Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of cyclooxygenase (COX)-2 protein in 4-nitroquinoline-1-oxide (4-NQO)-induced rat tongue lesions and the postinitiation chemopreventive potential of a selective COX-2 inhibitor, nimesulide (NIM), were examined in Fischer 344 male rats. NIM was administered in the diet at doses of 150, 300, and 600 ppm for 14 weeks after treatment with 25-35 ppm 4-NQO in the drinking water for 12 weeks. Western blot analysis revealed COX-2 protein to be barely expressed in the normal tongue epithelia, whereas it was increased approximately 6-fold in squamous cell carcinomas (SCCs). Immunohistochemically, COX-2 protein was diffusely present in SCCs and dysplasia but expressed only in basal cells in hyperplasia and papillomas. In basal cells of normal epithelia, it was also occasionally weakly stained. NIM dose-dependently decreased at doses of 150 and 300 ppm, the incidences of SCCs to 4 of 12 (33.3%) and 1 of 13 (7.7%) and their multiplicity to 0.33+/-0.49 and 0.08+/-0.28 per rat, respectively, as compared with 4-NQO alone group values of 9 of 11 (81.8%) and 1.00+/-0.77. A lesser decrease was observed with 600 ppm, the values being 5 of 12 (41.7%) and 0.50+/-0.67. NIM did not significantly affect the development of hyperplasias, dysplasias, and papillomas. These results clearly indicate chemopreventive potential of a selective COX-2 inhibitor against the postinitiation development of SCCs in rat tongue carcinogenesis.
 ...
PMID:Increased expression of cyclooxygenase-2 protein in 4-nitroquinoline-1-oxide-induced rat tongue carcinomas and chemopreventive efficacy of a specific inhibitor, nimesulide. 1124 50

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC). Although the exact mechanisms remain unclear, the inhibition of cyclooxygenase (COX) by NSAIDs appears to abort, if not prevent, CRC carcinogenesis or metastatic tumor progression. The aim of our study was to investigate the association between COX-2 expression and CRC tumor cell invasiveness. The differences in immunoblot-detectable COX-2 protein contents in primary CRCs, metastatic hepatic lesions and corresponding normal mucosa from the same individual were evaluated in 17 patients. Three different colon cancer cell lines, SW620, Lovo, HT-29 and a metastatic variant of HT-29, HT-29/Inv3, were employed to evaluate COX-2 expression and prostaglandin E(2) (PGE2) production in relation to their invasive abilities in vitro. The effects of a COX-2-selective inhibitor, etodolac, on cell proliferation and invasive activity were also determined. The results showed that 15 of 17 (88%) metastatic CRC cells from the liver and 14 of 17 (82%) primary CRC tissue exhibited much higher levels of COX-2 than corresponding adjacent normal mucosa from the same patient. Among those patients with relatively high COX-2 expression in the primary tumors, almost all exhibited even higher levels of COX-2 in their hepatic metastases. Among the 4 colon cancer cell lines, HT-29/Inv3 manifested the highest COX-2 expression, PGE2 production and in vitro invasive activity. The selective COX-2 inhibitor, etodolac, could especially exert cytotoxicity and markedly suppress the invasive property and PGE(2) production, although not the COX-2 protein level, in HT-29/Inv3 cells. Our results imply that COX-2 expression may be associated with the invasive and metastatic properties of CRC tumor cells.
 ...
PMID:Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. 1127 97

The cyclooxygenase (COX)-2 gene encodes an inducible prostaglandin synthase enzyme that is overexpressed in adenocarcinomas and other tumors. Deletion of the murine Cox-2 gene in Min mice reduced the incidence of intestinal tumors, suggesting that it is required for tumorigenesis. However, it is not known if overexpression of Cox-2 is sufficient to induce tumorigenic transformation. We have derived transgenic mice that overexpress the human COX-2 gene in the mammary glands using the murine mammary tumor virus promoter. The human Cox-2 mRNA and protein are expressed in mammary glands of female transgenic mice and were strongly induced during pregnancy and lactation. Female virgin Cox-2 transgenic mice showed precocious lobuloalveolar differentiation and enhanced expression of the beta-casein gene, which was inhibited by the Cox inhibitor indomethacin. Mammary gland involution was delayed in Cox-2 transgenic mice with a decrease in apoptotic index of mammary epithelial cells. Multiparous but not virgin females exhibited a greatly exaggerated incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. Cox-2-induced tumor tissue expressed reduced levels of the proapoptotic proteins Bax and Bcl-x(L) and an increase in the anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis of mammary epithelial cells contributes to tumorigenesis. These data indicate that enhanced Cox-2 expression is sufficient to induce mammary gland tumorigenesis. Therefore, inhibition of Cox-2 may represent a mechanism-based chemopreventive approach for carcinogenesis.
 ...
PMID:Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. 1127 47

Epidemiological studies and laboratory animal model assays suggest that a high intake of dietary fat promotes colorectal cancer. Several in vivo and in vitro studies support the hypothesis that omega-6 fatty acids promote colon tumorigenesis, whereas omega-3 fatty acids lack promoting activity. Fat intake in the United States traditionally includes high amounts (30% of total caloric intake) of saturated fat rather than omega-6 fatty acids. Therefore, the present study was designed to compare the modulatory effects of a high-fat diet containing mixed lipids (HFML), a diet rich in saturated fatty acids (the average American diet), a diet with fish oil (HFFO) that is rich in omega-3 fatty acids, and a low-fat corn oil diet (LFCO) on the formation of chemically induced colonic aberrant crypt foci (ACF) and tumors, cyclooxygenase (COX)-2 activity, and apoptosis during experimental colon carcinogenesis. At 5 weeks of age, groups of male F344 rats were fed a 5% corn oil diet (LFCO). At 7 weeks of age, rats intended for carcinogen treatment received s.c. injections of azoxymethane at a dose level of 15 mg/kg of body weight once weekly for 2 weeks. Beginning 1 day after the carcinogen treatment, groups of rats were then maintained on experimental diets containing 20% HFML or 20% HFFO. Rats were killed at 8, 23, or 38 weeks after azoxymethane treatment. Colonic ACF and tumors were evaluated histopathologically, and apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated nick end labeling method. Colonic mucosae and tumor samples harvested at week 38 were analyzed for COX-2 synthetic activity and expression. The rats fed the HFML diet showed significantly increased total colonic ACF (P < 0.001-0.0001) with a multiplicity of > or = 4 aberrant crypts/focus (P < 0.0001) compared with the effects of the HFFO or LFCO diets at week 8, 23, and 38. Interestingly, there was a 2- to 3-fold increase (> or = 4) in multicrypt foci in rats given the HFML diet as compared with such foci in rats fed the HFFO or LFCO diets. By week 23, the HFML diet had significantly increased the incidence of colonic tumors (30-60%) and their multiplicity (100-141%) when compared with the effects of the LFCO or HFFO diets. At week 38, the HFML diet had induced 100% colon tumor incidence and a 4-fold multiplicity of adenocarcinomas compared with the LFCO and HFFO diets. At weeks 23 and 38, a significantly lower percentage of apoptotic colonic epithelial cells were observed in the tumors of animals fed the HFML diet as compared with those fed the HFFO diet. The HFML diet caused significantly increased levels of COX-2 activity in colon tumors (P < 0.05-0.01), and these tumors had enhanced levels of COX-2 expression as compared with those in assays with LFCO or HFFO diets. These observations demonstrate for the first time that HFML diets containing high levels of saturated fatty acids (such as those in Western diets) promote colon carcinogenesis. Although the mechanisms involved in colon tumor promotion by a HFML diet are not fully known, our results indicate that the modulation of eicosanoid production via the influence on COX activity and the suppression of apoptosis may play a key role in HFML diet-induced colon tumorigenesis.
 ...
PMID:Modulation of experimental colon tumorigenesis by types and amounts of dietary fatty acids. 1128 Jul 48

Cyclooxygenase (COX)-2, the inducible form of the rate-limiting enzyme for prostaglandin synthesis, is up-regulated in gastrointestinal cancers and is a key mediator of epithelial cell growth. Helicobacter pylori is causally linked to gastric cancer. In H. pylori gastritis, COX-2 expression localizes to the subepithelial region, with variable levels in the epithelium. In contrast, in gastric cancer, COX-2 strongly predominates in the epithelium, suggesting that the transition to consistent epithelial COX-2 overexpression may be a critical molecular event in gastric carcinogenesis. Because aberrant promoter methylation inhibits expression of a variety of genes in gastrointestinal cancers, we sought to determine whether methylation of the COX-2 promoter could regulate the response to H. pylori in gastric epithelial cells. We assessed COX-2 expression and promoter methylation status in six gastric epithelial cell lines. In all four of the cell lines that exhibited basal expression of COX-2 and a significant increase in expression in response to H. pylori, the COX-2 promoter was unmethylated, whereas in the two cell lines that did not express COX-2, the COX-2 promoter was methylated. Treatment of COX-2-methylated cells with the demethylating agent 5-azacytidine had a modest effect on COX-2 expression, but when 5-azacytidine-treated cells were subsequently stimulated with H. pylori, there was a significant, 5-10-fold enhancement of both COX-2 mRNA and protein expression and release of the COX-2 product, prostaglandin E2. In contrast, in COX-2-expressing cell lines that were unmethylated at the COX-2 promoter, 5-azacytidine had no effect on H. pylori-stimulated COX-2 expression. These findings suggest that loss of COX-2 methylation may facilitate COX-2 expression and promote gastric carcinogenesis associated with H. pylori infection.
 ...
PMID:Promoter methylation regulates Helicobacter pylori-stimulated cyclooxygenase-2 expression in gastric epithelial cells. 1128 4

Chronic pulmonary inflammatory diseases predispose towards lung cancer by unknown mechanisms. Butylated hydroxytoluene (BHT) administration to mice causes lung injury and a subsequent inflammatory response, and when administered chronically to certain inbred strains following carcinogen treatment, increases lung tumor multiplicity. We hypothesize that inflammation promotes lung tumor growth in this model system and have begun to examine this hypothesis by assessing inflammatory parameters in inbred strains that vary in their susceptibility to promotion. Positive correlations were found between susceptibilities to tumor promotion and BHT induction of alveolar macrophage and lymphocyte infiltration into alveolar airspaces, and increased vascular permeability (P < .03, P < .04, and P < .005, respectively). The amounts of pulmonary cyclooxygenase (COX)-1 and COX-2 did not strongly correlate with promotion. Because persistent elevation of macrophage content is the hallmark of a chronic inflammatory response, the alveolar macrophage population was depleted by adding chlorine to the drinking water prior to carcinogenesis. This treatment reduced lung tumor multiplicity following 2-stage carcinogenesis (P < .05). These correlations between inflammatory and tumorigenic responses to BHT, along with decreased tumorigenesis after macrophage depletion, are consistent with a role of inflammation in promotion. Inflammatory mediators may provide targets for early diagnosis and chemoprevention.
 ...
PMID:Butylated hydroxytoluene (BHT) induction of pulmonary inflammation: a role in tumor promotion. 1129 24

It has been proposed that the omega-6 fatty acids increase the rate of tumor growth. Here we test that hypothesis in the PC-3 human prostate tumor. We found that the essential fatty acids, linoleic acid (LA) and arachidonic acid (AA), and the AA metabolite PGE(2) stimulate tumor growth while oleic acid (OA) and the omega-3 fatty acid, eicosapentaenoic acid (EPA) inhibited growth. In examining the role of AA in growth response, we extended our studies to analyze changes in early gene expression induced by AA. We demonstrate that c-fos expression is increased within minutes of addition in a dose-dependent manner. Moreover, the immediate early gene cox-2 is also increased in the presence of AA in a dose-dependent manner, while the constitutive cox-1 message was not increased. Three hours after exposure to AA, the synthesis of PGE(2) via COX-2 was also increased. Previous studies have demonstrated that AA was primarily delivered by low density lipoprotein (LDL) via its receptor (LDLr). Since it is known that hepatomas, acute myelogenous leukemia and colorectal tumors lack normal cholesterol feedback, we examined the role of the LDLr in growth regulation of the PC-3 prostate cancer cells. Analysis of ldlr mRNA expression and LDLr function demonstrated that human PC-3 prostate cancer cells lack normal feedback regulation. While exogenous LDL caused a significant stimulation of cell growth and PGE(2) synthesis, no change was seen in regulation of the LDLr by LDL. Taken together, these data show that normal cholesterol feedback of ldlr message and protein is lost in prostate cancer. These data suggest that unregulated over-expression of LDLr in tumor cells would permit increased availability of AA, which induces immediate early genes c-fos and cox-2 within minutes of uptake.
Carcinogenesis 2001 May
PMID:Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells. 1132 87

Non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or reduce the occurrence of colorectal cancers. Anti-carcinogenic properties of NSAIDs have been demonstrated in epidemiological studies of humans and experimental animals. In addition, clinical studies of familial adenomatous polyposis and sporadic adenomas have demonstrated that NSAIDs induce regression of colorectal adenomas and prevent formation of these tumors. NSAIDs thus induce early disruption of the adenoma-carcinoma sequence and may mainly suppress subsequent cancer formation at adenoma stage. The mechanism of the anti-carcinogenic effect of these drugs is not known, but results of most studies support that cyclooxygenase-2 (an inducible isoform of prostaglandin synthetase, COX-2) is a major target of NSAIDs in this effect. Recent immunohistochemical studies have revealed that COX-2 is expressed not in tumor cells but in interstitial cells of colonic adenomas. Accordingly, NSAIDs may exhibit anti-carcinogenic property through the inhibition of prostaglandin production by COX-2 expressing interstitial cells. Future research should be focused on the role of prostaglandins in the interaction of tumor cells and interstitial cells in colon carcinogenesis.
 ...
PMID:Colorectal cancer and non-steroidal anti-inflammatory drugs. 1132 34

We have consistently shown that several synthetic Organoselenium compounds are superior cancer chemopreventive agents and less toxic than selenite or certain naturally occurring selenoamino acids. 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) is the lead Organoselenium compound in that it has been shown to be the most effective and the least toxic agent in several experimental cancer models. It is not known whether p-XSC or one of its metabolites is responsible for its chemopreventive efficacy. As an initial step, we synthesized one of its putative metabolites, i.e., the glutathione conjugate of p-XSC (p-XSe-SG), and determined its stability in the pH range from 2 to 8 and in the diet under normal feeding conditions. We also assessed its maximum tolerated dose and examined its chemopreventive efficacy against azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. p-XSe-SG proved to be very stable over the pH range tested. The maximum tolerated dose of p-XSe-SG determined in a 6-week subchronic toxicity study was found to be >210 ppm (>40 ppm selenium) when the compound was added to AIN-76A high-fat diet. To assess the efficacy of this agent in the postinitiation period of colon carcinogenesis, male F344 rats 6 weeks of age were fed the high-fat diet, and at beginning of weeks 7 and 8, all of the rats intended for carcinogen treatment were given AOM at a dose of 15 mg/kg body weight by s.c. injection. Two days after the carcinogen treatment, the groups of rats consuming the high-fat control diet began their respective high-fat experimental diet regimens with 0, 56, or 84 ppm p-XSe-SG (0.1, 10, and 15 ppm of selenium) supplementation. All animals continued on their respective diets for 38 weeks after the AOM-treatment and were then killed. Colon tumors were evaluated histologically using routine procedures and were also analyzed for cyclooxygenase (COX)-1 and COX-2 expression and enzymatic activities. The results indicate that p-XSeSG administered during the post-initiation stage significantly inhibited both the incidence (P < 0.05-0.01) and the multiplicity (P < 0.05-0.005) of AOM-induced colon adenocarcinomas. This agent also greatly suppressed the multiplicity (P < 0.01-0.001) of AOM-induced exophytic adenocarcinomas in a dose-dependent manner. Feeding of 56 or 84 ppm p-XSe-SG in the diet significantly suppressed total COX activity (P < 0.02 to -0.01) and COX-2 specific activity (P < 0.005-0.0005) but had minimal effect on the protein expression levels of COX-1 and COX-2. These results suggest that the newly developed synthetic Organoselenium compound, p-XSe-SG, is stable in the diet and at wide pH ranges, inhibits colon carcinogenesis when administered during the postinitiation stage, and inhibits COX activity. Compared with previous efficacy studies and considering the toxicity associated with selenium, p-XSe-SG seems to be the least toxic Organoselenium chemopreventive agent thus far tested in the experimental colon carcinogenesis. Studies are in progress to delineate whether p-XSe-SG is also effective when administered during the progression stage of colon carcinogenesis.
 ...
PMID:Chemoprevention of colon cancer by a glutathione conjugate of 1,4-phenylenebis(methylene)selenocyanate, a novel organoselenium compound with low toxicity. 1132 34

We determined the effects of a crude green tea extract given as drinking fluid on the promotion/progression phase of colon carcinogenesis in rats after induction of the neoplastic process by azoxymethane. Adult Wistar rats were given azoxymethane (15 mg/kg i.p.) once a week for two weeks. One week after the second injection, the rats were randomly divided into two groups. One group (n = 8) received daily prepared aqueous solutions of green tea extracts (GTE; 0.02%, wt/vol); the control group (n = 8) received tap water. After six weeks, rats receiving GTE showed a 60% reduction in the number of colonic preneoplastic lesions (aberrant crypts). The number of individual crypts per aberrant crypt focus (crypt multiplicity) was significantly reduced in the GTE group; the majority (80%) of the remaining aberrant foci contained only one or two preneoplastic crypts. A significant and selective decrease of cyclooxygenase (COX)-2 activity was observed in the colon of rats receiving GTE (23 +/- 3 vs. 117 +/- 30 mU/mg protein in controls), whereas COX-1 showed no alterations. Our data demonstrate that GTE reduces COX-2 and suppresses the formation of colonic preneoplastic lesions. They provide new insights into the mechanism of chemopreventive and anti-inflammatory properties of green tea.
 ...
PMID:Suppression of azoxymethane-induced preneoplastic lesions and inhibition of cyclooxygenase-2 activity in the colonic mucosa of rats drinking a crude green tea extract. 1134 Oct 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>