhibit DMBA-DNA binding and both are better inhibitors than p-XSC; the latter appears to be slightly more effective than its sulfur analog p-XTC. Clearly, the structure of the selenium-containing compound is a critical factor in determining the extent of inhibition of DMBA-DNA binding. The described short-term in vivo assay may constitute the basis for future selection of chemopreventive agents in the rat mammary tumor model system.

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TL;DR: The results suggest that a mild energy restriction in HAS feeding is effective in prevention of mammary tumor progression.