Showing papers on "7,12-Dimethylbenz[a]anthracene published in 2011"

Antitumor Initiating Potential of Rosmarinic Acid in 7,12-Dimethylbenz( a )anthracene-Induced Hamster Buccal Pouch Carcinogenesis

Abstract: Oral cancer accounts for 40%-50% of all cancers in India. Tobacco and alcohol are the major etiological factors contributing to its pathogenesis. The aim of the present study was to explore the key mechanism behind the inhibitory effects of rosmarinic acid against 7,12-dimethylbenz(a)anthracene (DMBA)-induced oral carcinogenesis by evaluating the status of biochemical markers (lipid peroxidation, antioxidants, and detoxification enzymes) and immunoexpression patterns of p53 and bcl-2 proteins. Oral tumors were developed by painting the buccal pouches of golden Syrian hamsters with 0.5% DMBA in liquid paraffin 3 times a week for 14 weeks. We noticed 100% tumor formation in hamsters treated with DMBA alone, and the tumors were histopathologically confirmed as well-differentiated squamous cell carcinoma. Oral administration of rosmarinic acid (100 mg/kg body wt) to DMBA-treated hamsters completely prevented the tumor formation. In addition, rosmarinic acid significantly returned the status of biochemical and molecular markers to near normal range in DMBA-treated hamsters. The results of the present study suggest that rosmarinic acid suppresses oral carcinogenesis by stimulating the activities of detoxification enzymes, improves the status of lipid peroxidation and antioxidants, and downregulates the expression of p53 and bcl-2 during DMBA-induced oral carcinogenesis.

Assessment of genotoxicity induced by 7,12‐dimethylbenz(a)anthracene or diethylnitrosamine in the Pig‐a, micronucleus and Comet assays integrated into 28‐day repeat dose studies

Abstract: As part of the Stage 3 of the Pig-a international trial, we evaluated 7,12-dimethylbenz(a)anthracene (DMBA) for induction of Pig-a gene mutation using a 28-day repeat dose study design in Sprague-Dawley rats. In the same study, chromosomal damage in peripheral blood and primary DNA damage in liver were also investigated by the micronucleus (MN) assay and the Comet assay, respectively. In agreement with previously published data (Dertinger et al., [2010]: Toxicol Sci 115:401-411), DMBA induced dose-dependent increases of CD59-negative erythrocytes/reticulocytes and micronucleated reticulocytes (MN-RETs). However, there was no significant increase in DNA damage in the liver cells when tested up to 10 mg/kg/day, which appears to be below the maximum tolerated dose. When tested up to 200 mg/kg/day in a follow-up 3 dose study, DMBA was positive in the liver Comet assay. Additionally, we evaluated diethylnitrosamine (DEN), a known mutagen/hepatocarcinogen, for induction of Pig-a mutation, MN and DNA damage in a 28-day study. DEN produced negative results in both the Pig-a mutation assay and the MN assay, but induced dose-dependent increases of DNA damage in the liver and blood Comet assay. In summary, our results demonstrated that the Pig-a mutation assay can be effectively integrated into repeat dose studies and the data are highly reproducible between different laboratories. Also, integration of multiple genotoxicity endpoints into the same study not only provides a comprehensive evaluation of the genotoxic potential of test chemicals, but also reduces the number of animals needed for testing, especially when more than one in vivo genotoxicity tests are required.

Apigenin Prevents Development of Medroxyprogesterone Acetate-Accelerated 7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumors in Sprague–Dawley Rats

Abstract: The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague-Dawley rats by 7,12-dimethylbenz(a)anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA-induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor levels, or the number of estrogen receptor-positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor-positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins.

Protective effect of berberine on expression pattern of apoptotic, cell proliferative, inflammatory and angiogenic markers during 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis.

Abstract: Investigation of expression pattern of molecular markers in oral epithelial tissues would help to assess the cell differentiation and proliferation as well as early diagnosis of precancerous and cancerous lesions of the oral cavity. Aim of the present study was to investigate the protective effect of berberine on expression pattern of apoptotic, cell proliferative, inflammatory and angiogenic markers during 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. Immunohistochemical staining [p53, Bcl-2, Bax, Proliferating Cell Nuclear Antigen (PCNA) and Vascular Endothelial Growth Factor (VEGF)], Enzyme Linked Immuno Sorbent Assay (ELISA) [c-fos, COX-2, caspase-3 and -9] and Real-Time PCR [Cyclin D1 and NFkappaB] were utilized to assess the expression pattern of molecular markers in DMBA induced hamster buccal pouch carcinogenesis. Over expression of mutant p53, PCNA, Bcl-2 and VEGF were noticed in hamsters treated with DMBA alone. Decreased expression of Bax protein was noticed in hamsters treated with DMBA alone. Increased expression of C-fos, COX-2, NFkappaB and Cyclin D1 and decreased activities of caspase-3 and -9 were also noticed in hamsters treated with DMBA alone. Oral administration ofberberine at a dose of 75 mg kg(-1) b.w. brought back the expression of above mentioned molecular markers to near normal pattern in hamsters treated with DMBA. The present results thus suggest that berberine has potent anti-inflammatory, anti-angiogenic, anti-cell proliferative and apoptosis inducing properties in DMBA induced oral carcinogenesis.

Involvement of retrotransposition of long interspersed nucleotide element-1 in skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate.

Abstract: Tumor development induced by 7,12-dimethylbenz[a]anthracene (DMBA) plus 12-O-tetradecanoylphorbol-13-acetate (TPA) is a well-characterized model of multistep carcinogenesis. DMBA mutates the Ha-ras gene, whereas TPA promotes the growth of transformed cells by activating cellular signaling molecules. It remains to be clarified how repeated TPA treatment endows transformed cells with autonomous cell growth. Long interspersed nucleotide element-1 (L1) is an endogenous retroelement, and 80-100 copies of L1 function as autonomous mobile elements. Although the L1 retrotransposition (RTP) has been found in various human tumors, implying the possible mobility of L1 during carcinogenesis, little is known about how L1-RTP arises in tumor cells, owing to a lack of experimental models. To dissect the mechanism of L1-RTP during carcinogenesis, we established a line of transgenic mice carrying human L1 and enhanced green fluorescent protein (hL1-EGFP mice) and subjected them to DMBA/TPA-induced skin tumorigenesis. Of 15 skin tumors examined, 13 were positive for L1-RTP; L1-RTP was not detected in normal skin tissues adjacent to the tumors. Moreover, nine L1-RTP-positive tumors were positive for activated Ha-ras, and immunohistochemical analysis revealed cells positive for both L1-RTP and phosphorylated Stat3, a marker of tumor cells. Additional in vivo experiments suggested that L1-RTP occurred during tumor promotion by TPA. This is the first report on the involvement of L1-RTP in chemical carcinogenesis. We propose hL1-EGFP mice as a versatile system for investigating the mode of L1-RTP in tumor development and discuss the possible role of L1-RTP in tumorigenesis.

Chemopreventive efficacy of geraniol against 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis

Abstract: The status of lipid peroxidation, antioxidants, and detoxification enzymes were used as biochemical end points to assess the chemopreventive potential of geraniol, a monoterpene, in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Topical application of 0.5% DMBA in liquid paraffin, three times a week, for 14 weeks developed well-differentiated squamous cell carcinoma in the buccal pouch of golden Syrian hamsters. Although 100% tumor formation was noticed in hamsters treated with DMBA alone, intragastric administration of geraniol, at a dose of 250 mg/kg body weight (b.w.) to DMBA-treated hamster completely prevented the formation of oral tumors. Furthermore, geraniol significantly reduced lipid peroxidation by-products and improved the status of enzymatic and non-enzymatic antioxidants as well as modulated the status of phase I and phase II detoxification enzymes, favoring the excretion of carcinogenic metabolite, during DMBA-induced oral carcinogenesis. The present study concludes that the chemopreventive potential of geraniol relies on its anti-lipid peroxidative and antioxidant function as well as modulatory effects on phase I and II detoxification enzymes to excrete the carcinogenic metabolite, during DMBA-induced hamster buccal pouch carcinogenesis.

Genistein and daidzein, in combination, protect cellular integrity during 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in Sprague-Dawley rats.

Abstract: The status of glycoconjugates (protein bound hexose, hexosamine, sialic acid and fucose) in plasma or serum serve as potential biomarkers for assessing tumor progression and therapeutic interventions. Aim of the present study was to investigate the protective effect of two major soy isoflavones, genistein and daidzein, in combination on the status of glycoconjugates in plasma, erythrocyte membrane and mammary tissues during 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in female Sprague-Dawley rats. A single subcutaneous injection of DMBA (25 mg rat-1) in the mammary gland developed mammary carcinoma in female Sprague-Dawley rats. Elevated levels of plasma and mammary tissue glycoconjugates accompanied by reduction in erythrocyte membrane glycoconjugates were observed in rats bearing mammary tumors. Oral administration of genistein + daidzein (20 mg + 20 mg kg-1 bw/day) to DMBA treated rats significantly (p< 0.05) brought back the status of glycoconjugates to near normal range. The present study thus demonstrated that genistein and daidzein in combination protected the structural integrity of the cell surface and membranes during DMBA-induced mammary carcinogenesis.

Therapeutic potential of Dendrophthoe falcata (L.f) Ettingsh on 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in female rats: effect on antioxidant system, lipid peroxidation, and hepatic marker enzymes

Abstract: In this study, the therapeutic potential of the hydroalcoholic extract of Dendrophthoe falcata (L.f) Ettingsh (Loranthaceae; HEDF) on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma was investigated in Wistar female rats at 55 days of age. Thirty female rats were divided into five groups with six animals in each group: control, DMBA (25 mg in 0.5 ml olive oil by air pouch technique), and DMBA + HEDF (250, 475, and 950 mg/kg). After 90 days of induction, HEDF were administered for 28 days, by gastric intubations. The levels of lipid peroxides and activities of enzymic and nonenzymic antioxidants were measured in serum, liver, kidney, and breast of both control and experimental groups. In addition to this, liver marker enzymes were also assessed. Rats treated with DMBA showed an increase in lipid peroxidation accompanied by high malondialdehyde levels along with lowered activities of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase) and nonenzymic antioxidants (glutathione, ascorbic acid, and α-tocopherol). A significant decrease in alanine aminotransferase, aspartate aminotransferase with a sharp increase in alkaline phosphatase, acid phosphatase, and 5′-nucleotidase was observed in the liver of mammary cancer-bearing animals. HEDF treatment caused the activity of these liver marker enzymes’ return to almost normal control levels. Furthermore, the breast tumor weight decreased significantly in the DMBA + HEDF-treated groups. This result suggests that HEDF shows antioxidant activity and play a protective role against DMBA-induced breast carcinogenesis.

Anticancer mechanism of equol in 7,12-dimethylbenz(a)anthracene-treated animals

Abstract: This study investigated the anticancer effects of equol, the major metabolite of the antioxidant phytochemical daidzein, on 7,12-dimethylbenz(a)anthracene (DMBA)-treated animals and explored its anticancer mechanism. The experiment consisted of two parts. In the first part, Sprague-Dawley rats were given equol daily at 5 and 25 mg/kg body weight (BW) for 8 weeks after a single dose of DMBA (100 mg/kg BW). As a control, rats were divided into vehicle alone and DMBA alone groups. Equol administration at a higher dose effectively suppressed tumor formation and PCNA over-expression. The activation of p53 by equol subsequently affected the cyclin-dependent kinase inhibitor p21Cip1. This was associated with equol-induced apoptosis in mammary gland tumors, as evidenced by the decreased Bcl-2 expression and increased Bax expression, together with the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). In the second part, oral pre-administration of equol to mice which received DMBA intragastrically twice a week for 2 weeks significantly decreased their levels of biomarkers (thiobarbituric acid-reactive substances, carbonyl content and serum 8-hydroxy-2-deoxyguanosine) of DMBA-induced oxidative stress. Although several antioxidant enzymes were down-regulated in mice treated with DMBA alone, pre-administration of equol blocked much of this effect, increasing catalase and superoxide dismutase activity in a dose-dependent manner. Although equol did not affect the ratio of oxidized to reduced glutathione, it activated the glutathione peroxidase and glutathione reductase enzymes, and this effect was significant at a dose of 25 mg equol/kg body weight. DMBA treatment induced apoptosis, as shown by a decrease in the Bcl-2 levels and an increase in the levels of Bax, cleaved caspase-3 and poly(ADP-ribose) polymerase. These apoptotic effects were also reversed by equol at all doses tested. Based on these results, equol possesses anticancer activity that suppresses tumor formation via apoptosis induction in rats with DMBA-induced mammary gland tumors. In addition, equol showed a hepatic protective effect by acting as an antioxidant and by reducing apoptosis.

Plantago major protective effects on antioxidant status after administration of 7,12-Dimethylbenz(a)anthracene in rats.

Abstract: Aim: The present study was designed to evaluate effects of Plantago major extract on oxidative status in Wistar albino rats administrated 7,12-dimethylbenz(a)anthracene (DMBA). Methods: Rats were divided into three equal groups of 6 animals each: Group 1 controls, group 2 treated with DMBA (100 mg/kg, single dose) and group 3 receiving the DMBA and the aqueous extract at 100 mg/kg/d for 60 days. Results: Significant decrease in catalase (P<0.05), carbonic anhydrase (p≤0.01), reduced glutathione (GSH) (P<0.01) and total protein (P<0.01) values was observed in the DMBA group compared with the healthy controls and DMBA + Plantago major groups. Conclusion: The results suggest preventive effects of Plantago major on DMBA induced oxidative damage in Wistar albino rats that might be due to decreased free radical generation.

Evaluation of anticarcinogenic activity of Clerodendrum serratumleaf extract on liver and kidney of 7, 12-dimethylbenz[a]anthracene(DMBA) induced skin carcinogenesis in mice

Abstract: The evaluation of the anticarcinogenic activity of the Clerodendrum serratum leaf extract (CSLE) on liver and kidney of 7, 12-dimethylbenz[a]anthracene (DMBA) induced skin carcinogenesis in mice were studied. Group I served as control. The skin lesions were induced by twice-weekly topical application of DMBA for two weeks on the shaved backs of group II, III, IV and V mice. CSLE was administered to group III, IV and V mice at the dose of 300, 600 and 900 mg/kg b.wt/day, for 4 week before DMBA application, and continued till 45 days. On 46th day the mice were sacrificed, liver and kidney were dissected out freed from adherent tissue and weighed to nearest milligram and evaluated the effect of administration of CSLE on biochemical and oxidative stress parameters. Our findings showed that there was a recovery in biochemical and oxidative stress parameters in the liver and kidney of the CSLE administered mice. Together, these findings suggest that Clerodendrum serratum leaf extract has anticarcinogenic efficacy against skin carcinogenesis.

Study on cow ghee versus soybean oil on 7,12-dimethylbenz(a)-anthracene induced mammary carcinogenesis & expression of cyclooxygenase-2 & peroxisome proliferators activated receptor- γ in rats

Abstract: Background & objectives : Breast cancer is a leading cause of cancer death in women; dietary fat is the one of the factors that influences its incidence. In the present study we investigated the effect of feeding cow ghee versus soybean oil on 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary cancer in rat and expression of cyclooxygenase-2 and peroxisome proliferators activated receptor- γ (PPAR-γ) in mammary gland. Methods : Two groups of 21 day old female rats (30 each) were fed for 44 wk diet containing cow ghee or soybean oil (10%). The animals were given DMBA (30mg/kg body weight) through oral intubation after 5 wk feeding. Another two groups (8 each) fed similarly but not given DMBA served as control for the gene expression study. Results : In DMBA treated groups, the animal fed soybean oil had higher tumour incidence (65.4%), tumour weight (6.18 g) and tumour volume (6285 mm 3 ) compared to those fed cow ghee (26.6%, 1.67 g, 1925 mm 3 , respectively). Tumour latency period was 23 wk on soybean oil compared to 27 wk on cow ghee. Histological analysis of tumours showed that the progression of carcinogenesis was more rapid on soybean oil than on cow ghee. The expression of cyclooxygenase-2 was observed only in DMBA treated rats and it was significantly less on cow ghee than on soybean oil. The expression of PPAR-γ was significantly more on cow ghee than on soybean oil. Interpretation & conclusions : Our results show that dietary cow ghee opposed to soybean oil attenuates mammary carcinogenesis induced by DMBA; and the effect is mediated by decreased expression of cyclooxygenase-2 and increased expression of PPAR-γ in the former group.

Chronic unpredictable stress exacerbates 7,12-dimethylbenz (a) anthracene induced hepatotoxicity and nephrotoxicity in Swiss albino mice

Abstract: Oxidative stress, a pervasive condition induced by stress has been implicated and recognized to be a prominent feature of various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) on hepatic and renal toxicity in terms of alterations of various in vivo biochemical parameters, oxidative stress markers and the extent of DNA damage in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz (a) anthracene (DMBA) alone (topical), DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical), and exposure to CUS prior to DMBA or DMBA-TPA treatment, and sacrificed after 16 weeks of treatment. Prior exposure to CUS increased the pro-oxidant effect of carcinogen as depicted by significantly compromised levels of antioxidants; superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, reduced glutathione in hepatic and renal tissues accompanied by a significant elevation of thiobarbituric acid reactive species (TBARS) as compared to DMBA alone or DMBA-TPA treatments. Loss of structural integrity at the cellular level due to stress-induced oxidative damage was demonstrated by significant increases in the hepatic levels of intracellular marker enzymes such as glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase, and significantly reduced levels of uric acid in kidney tissues. The results of DNA damage studies further positively correlated with all the above biochemical measurements. Thus, exposure to physical or psychological stress may significantly enhance the hepatotoxic and nephrotoxic potential of carcinogens through enhanced oxidative stress even if the treatment is topical.

Coumarin protects 7,12-dimethylbenz(a)anthracene-induced genotoxicity in the bone marrow cells of golden Syrian hamsters

Abstract: Aim : Aim of the present study was to evaluate the antigenotoxic effect of coumarin by measuring the frequencies of micronuclei and the degree of DNA damage in the bone marrow cells of hamster treated with 7,12-dimethylbenz(a)anthracene (DMBA). Materials and Methods: Genotoxicity was induced in experimental hamsters by single intraperitoneal injection of DMBA (30 mg/kg b.w.). The frequency of micronucleated polychromatic erythrocytes (MnPCEs) and DNA damage were assessed in the bone marrow cells of experimental hamsters. The status of lipid peroxidation, antioxidants and phase I and II detoxification agents were utilized as biochemical end points to assess the dose-dependent antigenotoxic potential of coumarin in DMBA-induced genotoxicity. Results: Increase in micronuclei frequency was accompanied by increase in tail length, percent of tail DNA, tail movement and olive tail movement in the bone marrow cells of hamsters treated with DMBA alone. A significant increase in the levels of thiobarbituric acid reactive substances, antioxidants and phase I and II detoxification agents were also noticed in hamsters treated with DMBA alone. Oral pretreatment of coumarin at a dose of 100 mg/kg b.w to hamsters treated with DMBA significantly decreased the frequency of MnPCEs and DNA damage in the bone marrow cells. Also, coumarin restored the status of biochemical variables in the plasma and liver of hamsters treated with DMBA. Conclusions: Present study demonstrated the antigenotoxic effect of coumarin in DMBA-induced genotoxicity. The antigenotoxic potential of coumarin is probably due to its antioxidant potential and modulating effect on detoxification cascade during DMBA-induced genotoxicity.

Chemopreventive Potential of 18β-glycyrrhetinic Acid: An Active Constituent of Liquorice, in 7,12-dimethylbenz(a)anthracene Induced Hamster Buccal Pouch Carcinogenesis

Abstract: Chemoprevention, a useful and attractive approach in experimental oncology, helps to investigate the cancer preventive potential of natural products and synthetic entities. Present study evaluated the chemopreventive potential of glycyrrhetinic acid in 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. Oral tumor was developed in the buccal pouch of golden Syrian hamsters by painting with DMBA three times a week for 14 weeks. The tumor incidence and the status of phase I and phase II detoxification enzymes were assessed in hamsters treated with DMBA alone and DMBA+glycyrrhetinic acid treated hamsters. One hundred percent tumor formations, which were histopathologically confirmed as well-differentiated squamous cell carcinoma, were observed in hamsters treated with DMBA alone. Also, the status of detoxification enzymes were markedly altered in the liver and buccal mucosa of hamsters treated with DMBA alone. Oral administration ofglycyrrhetinic acid at a dose of 45 mg kg(-1) body weight to hamsters treated with DMBA completely prevented the tumor formation as well as restored the status of detoxification enzymes. Present study thus demonstrated the chemopreventive potential of glycyrrhetinic acid in DMBA induced oral carcinogenesis.

Anticarcinogenic activity of Labisia pumila against 7, 12- dimethylbenz (a) anthracene (DMBA)/croton oil- induced mouse skin carcinogenesis

Abstract: Labisia pumila or locally known as Kacip Fatimah, is one of the most popular medicinal herb in Malaysia. Anticarcinogenic activity of this medicinal herb however, has not been reported until today. In this paper, the in vivo anticarcinogenic activity of L. pumilaethanol extract on two-stage mouse skin carcinogenesis model is reported. In the present study, we investigated whether L. pumila ethanol extract have an effect on tumor growth in vivo. Therefore, varying doses (25, 50 and 100 mg/kg bwt) of L. pumilaethanol extract were tested on 7, 12-dimethylbenz(a)anthracene (DMBA)/croton oil-induced mouse skin carcinogenesis. At the end of the experiment of 20 weeks, animals in carcinogen control group developed a mean number of 5.70 ± 1.3 skin tumors per tumor-bearing mouse and on the 16th week prompted a tumor incidence of 100%. Animals that have been treated with 25, 50 and 100 mg/kg bwt of L. pumila extract topically for 30 min developed a mean number of 3.60 ± 1.1, 3.20 ± 0.8 and 2.40 ± 0.7 skin tumors per tumor-bearing mouse with tumor incidence of 90, 60 and 50%, respectively. The tumor volume per tumor-bearing mice of carcinogen control animals was 121.03 ± 3.46 mm3, which was significantly (p<0.05) reduced to 92.27 ± 2.68, 69.24 ± 3.93 and 54.24 ± 4.38 mm3 for the animals treated with 25, 50 and 100 mg/kg bwt of L. pumila extract, respectively. In terms of tumor incidence and tumor burden, the highest dose (100 mg/kg bwt) of L. pumila ethanol extract was almost equipotent with curcumin (10 mg/kg bwt). The extract of L. pumila not only decreased the tumor incidence, tumor burden and tumor volume in DMBA/croton oil-induced mice but also delayed the skin tumor growth as compared to carcinogen control group. Further histopathological examination revealed that tumors from animals that have been treated with L. pumila showed intact basement membrane as compared to the tumors from the untreated animals. This finding suggested that L. pumila extract was able to suppress the progression of benign tumors to malignant stage in DMBA/croton oil-induced mice. Further studies should be carried out in order to identify the active compound responsible for the anticarcinogenic activities and the mechanism of action of L. pumilaat the molecular level.

Effects of morin on the pharmacokinetics of docetaxel in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors.

Abstract: Docetaxel is a P-glycoprotein (P-gp) substrate and metabolized via cytochrome P450 (CYP) 3A subfamily in rats. Morin is an inhibitor of both CYPs and P-gp. Hence, the effects of morin on the intravenous and oral pharmacokinetics of docetaxel were investigated using 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor rats (DMBA rats) as an animal model of human breast cancer. Docetaxel was administered intravenously (4 mg/kg) and orally (20 mg/kg) without and with morin (15 mg/kg) in DMBA rats. After the intravenous administration of docetaxel in control and DMBA rats with and without morin, the values of non-renal clearance and area under the plasma concentration-time (AUC) for docetaxel were comparable. Morin did not increase AUC or the absolute oral bioavailability (F) for docetaxel after the oral administration of docetaxel in control and DMBA rats with and without morin. The inhibition of hepatic and intestinal metabolism of docetaxel by morin and/or DMBA and the effect of intestinal P-gp inhibition by morin on the pharmacokinetics of docetaxel did not seem to be considerable in DMBA-induced mammary tumor rats.

Phellinus rimosus (Berk.) pilat attenuates 7,12-dimethylbenz[a] anthracene induced and croton oil promoted skin papilloma formation in mice.

Abstract: The roles of 7,12-dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon (PAH), and 12-O-tetradecanoylphorbol-13-acetate (TPA) a skin tumor promoter present in croton oil, are clearly implicated in the formation of skin papilloma. The effect of ethyl acetate extract of Phellinus rimosus, a polypore macro fungus, against croton oil-induced skin inflammation, lipid peroxidation and tumor promotion was studied. The antiinflammatory and lipid peroxidation inhibiting activities were determined by topical application of extract of P. rimosus (10 and 20 mg) prior to the application of 0.1 ml of 50% croton oil in acetone. The tumor promotion inhibiting effect of P. rimosus was evaluated against DMBA-initiated, croton oil promoted two-stage carcinogenesis model in mouse skin. The results showed that topical application of the extract (10 and 20 mg) significantly (p < 0.01) and dose dependently attenuate the inflammatory edema as well as lipid peroxidation induced by croton oil. Similarly, topical application of extract (1 and 5 mg) effectively ameliorated the croton oil promoted skin papilloma formation. The results of this study concluded that ethyl acetate extract of P. rimosus showed antitumor activity against DMBA initiated, croton oil promoted skin papilloma formation which can be partially ascribed to the antiperoxidative and anti-inflammatory effects of the extract.

The role of P53 and Bcl-2 proteins in 7, 12-dimethylbenz-(a)-anthracene-induced tumor growth.

Abstract: 7, 12- Dimethylbenz-(a)-anthracene (DMBA) has been used for a long time to induce rat mammary gland carcinogenesis. In a previous paper we described the effects of diet, of non-steroidal anti-inflammatory drugs and the combination of these two factors on breast cancer. We also pointed out that DMBA tumor generating process is still poorly understood. The present study attempts to explore whether P53 or the pro-apoptotic protein Bcl-2 are potential targets of DMBA in its induction of breast tumors in the Sprague-Dawley rat breast tumorigenesis model. Our results indicate that the DBMA-induced tumors are apparently the result of P53 inactivation. This inactivation results in tumorigenesis, probably aided by the absence of Bcl-2 in the tumor cells of the Sprague-Dawley rat animal model. We discuss the potential mechanisms by which P53 inactivation results in tumorigenesis.

Carnosic acid protects cell surface glycoconjugates abnormalities during 7,12-dimethylbenz(a)anthracene(DMBA) induced oral carcinogenesis

Abstract: Aim of the present study was to focus the protective effect of carnosic acid on 7,12-dimethylbenz(a)anthracene (DMBA) induced cell surface glycoconjugates (Protein bound hexose, Hexosamine, Lipid bound sialic acid, Total sialic acid and Fucose) abnormalities in the plasma and buccal mucosa of golden Syrian hamsters. Oral squamous cell carcinoma was developed in the buccal pouch of hamsters by painting with 0.5% DMBA three times a week for 14 weeks. Glycoconjugates status was assessed both histologically and biochemically in the buccal mucosa of DMBA treated hamsters. The levels of glycoconjugates were increased in both plasma and buccal mucosa of DMBA treated hamsters. Oral administration of carnosic acid at a dose of 10mg/kg bw brought back the status of glycoconjugates to near normal concentrations in DMBA treated hamsters. Present results thus suggest that carnosic acid protected DMBA induced cell surface abnormalities during DMBA induced hamster buccal pouch carcinogenesis.

Protective effect of coumarin on cell surface glycoconjugates abnormalities during 7,12-dimethylbenz(a)anthracene (DMBA) induced oral carcinogenesis

Abstract: Aims: The major aims of the present study was to focus the protective effect of coumarin on cell surface glycoconjugates abnormalities during 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. Methods: DMBA painting in the hamster buccal pouch three times per week for 14 weeks developed oral squamous cell carcinoma. The levels of glycoconjugates (protein bound hexose, hexosamine, sialic acid and fucose) were analyzed by using specific colorimetric methods. Results: An increase in glycoconjugates was noticed in the plasma and buccal mucosa of oral cancer bearing golden Syrian hamsters. Coumarin administration orally at a dose of 100mg/kg b.w to hamsters treated with DMBA brought back the status of glycoconjugates to near normal range. Conclusion: Present study thus focused the protective effect of coumarin on cell surface abnormalities occurring during DMBA-induced hamster buccal pouch carcinogenesis.

Evaluation of 3-(4'-(4″-fluorophenyl)-6'-phenylpyrimidin-2'-yl)-2-phenylthiazolidin-4-one for in vivo modulation of biomarkers of chemoprevention in the 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.

Abstract: A new bis heterocycle comprising both bioactive 2-aminopyrimidine and thiazolidin-4-one nuclei namely 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one 3 was synthesized, characterized with the help of melting point, elemental analysis, FT-IR, MS, one-dimensional NMR (1H, 13C) spectra and we evaluated the chemopreventive potential of 3-(4′-(4″-fluorophenyl)-6′-phenylpyrimidin-2′-yl)-2-phenylthiazolidin-4-one based on in vivo inhibitory effects on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Administration of 3 effectively suppressed oral carcinogenesis initiated with DMBA as revealed by the reduced incidence of neoplasms. Lipid peroxidation, glutathione (GSH) content, and the activities of glutathione peroxidase (GPx), glutathione S-transferase (GST) were used to biomonitor the chemopreventive potential of 3. Lipid peroxidation was found to be significantly decreased, whereas GSH, GPx, GST, and GGT were elevated in the oral mucosa of tumor-be...