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Showing papers in "Carcinogenesis in 1999"


Journal ArticleDOI
TL;DR: A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors, which would allow normalization of critical cellular processes in the early stages of transformation.
Abstract: Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se. There is extensive evidence that monomethylated forms of Se are critical metabolites for chemopreventive effects of Se. Induction of apoptosis in transformed cells is an important chemopreventive mechanism. Apoptosis can be triggered by micromolar levels of monomethylated forms of Se independent of DNA damage and in cells having a null p53 phenotype. Cell cycle protein kinase cdk2 and protein kinase C are strongly inhibited by various forms of Se. Inhibitory mechanisms involving modification of cysteine residues in proteins by Se have been proposed that involve formation of Se adducts of the selenotrisulfide (S-Se-S) or selenenylsulfide (S-Se) type or catalysis of disulfide formation. Selenium may facilitate reactions of protein cysteine residues by the transient formation of more reactive S-Se intermediates. A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors. A time-limited activation mechanism for such proteins, with deactivation facilitated by Se, would allow normalization of critical cellular processes in the early stages of transformation. There is uncertainty at the present time regarding the role of selenoproteins in chemoprevention model systems where supranutritional levels of Se are employed. Mammalian thioredoxin reductase is one selenoprotein that shows increased activity with Se supplementation in the nutritional to supranutritional range. Enhanced thioredoxin reduction could have beneficial effects in oxidative stress, but possible adverse effects are considered. Other functions of thioredoxin reductase may be relevant to cell signaling pathways. The functional status of the thioredoxin/thioredoxin reductase system during in vivo chemoprevention with Se has not been established. Some in vitro studies have shown inhibitory effects of Se on the thioredoxin system correlated with growth inhibition by Se. A potential inactivating mechanism for thioredoxin reductase or other selenoenzymes involving formation of a stable diselenide form resistant to reduction is discussed. New aspects of Se biochemistry and possible functions of new selenoproteins in chemoprevention are described.

687 citations


Journal ArticleDOI
TL;DR: Results of further studies suggest that suppression of transcriptional activation of COX-2 and iNOS by apigenin might mainly be mediated through inhibition of IkB kinase activity.
Abstract: Prostaglandins biosynthesis and nitric oxide production have been implicated in the process of carcinogenesis and inflammation. In this study, we investigated the effect of various flavonoids and (-)-epigallocatechin-3-gallate on the activities of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Apigenin, genistein and kaempferol were markedly active inhibitors of transcriptional activation of COX-2, with IC(50) < 15 microM. In addition, apigenin and kaempferol were also markedly active inhibitors of transcriptional activation of iNOS, with IC(50) < 15 microM. Of those compounds tested, apigenin was the most potent inhibitor of transcriptional activation of both COX-2 and iNOS. Western and northern blot analyses demonstrated that apigenin significantly blocked protein and mRNA expression of COX-2 and iNOS in LPS-activated macrophages. Transient transfection experiments showed that LPS caused an approximately 4-fold increase in both COX-2 and iNOS promoter activities, these increments were suppressed by apigenin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that apigenin blocked the LPS-induced activation of nuclear factor-kB (NF-kB). The inhibition of NF-kB activation occurs through the prevention of inhibitor kB (IkB) degradation. Transient transfection experiments also showed that apigenin inhibited NF-kB-dependent transcriptional activity. Finally, we showed that apigenin could inhibit the IkB kinase activity induced by LPS or interferon-gamma. The results of further studies suggest that suppression of transcriptional activation of COX-2 and iNOS by apigenin might mainly be mediated through inhibition of IkB kinase activity. This study suggests that modulation of COX-2 and iNOS by apigenin and related flavonoids may be important in the prevention of carcinogenesis and inflammation.

581 citations


Journal ArticleDOI
TL;DR: Current evidence from experimental and human studies is summarized that implicates a high intake of omega-6 PUFAs in cancer of the breast, colon and, possibly, prostate and which indicates that omega-3PUFAs and monounsaturated fatty acids such as oleic acid (omega-9) are protective.
Abstract: The hypothesis that a high-fat diet promotes the development of postmenopausal breast cancer is supported by international data showing a strong correlation between fat intake and breast cancer rates and a modest positive association with high-fat diet in case-control studies. Dietary fat intake was found to be unrelated to the risk of breast cancer in cohort studies. In view of these conflicting findings it has been difficult to make nutritional recommendations for the prevention of breast cancer. Studies in animal models and recent observations in humans, however, have provided evidence that a high intake of omega-polyunsaturated fatty acids (PUFAs), stimulates several stages in the development of mammary and colon cancer, from an increase in oxidative DNA damage to effects on cell proliferation, free estrogen levels to hormonal catabolism. In contrast, fish oil-derived omega-3 fatty acids seem to prevent cancer by influencing the activity of enzymes and proteins related to intracellular signalling and, ultimately, cell proliferation. In this commentary, current evidence from experimental and human studies is summarized that implicates a high intake of omega-6 PUFAs in cancer of the breast, colon and, possibly, prostate and which indicates that omega-3 PUFAs and monounsaturated fatty acids such as oleic acid (omega-9) are protective. Plausible mechanisms for modulation of steps in the multistage carcinogenesis process by fats are discussed. Properly designed epidemiological studies are now needed, that integrate relevant biomarkers to unravel the contributions of different types of fat, their interactions with hormonal catabolism, protective nutritional factors and human cancer risk.

494 citations


Journal ArticleDOI
TL;DR: This review compiles the literature on AIA-DNA adducts including their identification and characterization, pathways of formation, mutagenesis in vitro and in vivo, and their association with carcinogenesis in animal models.
Abstract: The heterocyclic amines (HCAs) are a family of mutagenic/carcinogenic compounds produced during the pyrolysis of creatine, amino acids and proteins. The major subclass of HCAs found in the human diet comprise the aminoimidazoazaarenes (AIAs) 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). All, except DiMeIQx, have been shown to be carcinogenic in animals. These compounds are present in cooked muscle meats at the p.p.b. level. Since the discovery of the HCAs in the late 1970s, many studies have examined the DNA adducts of these compounds. This review compiles the literature on AIA-DNA adducts including their identification and characterization, pathways of formation, mutagenesis in vitro and in vivo, and their association with carcinogenesis in animal models. It is now known that metabolic activation leading to the formation of DNA adducts is critical for mutagenicity and carcinogenicity of these compounds. All of the AIAs studied adduct to the guanine base, the major adduct being formed at the C8 position. Two AIAs, IQ and MeIQx, also form minor adducts at the N2 position of guanine. A growing body of literature has reported on the mutation spectra induced by AIA-guanine adducts. Studies of animal tumors induced by AIAs have begun to relate AIA-DNA adduct-induced mutagenic events with the mutations found in critical genes associated with oncogenesis. Several studies have demonstrated the feasibility of chemoprevention of AIA tumorigenesis. Only a few studies have reported on the detection of AIA-DNA adducts in human tissues; difficulties persist in the routine detection of AIA-DNA adducts in humans for the purpose of biomonitoring of exposure to AIAs. The AIAs are nevertheless regarded as possible human carcinogens, and future research on AIA-DNA adducts is likely to help address the role of AIAs in human cancer.

351 citations


Journal ArticleDOI
TL;DR: It is demonstrated for the first time that resveratrol induces apoptosis through activation of p53 activity, suggesting that its anti-tumor activity may occur through the induction of apoptosis.
Abstract: Resveratrol, a plant constituent enriched in the skin of grapes, is one of the most promising agents for the prevention of cancer. However, the mechanism of the anti-carcinogenic activity of resveratrol is not well understood. Here we offer a possible explanation of its anti-cancer effect. Resveratrol suppresses tumor promoter-induced cell transformation and markedly induces apoptosis, transactivation of p53 activity and expression of p53 protein in the same cell line and at the same dosage. Also, resveratrol-induced apoptosis occurs only in cells expressing wild-type p53 (p53+/+), but not in p53-deficient (p53-/-) cells, while there is no difference in apoptosis induction between normal lymphoblasts and sphingomyelinase-deficient cell lines. These results demonstrate for the first time that resveratrol induces apoptosis through activation of p53 activity, suggesting that its anti-tumor activity may occur through the induction of apoptosis.

345 citations


Journal ArticleDOI
TL;DR: Results showed that increased TJ permeability of the colon epithelium and consequently a decrease in epithelial barrier function precede the development of colon tumors.
Abstract: Epithelial tissues act as barriers between two fluid compartments, and the epithelial barrier function is provided by the epithelial cells and the tight junctions (TJs) that connect them. We have shown previously that chronic treatment of a cultured epithelial monolayer with phorbol ester tumor promoters induces an increase in transepithelial paracellular permeability and produces tumor-like polyps, suggesting an association between TJ permeability and tumor formation. In this study, we analyzed the association between TJ permeability and formation of tumors in vivo. The permeability of the TJs was assessed in normal human and rat colon epithelia and in colon tumors by measuring the transepithelial electrical resistance, the paracellular flux rate of D-[ 14 C]mannitol and the electron microscopic evaluation of the penetration of the electron dense dye ruthenium red across the TJs. By these criteria, the TJs of human colon tumors, including carcinomas and adenomatous polyps, and the TJs of 1,2-dimethylhydrazine (DMH)-induced rat colon tumors were leakier than the TJs of normal colon. Treatment of rats with the carcinogen DMH induced a progressive increase in the number of aberrant colonic crypts, considered the putative pre-neoplastic colonic phenotype while increasing TJ permeability of the colon epithelium prior to the development of tumors. These results showed that increased TJ permeability of the colon epithelium and consequently a decrease in epithelial barrier function precede the development of colon tumors.

337 citations


Journal ArticleDOI
TL;DR: Results show that grape seed polyphenols possess high anti-tumor-promoting activity due to the strong antioxidant effect of procyanidins present therein, and should be studied in more detail to be developed as cancer chemopreventive and/or anticarcinogenic agents.
Abstract: Procyanidins present in grape seeds are known to exert anti-inflammatory, anti-arthritic and anti-allergic activities, prevent skin aging, scavenge oxygen free radicals and inhibit UV radiation-induced peroxidation activity. Since most of these events are associated with the tumor promotion stage of carcinogenesis, these studies suggest that grape seed polyphenols and the procyanidins present therein could be anticarcinogenic and/or anti-tumor-promoting agents. Therefore, we assessed the anti-tumor-promoting effect of a polyphenolic fraction isolated from grape seeds (GSP) employing the 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol 13-acetate (TPA)-promoted SENCAR mouse skin two-stage carcinogenesis protocol as a model system. Following tumor initiation with DMBA, topical application of GSP at doses of 0.5 and 1.5 mg/mouse/application to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The observed anti-tumor-promoting effects of GSP were dose dependent and were evident in terms of a reduction in tumor incidence (35 and 60% inhibition), tumor multiplicity (61 and 83% inhibition) and tumor volume (67 and 87% inhibition) at both 0.5 and 1.5 mg GSP, respectively. Based on these results, we directed our efforts to separate and identify the individual polyphenols present in GSP and assess their antioxidant activity in terms of inhibition of epidermal lipid peroxidation. Employing HPLC followed by comparison with authentic standards for retention times in HPLC profiles, physiochemical properties and spectral analysis, nine individual polyphenols were identified as catechin, epicatechin, procyanidins B1-B5 and C1 and procyanidin B5-3'-gallate. Five of these individual polyphenols with evident structural differences, namely catechin, procyanidin B2, procyanidin B5, procyanidin C1 and procyanidin B5-3'-gallate, were assessed for antioxidant activity. All of them significantly inhibited epidermal lipid peroxidation, albeit to different levels. A structure-activity relationship study showed that with an increase in the degree of polymerization in polyphenol structure, the inhibitory potential towards lipid peroxidation increased. In addition, the position of linkage between inter-flavan units also influences lipid peroxidation activity; procyanidin isomers with a 4-6 linkage showed stronger inhibitory activity than isomers with a 4-8 linkage. A sharp increase in the inhibition of epidermal lipid peroxidation was also evident when a gallate group was linked at the 3'-hydroxy position of a procyanidin dimer. Procyanidin B5-3'-gallate showed the most potent antioxidant activity with an IC(50) of 20 microM in an epidermal lipid peroxidation assay. Taken together, for the first time these results show that grape seed polyphenols possess high anti-tumor-promoting activity due to the strong antioxidant effect of procyanidins present therein. In summary, grape seed polyphenols in general, and procyanidin B5-3'-gallate in particular, should be studied in more detail to be developed as cancer chemopreventive and/or anticarcinogenic agents.

327 citations


Journal ArticleDOI
TL;DR: The hypothesis that a polymorphic XRCC1 DNA repair gene contributes to risk of developing SCCHN is supported.
Abstract: Because reduced DNA repair capacity (phenotype) has been suggested as a risk factor for squamous cell carcinoma of the head and neck (SCCHN), newly-identified DNA repair gene polymorphisms (genotype) may also be implicated in risk. To test this hypothesis, we conducted a case-control study of 203 SCCHN patients and 424 control subjects (matched for age, sex and ethnicity) to investigate the role of two XRCC1 polymorphisms (XRCC1 26304 T and XRCC1 28152 A, respectively) in SCCHN. Multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (CI). A total of 180 cases (88.7%) and 363 controls (85.6%) lacked the XRCC1 26304 T allele [adjusted OR = 1.34 (CI, 0.80-2.25)]. Lack of this polymorphism was a significant risk factor specifically for cancers of the oral cavity and pharynx [adjusted OR = 2.46 (CI, 1.22-4.97)]. Thirty-two cases (15.8%) and 46 controls (10.8%) were homozygous for the XRCC1 28152 A allele [adjusted OR = 1.59 (CI, 0.97-2.61) for all cases, and 1.41 (CI, 0. 80-2.48) for oral and pharyngeal cancer only]. Furthermore, when the two genotypes were combined into a three-level model of risk, a polymorphism-polymorphism interaction of increasing risk (trend test, P = 0.049) was evident: OR = 1.0 for those with neither risk genotype (referent group), adjusted OR = 1.51 (CI, 0.87-2.61) for those with either risk genotype, and 2.02 (CI, 1.00-4.05) for those with both risk genotypes. For oral and pharyngeal cancer, this trend was even more pronounced with the adjusted OR = 2.68 (CI, 1.28-5.61) for those with either risk genotype, and 3.22 (CI, 1.33-7.81) for those with both risk genotypes. The findings support the hypothesis that a polymorphic XRCC1 DNA repair gene contributes to risk of developing SCCHN.

320 citations


Journal ArticleDOI
TL;DR: The results show that the orally administered selective COX-2 inhibitor Celecoxib prevents new tumor formation after the onset of photocarcinogenesis and suggest that treatment with celecoxib may be very useful in preventing UV-induced skin tumors in humans.
Abstract: UV light is a complete carcinogen, inducing both basal and squamous cell skin cancers. The work described uses the selective COX-2 inhibitor celecoxib to examine the efficacy of COX-2 inhibition in the reduction of UV light-induced skin tumor formation in hairless mice. UVA-340 sun lamps were chosen as a light source that effectively mimics the solar UVA and UVB spectrum. Hairless mice were irradiated for 5 days a week for a total dose of 2.62 J/cm(2). When 90% of the animals had at least one tumor, the mice were divided into two groups so that the tumor number and multiplicity were the same (P < 0.31). Half of the mice were then fed a diet containing 1500 p.p.m. celecoxib. Tumor number, multiplicity and size were then observed for the next 10 weeks. Ninety-five percent of the tumors formed were histopathologically evaluated as squamous cell carcinoma. COX-2 expression and activity were increased in tumors. After 10 weeks, the difference in tumor number and multiplicity in the drug-treated group was 56% of UV controls (P < 0.001). The results show that the orally administered selective COX-2 inhibitor celecoxib prevents new tumor formation after the onset of photocarcinogenesis and suggest that treatment with celecoxib may be very useful in preventing UV-induced skin tumors in humans.

319 citations


Journal ArticleDOI
TL;DR: Curcumin directly inhibited the activity of COX-2 in several gastrointestinal cell lines and these data provide new insights into the anticancer properties of curcumin.
Abstract: We investigated whether curcumin, a chemopreventive agent, inhibited chenodeoxycholate (CD)- or phorbol ester (PMA)-mediated induction of cyclooxygenase-2 (COX-2) in several gastrointestinal cell lines (SK-GT-4, SCC450, IEC-18 and HCA-7). Treatment with curcumin suppressed CD- and PMA-mediated induction of COX-2 protein and synthesis of prostaglandin E2. Curcumin also suppressed the induction of COX-2 mRNA by CD and PMA. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with CD or PMA and these effects were inhibited by curcumin. Treatment with CD or PMA increased binding of AP-1 to DNA. This effect was also blocked by curcumin. In addition to the above effects on gene expression, we found that curcumin directly inhibited the activity of COX-2. These data provide new insights into the anticancer properties of curcumin.

286 citations


Journal ArticleDOI
TL;DR: The results indicate that the polymorphisms in the human CYP1B1 gene cause some alterations in catalytic function towards procarcinogens and steroid hormones and thus may make some contribution to susceptibilities of individuals towards mammary and lung cancers in humans.
Abstract: Four polymorphic human cytochrome P450 (CYP) 1B1 allelic variants, namely Arg48,Ala119,Leu432,Asn453, Arg48,Ser119,Leu432,Asn453, Arg48, Ala119,Val432,Asn-453 and Arg48,Ser119,Val432,Asn453, were expressed in Escherichia coli together with human NADPH-P450 reductase and the recombinant proteins (in bacterial membranes) were used to assess whether CYP1B1 polymorphisms affect catalytic activities towards a variety of P450 substrates, including diverse procarcinogens and steroid hormones. Activities for activation of 19 procarcinogens to DNA-damaging products by these four CYP1B1 variants in a Salmonella typhimurium NM2009 umu response system were found to be essentially similar, except that a Arg48, Ser119,Leu432,Asn453 variant was slightly more active (1.2- to 1.5-fold) than the other three CYP1B1 enzymes in catalyzing activation of (+)- and (-)-benzo[a]pyrene-7, 8-diols, 7,12-dimethylbenz[a]anthracene-3,4-diol, benzo[g]chrysene-11,12-diol, benzo[b]fluoranthene-9,10-diol, 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-aminofluorene. Kinetic analysis of 17beta-estradiol hydroxylation showed that V(max) values for 4-hydroxylation ranged between 0.9 and 1.5 nmol/min/nmol P450 for 4-hydroxylation and 0.3 and 0.6 nmol/min/nmol P450 for 2-hydroxylation in these CYP1B1 variants, with K(m) values ranging from 1 to 9 microM. Interestingly, the ratio of product formation of 4-hydroxyestradiol to 2-hydroxyestradiol was higher for the Val432 variants of CYP1B1 variants than the Leu432 variants of the enzyme. The same trend was noted in the ratio of estrone 4-hydroxylation to estrone 2-hydroxylation catalyzed by CYP1B1 variants. Mutation in the CYP1B1 genes also affected the K(m) and V(max) values in the 6beta-hydroxylation of testosterone and 6beta- and 16alpha-hydroxylation of progesterone. These results indicate that the polymorphisms in the human CYP1B1 gene cause some alterations in catalytic function towards procarcinogens and steroid hormones and thus may make some contribution to susceptibilities of individuals towards mammary and lung cancers in humans.

Journal ArticleDOI
TL;DR: The results demonstrate that loss of BM type IV collagen along with elevations in M MP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis, and suggest that control of typeIV collagenase activation may be beneficial in preventing human coloreCTal tumor progression.
Abstract: Breakdown of basement membrane (BM) is believed to be an essential step for tumor invasion and metastases. We have previously demonstrated that matrix metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with metastases in human colorectal cancer (CRC). This study explores the relationship between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and pattern of type IV collagen expression during human colorectal tumorigenesis. Thirty-four CRC patients, including four synchronous adenomas and one synchronous liver metastases, were involved in this study. By immunohistochemical staining, type IV collagen expression was noted to be continuous in the BM of normal mucosa, adenoma and in two cases of carcinoma in situ. Limited or absent type IV collagen staining pattern was seen in 100 (19/19) and 23% (3/13) of CRC with and without metastases, respectively. By double immunostaining, MMP-9 protein expression was noted to localize within areas of limited type IV collagen staining. Similarly, type IV collagen staining was noted to be greatest in areas devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa proenzyme forms in all CRC and normal mucosa extracts examined. The mean tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6+/-0.1 (mean +/- SE) and 2.4+/-0.5 in adenomas, and 2.1+/-0.2 and 4.1+/-0.7 in CRC, respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19) of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC without metastases, respectively. These differences were significant (P = 0.045 and P = 0.030, respectively). Our results demonstrate that loss of BM type IV collagen along with elevations in MMP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis. Our data suggest that control of type IV collagenase activation may be beneficial in preventing human colorectal tumor progression.

Journal ArticleDOI
TL;DR: All curcuminoids elevate the specific activity of quinone reductase in both wild type and mutant cells defective in either the aryl hydrocarbon (Ah) receptor or cytochrome P4501A1 activity, which indicates that neither binding to this receptor, nor metabolic activation by P45 01A1 are required for the signaling process originating from this family of electrophiles and ultimately resulting in Phase 2 enzyme induction.
Abstract: A series of naturally occurring as well as synthetic structural analogs of the dietary constituent curcumin were examined in order to elucidate which portions of the molecule are critical for the ability to induce Phase 2 detoxification enzymes in murine hepatoma cells, and hence to assess the chemoprotective potential of these compounds. Two groups of compounds were studied: classical Michael reaction acceptors such as curcumin and related beta-diketones such as dibenzoylmethane which lack direct Michael reactivity. The presence of two structural elements was found to be required for high inducer potency: (i) hydroxyl groups at ortho-position on the aromatic rings and (ii) the beta-diketone functionality. All curcuminoids elevate the specific activity of quinone reductase in both wild type and mutant cells defective in either the aryl hydrocarbon (Ah) receptor or cytochrome P4501A1 activity. This indicates that neither binding to this receptor, nor metabolic activation by P4501A1 are required for the signaling process originating from this family of electrophiles and ultimately resulting in Phase 2 enzyme induction.

Journal ArticleDOI
TL;DR: Results of this study indicate that consumption of a diet that significantly increased vegetable and fruit intake from a diverse number of botanical families resulted in significant reductions in markers of oxidative cellular damage to DNA and lipids.
Abstract: The goal of this study was to test the hypothesis that increased consumption of vegetables and fruit would reduce markers of oxidative cellular damage that can be assessed in blood or urine. Twenty-eight women participated in a 14 day dietary intervention. The primary end-points assessed were: 8-hydroxydeoxyguanosine (8-OHdG) in DNA isolated from peripheral lymphocytes, determined by HPLC with electrochemical detection; 8-OHdG excreted in urine, measured by ELISA; malondialdehyde (MDA) in urine, measured by fluorimetric detection following derivatization with thiobarituric acid and separation via HPLC; urinary 8-isoprostane F-2alpha (8-EPG) detected by ELISA. Pre- and post-intervention plasma levels of selected carotenoids were determined by HPLC. Subjects were free living and consumed a completely defined recipe-based diet that increased their average daily consumption of vegetables and fruit from 5.8 servings at baseline to 12.0 servings throughout the intervention. Overall, the level of 8-OHdG in DNA isolated from lymphocytes and in urine and the level of 8-EPG in urine were reduced by the intervention, whereas urine concentrations of MDA were minimally affected. The reduction in lymphocyte 8-OHdG was greater in magnitude (32 versus 5%) in individuals with lower average pre-intervention levels of plasma alpha-carotene (56 ng/ml) than in individuals with higher average pre-intervention plasma levels of alpha-carotene (148 ng/ml). The results of this study indicate that consumption of a diet that significantly increased vegetable and fruit intake from a diverse number of botanical families resulted in significant reductions in markers of oxidative cellular damage to DNA and lipids.

Journal ArticleDOI
TL;DR: The hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk is supported.
Abstract: Prostate cancer is the most common malignancy in males and is the second most common cause of cancer mortality in American men. Polymorphisms have been identified in two genes, the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5-reductase type II gene (SRD5A2) that are involved with androgen biosynthesis and metabolism. The CYP17 A2 allele contains a T-->C transition in the 5' promoter region that creates an additional Sp1-type (CCACC box) promoter site. The SRD5A2 valine to leucine (V89L) polymorphism has been correlated with lower dihydroxytestosterone levels. We tested genotypes in 108 prostate cases and 167 controls along with samples (n = 340) from several different ethnic groups. The CYP17 A2 allele (combined A1/A2 and A2/A2 genotypes) occurred at a higher frequency in Caucasian patients with prostate cancer (70%) than in Caucasian clinical control urology patients (57%), suggesting that the A2 allele may convey increased risk for prostate cancer [odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.0-3.0]. Blacks and Caucasians had a similar frequency of the A2 genotype (16 and 17%, respectively) while Taiwanese had the highest frequency (27%). The SRD5A2 leucine genotype was most frequent in Taiwanese (28%), intermediate in Caucasians (8.5%) and lowest in Blacks (2.5%). Genotypes having a SRD5A2 leucine allele were somewhat more common in prostate cancer cases (56%) than in controls (49%) (OR = 1.4, 95% CI = 0.8-2.2) but this difference was not significant. These results support the hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk.

Journal ArticleDOI
TL;DR: It is demonstrated that both MNNG and radiation-progressed malignant variants showed elevated ROS levels that contributed to their proliferative capacity in vitro as well as in vivo and increased Erk-1/2 and p38 MAP kinase activities were found to be important components of ROS-mediated signaling.
Abstract: There is evidence that reactive oxygen species (ROS) are important mediators of tumor promotion and progression. The molecular mechanisms involved in ROS-mediated signaling, however, are unclear at present. Using ionizing radiation and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as model physical and chemical carcinogens, we have malignantly progressed 308 cells, a papilloma-producing mouse keratinocyte cell line, and investigated the molecular alterations in the progressed phenotypes. In this study, we demonstrate that both MNNG and radiation-progressed malignant variants showed elevated ROS levels that contributed to their proliferative capacity in vitro as well as in vivo. We found increased Erk-1/2 and p38 MAP kinase activities to be important components of ROS-mediated signaling. The pro-oxidant state also contributed to constitutive elevation of AP-1, NFkappaB and cAMP response element transactivation in the malignant phenotype. Our data provide evidence for a functional role of elevated ROS levels in tumor progression and implicate Erk-1/2 and p38 MAP kinase activation in the malignant progression of mouse keratinocytes.

Journal ArticleDOI
TL;DR: Application of EGCG before UVB exposure decreased UVB-induced production of the immunomodulatory cytokine interleukin (IL)-10 in skin as well as in draining lymph nodes (DLN), whereas production of IL-12 was found to be markedly increased in DLN when compared with UVB alone-exposed mice.
Abstract: UV exposure of the skin, particularly UVB (290-320 nm), causes adverse biological effects, including alterations in cutaneous immune cells, photoaging and photocarcinogenesis. Several studies have shown that polyphenolic compounds isolated from green tea afford protection against UVB-induced inflammatory responses and photocarcinogenesis in murine models. In this study we show that topical application of (-)-epigallocatechin-3-gallate (EGCG) (3 mg/mouse), a major polyphenolic component of green tea, before a single low dose UVB exposure (72 mJ/cm(2)) to C3H/HeN mice prevented UVB-induced inhibition of the contact hypersensitivity response and tolerance induction to the contact sensitizer 2, 4-dinitrofluorobenzene. Topical application of EGCG before UVB exposure reduced the number of CD11b+ monocytes/macrophages and neutrophils infiltrating into skin inflammatory lesions, which are considered to be responsible for creating the UV-induced immunosuppressive state. In addition, application of EGCG before UVB exposure decreased UVB-induced production of the immunomodulatory cytokine interleukin (IL)-10 in skin as well as in draining lymph nodes (DLN), whereas production of IL-12, which is considered to be a mediator and adjuvant for induction of contact sensitivity, was found to be markedly increased in DLN when compared with UVB alone-exposed mice. Taken together, our data demonstrate that EGCG protects against UVB-induced immunosuppression and tolerance induction by: (i) blocking UVB-induced infiltration of CD11b+ cells into the skin; (ii) reducing IL-10 production in skin as well as in DLN; (iii) markedly increasing IL-12 production in DLN. Protection against UVB-induced immunosuppression by EGCG may be associated with protection against UVB-induced photocarcinogenesis.

Journal ArticleDOI
TL;DR: Investigation of the influence of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on the proliferation, apoptosis and tumorigenesis of breast cancer cells shows that induction of apoptosis may be the primary biological response resulting from PPARGamma activation in some breast cancer Cells and suggests a potential role for PPAR Gamma ligands for the treatment of breast cancers.
Abstract: This study was undertaken to investigate the influence of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on the proliferation, apoptosis and tumorigenesis of breast cancer cells. PPARgamma investigation has been largely restricted to adipose tissue, where it plays a key role in differentiation, but recent data reveal that PPARgamma is expressed in several transformed cells. However, the function of PPARgamma activation in neoplastic cells is unclear. Activation of PPARgamma with the known prostanoid agonist 15-deoxy-Delta12,14-prostaglandin J(2) (15dPGJ(2)) or the thiazolidinedione (TZD) agonist troglitazone (TGZ) attenuated cellular proliferation of the estrogen receptor-negative breast cancer cell line MDA-MB-231, as well as the estrogen receptor-positive breast cancer cell line MCF-7. This was marked by a decrease in total cell number and by an inhibition of cell cycle progression. Addition of 15dPGJ(2) was not associated with an increase in cellular differentiation, as has been seen in other neoplastic cells, but rather induction of cellular events associated with programmed cell death, apoptosis. Video time-lapse microscopy revealed that 15dPGJ(2) induced morphological changes associated with apoptosis, including cellular rounding, blebbing, the production of echinoid spikes, blistering and cell lysis. In contrast, TGZ caused only a modest induction of apoptosis. These results were verified by histochemistry using the specific DNA stain DAPI to observe nuclear condensation, a marker of apoptosis. Finally, a brief exposure of MDA-MB-231 cells to 15dPGJ(2) initiated an irreversible apoptotic pathway that inhibited the growth of tumors in a nude mouse model. These findings illustrate that induction of apoptosis may be the primary biological response resulting from PPARgamma activation in some breast cancer cells and further suggests a potential role for PPARgamma ligands for the treatment of breast cancer.

Journal ArticleDOI
TL;DR: Observations suggest that iNOS may play a key regulatory role in colon carcinogenesis and developingiNOS-specific inhibitors may provide a selective and safe chemopreventive strategy for colon cancer treatment.
Abstract: Inducible nitric oxide synthase (iNOS) is overexpressed in colonic tumors of humans and also in rats treated with a colon carcinogen. iNOS appear to regulate cyclooxygenase-2 (COX-2) expression and production of proinflammatory prostaglandins, which are known to play a key role in colon tumor development. Experiments were designed to study the inhibitory effects of S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT) a selective iNOS-specific inhibitor, measured against formation of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). Beginning at 5 weeks of age, male F344 rats were fed experimental diets containing 0 or 50 p.p.m. of PBIT, or 2000 p.p.m. of curcumin (non-specific iNOS inhibitor). One week later, rats were injected s.c. with AOM (15 mg/kg body wt, once weekly for 2 weeks). At 17 weeks of age, all rats were killed, colons were evaluated for ACF formation and colonic mucosa was assayed for isoforms of COX and NOS activities. Both COX and iNOS activities in colonic mucosa of the AOM-treated rats were significantly induced. Importantly, 50 p.p.m. PBIT suppressed AOM-induced colonic ACF formation to 58% (P < 0.0001) and crypt multiplicity containing four or more crypts per focus to 78% (P < 0.0001); it also suppressed AOM-induced iNOS activity. Curcumin inhibited colonic ACF formation by 45% (P < 0.001). These observations suggest that iNOS may play a key regulatory role in colon carcinogenesis. Developing iNOS-specific inhibitors may provide a selective and safe chemopreventive strategy for colon cancer treatment.

Journal ArticleDOI
TL;DR: This review describes the knowledge about cancer of the stomach regarding epidemiology, pathogenesis and prevention.
Abstract: Cancer of the stomach is one of the most commonly diagnosed malignancies and remains an important cause of mortality world wide. This type of cancer is not uniformly distributed among populations but shows a marked variation in both incidence and mortality. Although gastric cancer is declining in many parts of the world, the reasons for this decline are not well understood and its etiology remains unclear. Several factors are suspected to play a role in gastric carcinogenesis, including the effects of diet, exogenous chemicals, intragastric synthesis of carcinogens, genetic factors, infectious agents and pathological conditions in the stomach (such as gastritis). A new look at the results of epidemiological and experimental studies is important for the establishment of strategies for control. Since cancer of the stomach has a very poor prognosis in its more advanced stages, such a control program must have its main focus on primary prevention. This review describes our knowledge about cancer of the stomach regarding epidemiology, pathogenesis and prevention.

Journal ArticleDOI
Min Wei1, Hideki Wanibuchi1, Shinji Yamamoto1, Wei Li1, Shoji Fukushima1 
TL;DR: It is demonstrated that long-term p.p. o. administration of DMA induced urinary bladder carcinomas in male F344 rats, indicating that DMA is carcinogenic for the rat urinary bladder, which may be related to the human carcinogenicity of arsenicals.
Abstract: The present study was conducted to determine the carcinogenicity of dimethylarsinic acid (DMA) administered to male F344 rats in a 2 year bioassay. A total of 144 rats (10 weeks old at the start) were divided into four groups of 36 rats each. Groups 1-4 received DMA (purity 100%) at concentrations of 200, 50, 12.5 and 0 p.p.m. in the drinking water, respectively, for 104 weeks. From weeks 97 to 104, urinary bladder tumors were observed in 12 of 31, eight of 31 and none of 33 in groups 1-3, respectively. No bladder tumors were observed in group 4. The present study demonstrated that long-term p. o. administration of DMA induced urinary bladder carcinomas in male F344 rats. Therefore, the results indicate that DMA is carcinogenic for the rat urinary bladder, which may be related to the human carcinogenicity of arsenicals.

Journal ArticleDOI
TL;DR: TheCLA dose-response effect on arachidonic acid suppression corresponded closely with the CLA dose- response effect on cancer protection in the mammary gland, and optimal CLA nutrition during pubescence could conceivably control the population of cancer-sensitive target sites in the breast gland.
Abstract: Previous research suggested that conjugated linoleic acid (CLA) feeding during the period of pubescent mammary gland development in the rat resulted in diminished mammary epithelial branching which might account for the reduction in mammary cancer risk. Terminal end buds (TEB) are the primary sites for the chemical induction of mammary carcinomas in rodents. One of the objectives of the present study was to investigate the modulation of TEB density by increasing levels of dietary CLA and to determine how this might affect the risk of methylnitrosourea-induced mammary carcinogenesis. The data show a graded and parallel reduction in TEB density and mammary tumor yield produced by 0.5 and 1% CLA. No further decrease in either parameter was observed when CLA in the diet was raised to 1.5 or 2%. Thus, optimal CLA nutrition during pubescence could conceivably control the population of cancer-sensitive target sites in the mammary gland. Since both CLA and linoleic acid are likely to share the same enzyme system for chain desaturation and elongation, it is possible that increased CLA intake may interfere with the further metabolism of linoleic acid. Fatty acid analysis of total lipid showed that CLA and CLA metabolites continued to accumulate in mammary tissue in a dose-dependent manner over the range 0.5-2% CLA. There was no perturbation in tissue linoleic acid, however, linoleic acid metabolites (including 18:3, 20:3 and 20:4) were consistently depressed by up to 1% CLA. Of particular interest was the significant drop in 20:4 (arachidonic acid), which is the substrate for the cyclooxygenase and lipoxygenase pathways of eicosanoid biosynthesis. Thus the CLA dose-response effect on arachidonic acid suppression corresponded closely with the CLA dose-response effect on cancer protection in the mammary gland. This information is critical in providing new insights regarding the biochemical action of CLA.

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TL;DR: Results suggest that some plant polysaccharides produced both anti-genotoxic and anti-tumor promoting activities in in vitro models and, therefore, might be considered as potential agents for cancer chemoprevention.
Abstract: A plant polysaccharide, Aloe gel extract, was reported to have an inhibitory effect on benzo[a]pyrene (B[a]P)-DNA adduct formation in vitro and in vivo. Hence, chemopreventive effects of plant polysaccharides [Aloe barbadensis Miller (APS), Lentinus edodes (LPS), Ganoderma lucidum (GPS) and Coriolus versicolor (CPS)] were compared using in vitro short-term screening methods associated with both initiation and promotion processes in carcinogenesis. In B[a]P-DNA adduct formation, APS (180 micrograms/ml) was the most effective in inhibition of B[a]P binding to DNA in mouse liver cells. Oxidative DNA damage (by 8-hydroxydeoxyguanosine) was significantly decreased by APS (180 micrograms/ml) and CPS (180 micrograms/ml). In induction of glutathione S-transferase activity, GPS was found to be the most effective among plant polysaccharides. In screening anti-tumor promoting effects, APS (180 micrograms/ml) significantly inhibited phorbol myristic acetate (PMA)-induced ornithine decarboxylase activity in Balb/3T3 cells. In addition, APS significantly inhibited PMA-induced tyrosine kinase activity in human leukemic cells. APS and CPS significantly inhibited superoxide anion formation. These results suggest that some plant polysaccharides produced both anti-genotoxic and anti-tumor promoting activities in in vitro models and, therefore, might be considered as potential agents for cancer chemoprevention.

Journal ArticleDOI
TL;DR: The existing data suggest that k-ras mutation may be associated with shortened survival in NSCLC, although this finding awaits confirmation in well-designed multivariate analyses which adjust for the effect of known prognostic indicators.
Abstract: The treatment of non-small cell lung cancer (NSCLC) remains unsatisfactory, with most patients succumbing to metastatic disease within 5 years of diagnosis. Improved selection of patients for aggressive adjuvant therapy may contribute to improved survival. Mutation of the k-ras oncogene is considered a potentially clinically useful prognostic biomarker for this purpose. This report presents the results of a meta-analysis performed to determine whether the existing data support such a role for k-ras mutations in NSCLC. Two year survival data derived from 881 NSCLC patients in eight published studies were analyzed using a general variance-based meta-analytical method employing confidence intervals. The outcome of interest was a summary relative risk (RR(s)) reflecting the risk of death at 2 years associated with k-ras mutation-positive versus k-ras mutation-negative disease. Prior to calculation of RR(s), analysis for heterogeneity showed Q to equal 15.52 (7 df, P = 0.03). This indicated heterogeneity across the analyzed studies in terms of their estimate of effect. Possible sources of heterogeneity were identified and included selection bias and various other sources of uncontrolled confounding. Although a RR(s) of 2.35 (95% CI = 1.61-3. 22) was found when all eight studies were combined (favoring a negative prognostic role for k-ras mutation), it is unclear whether the magnitude of the RR(s) would persist after adjusting for other well-established prognostic indicators (e.g. stage). The existing data suggest that k-ras mutation may be associated with shortened survival in NSCLC, although this finding awaits confirmation in well-designed multivariate analyses which adjust for the effect of known prognostic indicators.

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TL;DR: The results of the present study clearly demonstrate the bioavailability of and phase II enzyme induction by systemically administered silibinin in different tissues, including skin, where silymarin has been shown to be a strong cancer chemopreventive agent, and suggest further studies to assess the cancer preventive and anticarcinogenic effects of silibine in different cancer models.
Abstract: Polyphenolic antioxidants are being identified as cancer preventive agents. Recent studies in our laboratory have identified and defined the cancer preventive and anticarcinogenic potential of a polyphenolic flavonoid antioxidant, silymarin (isolated from milk thistle). More recent studies by us found that these effects of silymarin are due to the major active constituent, silibinin, present therein. Here, studies are done in mice to determine the distribution and conjugate formation of systemically administered silibinin in liver, lung, stomach, skin, prostate and pancreas. Additional studies were then performed to assess the effect of orally administered silibinin on phase II enzyme activity in liver, lung, stomach, skin and small bowel. For tissue distribution studies, SENCAR mice were starved for 24 h, orally fed with silibinin (50 mg/kg dose) and killed after 0.5, 1, 2, 3, 4 and 8 h. The desired tissues were collected, homogenized and parts of the homogenates were extracted with butanol:methanol followed by HPLC analysis. The column eluates were detected by UV followed by electrochemical detection. The remaining homogenates were digested with sulfatase and beta-glucuronidase followed by analysis and quantification. Peak levels of free silibinin were observed at 0.5 h after administration in liver, lung, stomach and pancreas, accounting for 8.8 +/- 1.6, 4. 3 +/- 0.8, 123 +/- 21 and 5.8 +/- 1.1 (mean +/- SD) microg silibinin/g tissue, respectively. In the case of skin and prostate, the peak levels of silibinin were 1.4 +/- 0.5 and 2.5 +/- 0.4, respectively, and were achieved 1 h after administration. With regard to sulfate and beta-glucuronidate conjugates of silibinin, other than lung and stomach showing peak levels at 0.5 h, all other tissues showed peak levels at 1 h after silibinin administration. The levels of both free and conjugated silibinin declined after 0.5 or 1 h in an exponential fashion with an elimination half-life (t((1/2))) of 57-127 min for free and 45-94 min for conjugated silibinin in different tissues. In the studies examining the effect of silibinin on phase II enzymes, oral feeding of silibinin at doses of 100 and 200 mg/kg/day showed a moderate to highly significant (P < 0.1-0.001, Student's t-test) increase in both glutathione S-transferase and quinone reductase activities in liver, lung, stomach, skin and small bowel in a dose- and time-dependent manner. Taken together, the results of the present study clearly demonstrate the bioavailability of and phase II enzyme induction by systemically administered silibinin in different tissues, including skin, where silymarin has been shown to be a strong cancer chemopreventive agent, and suggest further studies to assess the cancer preventive and anticarcinogenic effects of silibinin in different cancer models.

Journal ArticleDOI
TL;DR: Observations indicate that human colon cancers are associated with a down-regulation in 15-LOX-1 expression and a reduction in 13-S-HODE intracellular levels and can suppress cell proliferation and induce apoptosis in transformed colonic epithelial cells.
Abstract: 13-S-Hydroxyoctadecadienoic acid (13-S-HODE), the product of 15-lipoxygenase (15-LOX) metabolism of linoleic acid, enhances cellular mitogenic responses to certain growth factors. Other observations have questioned whether 13-S-HODE has tumorigenic effects. Our study evaluated the hypothesis that 15-LOX-1 is overexpressed in colon cancers resulting in an increase in intracellular 13-S-HODE. 15-LOX-1 and 13-S-HODE were quantified using western blots, ELISA and immunohistochemistry in 18 human colon cancers with paired normal colonic mucosa. Additionally, 15-LOX-1 expression was measured by western blots in three transformed colonic cell lines and in a human umbilical vein endothelial cell line. Next, we evaluated 13-S-HODE effects on cellular proliferation, cell cycle distribution and apoptosis in a transformed colonic cell line (RKO). Cell cycle distributions were measured by flow cytometry and apoptosis was assessed by phase contrast microscopy, electron microscopy, flow cytometry and DNA fragmentation assay. 15-LOX-1 immunohistochemistry staining scores were reduced in tumor tissues (P

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TL;DR: Stable DNA adducts rather than AP sites are responsible for tumor initiation by carcinogenic PAHs, with the most potent carcinogen, DB[a,l]P, induced the highest level of stableAdducts and the lowest level of AP sites in epidermal DNA.
Abstract: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants with high carcinogenic potencies that have been linked to the etiology of human cancers through their presence in cigarette smoke and environmental mixtures. They are metabolically activated in cells by cytochrome P450 enzymes and/or peroxidases to reactive intermediates that damage DNA. One pathway of activation forms dihydrodiol epoxides that covalently bind to exocyclic amino groups of purines in DNA to form stable adducts. Another pathway involves formation of radical cations that bind to the N7 or C8 of purines to form unstable adducts that depurinate to leave apurinic (AP) sites in DNA. In the present study the proportions of stable DNA adducts and AP sites formed by the carcinogenic PAHs dibenzo[a,l]-pyrene (DB[a,l]P), 7,12-dimethylbenz[a]anthracene (DMBA), and benzo[a]pyrene (B[a]P) have been investigated in a target tissue for carcinogenesis, mouse epidermis. After topical application of the PAHs on the skin of female SENCAR mice epidermal DNA was isolated and the formation of stable DNA adducts was measured by (33)P-postlabeling and HPLC analysis. AP sites in DNA were measured with an aldehyde reactive probe in a slot-blot assay. At both 4 and 24 h after exposure, DB[a,l]P formed significantly higher amounts of stable DNA adducts than DMBA, and B[a]P exhibited the lowest level of binding. In contrast, the number of AP sites present in mice treated with these PAHs was in the order: DMBA > B[a]P >> DB[a,l]P. The level of AP sites was significantly lower than the level of stable adducts for each PAH. The most potent carcinogen, DB[a,l]P, induced the highest level of stable adducts and the lowest level of AP sites in epidermal DNA. These results indicate that stable DNA adducts rather than AP sites are responsible for tumor initiation by carcinogenic PAHs.

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TL;DR: The proliferative and apoptotic response of the colonic crypt to carcinogen and fish oil, coupled with the reduced incidence of ACF, suggest n-3 PUFA can protect against the carcinogenic effects of DMH by mediating changes in the balance proliferation and cell death.
Abstract: The effect of dietary fish oil on colonic crypt cell apoptosis and proliferation was examined in male Wistar rats, 24 and 48 h after administration of 1,2-dimethylhydrazine (DMH), and its influence on the induction of aberrant crypt foci (ACF) in the distal colon was assessed. Rats (125-150 g) fed a high-fat semi-synthetic diet containing corn oil (CO) were given DMH (30 mg/kg body wt) or a sham injection of EDTA/NaCl. Animals were then fed either the CO diet or a diet in which fish oil (EPA 18.7%; DHA 8%) was substituted for corn oil. Subgroups of rats (n = 5) were killed after 24 and 48 h, and crypt cell apoptosis and proliferation were quantified by morphological criteria in isolated intact crypts from the mid and distal colon. Consumption of the fish oil diet (FO) was associated with increased apoptotic cell death (P < 0.001) and suppression of proliferation (P < 0.05) in colonic crypts both 24 and 48 h after DMH. In a second experiment, animals were given three injections of DMH or sham injections of carrier at weekly intervals. For 48 h after each injection animals were fed either the CO or FO diet, but otherwise maintained on the CO throughout. The number and crypt multiplicity of ACF in the distal colon were determined after 18 weeks, and animals given the FO diet for the 48 h period following carcinogen administration were found to have significantly fewer ACF than rats fed the CO diet (P < 0.05). The data demonstrate that the fatty acid composition of the diet is an important determinant in the induction of carcinogenesis by DMH. The proliferative and apoptotic response of the colonic crypt to carcinogen and fish oil, coupled with the reduced incidence of ACF, suggest n-3 PUFA can protect against the carcinogenic effects of DMH by mediating changes in the balance proliferation and cell death.

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TL;DR: The level in rat lung DNA increases markedly at an early phase after DEP exposure, by the generation of ROS and the inhibition of 8-OH-Gua repair activity, and induction of OGG1 mRNA is also a good marker of cellular oxidative stress during carcinogenesis.
Abstract: Diesel exhaust particles (DEP), an environmental pollutant, are known to induce lung cancer in experimental animals. To clarify whether reactive oxygen species (ROS) are involved in its carcinogenic mechanism, we examined the levels of 8-hydroxyguanine (8-OH-Gua), its total repair and the repair enzyme OGG1 mRNA in female Fischer 344 rat lungs, as markers of the response to ROS, after DEP was intratracheally instilled. The 8-OH-Gua levels in both DEP-treated groups (2 and 4 mg) were increased during the 2-8 h following exposure to DEP. The 8-OH-Gua repair activities in the DEP-treated groups decreased during the period from 2 h to 2 days following DEP exposure and then recovered to the level of the control group at 5 days after exposure. OGG1 mRNA was induced in rats treated with 4 mg DEP for 5-7 days after administration. In conclusion, the 8-OH-Gua level in rat lung DNA increases markedly at an early phase after DEP exposure, by the generation of ROS and the inhibition of 8-OH-Gua repair activity, and induction of OGG1 mRNA is also a good marker of cellular oxidative stress during carcinogenesis.

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TL;DR: The results suggest that not only the green tea polyphenol, EGCG, but also the black tea poly phenol, TF-3, have an antiproliferative activity on tumor cells, and the molecular mechanisms of antiproliferation may block the growth factor binding to its receptor and thus suppress mitogenic signal transduction.
Abstract: Previous studies in our laboratory have shown that the major green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), suppressed autophosphorylation of epidermal growth factor (EGF) receptor induced by EGF in human A431 epidermoid carcinoma cells. In this study, we examined the inhibitory effects of black tea polyphenols, including theaflavin (TF-1), a mixture (TF-2) of theaflavin-3-gallate (TF-2a) and theaflavin-3'-gallate (TF-2b), theaflavin-3,3'-digallate (TF-3) and the thearubigin fraction on the autophosphorylation of the EGF and PDGF receptors in A431 cells and mouse NIH3T3 fibroblast cells, respectively. First, we examined the effects of these polyphenols on the proliferation of A431 and NIH3T3 cells. Both EGCG and TF-3 strongly inhibited the proliferation of A431 and NIH3T3 cells more than the other theaflavins did. In cultured cells with pre-treatment of tea polyphenol, TF-3 was stronger than EGCG on the reduction of EGF receptor and PDGF receptor autophosphorylation induced by EGF and PDGF, respectively. Other theaflavins slightly reduced the autophosphorylation of the EGF and PDGF receptors; furthermore, TF-3 could reduce autophosphorylation of the EGF receptor (or PDGF receptor) even with co-treatment with EGF (or PDGF) and TF-3, but EGCG was inactive under these conditions. In addition, TF-3 was stronger than EGCG in blocking EGF binding to its receptor. These results suggest that not only the green tea polyphenol, EGCG, but also the black tea polyphenol, TF-3, have an antiproliferative activity on tumor cells, and the molecular mechanisms of antiproliferation may block the growth factor binding to its receptor and thus suppress mitogenic signal transduction.