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)

In an animal model of hormone-mediated carcinogenesis, male golden Syrian hamsters develop renal carcinoma following prolonged exposure to 17beta-estradiol. The basis for the species and tissue specificity is unclear. Detailed information on the disposition of 17beta-estradiol in this model is lacking. Because catechol estrogens have been implicated in this model of carcinogenesis, we investigated the metabolism and nephrotoxicity of 17beta-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers. 17beta-Estradiol (50 micromol/kg, i.p.) is a mild nephrotoxicant, causing significant elevations in the urinary excretion of gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase, glutathione S-transferase (GST) and glucose. Increases in renal protein carbonyls and lipid hydroperoxides, which are markers of oxidative damage, also occur after administration of 17beta-estradiol (50 micromol/kg, i.p.). 17beta-Estradiol-mediated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of gamma-GT, implying that toxicity is mediated by metabolites requiring metabolism by this enzyme. Following administration of 17beta-[14C]estradiol (100 micromol/kg) to hamsters, 9.7% of the dose is recovered in bile after 5 h, the majority (7.9%) representing aqueous metabolites. Seven catechol estrogen GSH conjugates were identified, 2-hydroxy-1,4-bis-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-estrone, 2-hydroxy-1-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-17beta-estradiol, and 2-hydroxy-1-(glutathion-S-yl)-17beta-estradiol. At 5.4 micromol/kg of 17beta-estradiol, a dose-reflective of daily exposure levels in the hamster model of nephrocarcinogenicity, 12% of the dose is recovered within 5 h as a combination of GSH conjugates of 2- and 4-hydroxy-17beta-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrogens, followed by GSH conjugation, occurs in vivo and 17beta-estradiol is a mild nephrotoxicant in a manner dependent on the activity of gamma-GT.
Carcinogenesis 1997 Mar
PMID:Formation of catechol estrogen glutathione conjugates and gamma-glutamyl transpeptidase-dependent nephrotoxicity of 17beta-estradiol in the golden Syrian hamster. 906 57

The main objective of the present study was to test the hypothesis that exogenous insulin would enhance colon carcinogenesis. Thirty-six female Fischer 344 rats were fed ad libitum a low-fat rodent chow and given a single azoxymethane injection (20 mg/kg); one week later, they were randomized into two groups. Control rats were given a subcutaneous saline injection, 5 days/wk, and experimental rats were given Ultralente bovine insulin (20 U/kg). The promoting effect of insulin injections was assessed by the multiplicity (number of crypts) of aberrant crypt foci after 100 days of treatment (72 injections). The rats given insulin ate more and were heavier than controls (215 +/- 11 vs. 182 +/- 7 g, p < 0.001). Insulin injections also increased the amount of abdominal fat, plasma triglycerides, and insulinemia and decreased blood glucose (all p < 0.05). The number of aberrant crypt foci was the same in both groups, but their multiplicity was significantly increased by the insulin injections (2.8 +/- 0.3 vs. 2.5 +/- 0.2 crypt/focus in controls, p = 0.007). In addition, the proportion of sialomucin-producing foci was higher in insulin-injected rats than in controls (p = 0.04). These data show that exogenous insulin can promote colon carcinogenesis in rats and suggest that life-style and diets leading to low blood insulin might protect humans against colorectal cancer.
 ...
PMID:Insulin injections promote the growth of aberrant crypt foci in the colon of rats. 910 63

In vivo, butyrate is a major energy source for the colonic epithelium and is thought to stimulate proliferation. In contrast, butyrate in vitro has been shown to inhibit proliferation and induce differentiation and apoptosis in colonic epithelial cells. Most colon cell cultures are grown in medium containing high concentrations of glucose, whereas in vivo, the main energy source used by the colon cells is butyrate. The aim of this study was to determine whether the apparent contrasting roles of butyrate in vivo and in vitro could be as a consequence of differences in glucose availability. The sensitivity of two human colorectal tumour cell lines, one adenoma (S/RG/C2) and one carcinoma (HT29) to butyrate-induced growth inhibition and apoptosis was investigated to determine whether these cellular effects were altered under glucose depleted culture conditions. Glucose depletion resulted in increased apoptosis in both cell lines in the absence of butyrate. Butyrate in standard culture conditions (containing 25 mM glucose and 1 mM pyruvate) inhibited growth and induced apoptosis in both cell lines. However, low concentrations of butyrate in glucose depleted culture conditions (i.e. standard growth medium without glucose and pyruvate supplements) were found to reduce apoptosis induced by glucose deprivation and increase cell yield in both cell lines. The results show that in glucose depleted culture conditions, butyrate at low concentrations (0.5 mM for S/RG/C2, and 0.5 and 2 mM for HT29 cells) was found to be growth stimulatory whereas in the presence of glucose, these same concentrations of butyrate induced apoptosis. Thus, whether butyrate is growth stimulatory or growth inhibitory may depend on the availability of other energy sources. These observations may, in part, provide an explanation for the apparent opposite effects of butyrate on proliferation reported in vivo and in vitro.
Carcinogenesis 1997 Jun
PMID:Butyrate can act as a stimulator of growth or inducer of apoptosis in human colonic epithelial cell lines depending on the presence of alternative energy sources. 921 12

Many patients with exocrine pancreatic cancer develop diabetes mellitus due to insulin resistance. This may relate to concurrent over-production of islet amyloid polypeptide (IAPP) by the pancreatic beta cells. We investigated the effects of pancreatic cancer on circulating IAPP and glucose homeostasis in azaserine-treated rats (developing acinar pancreatic tumours) and BOP-treated hamsters (developing ductular pancreatic tumours). Glucose, insulin and IAPP levels in plasma were neither affected in azaserine-only treated rats nor in animals with enhanced carcinogenesis after chronic caerulein treatment. Azaserine-treated rats on a high-fat diet had decreased insulin levels and enhanced IAPP/insulin ratios in plasma, without hyperglycaemia. All BOP-treated hamsters showed pancreatic carcinogenesis at 6 months post-treatment. Supranormal plasma glucose levels in animals on a low-fat diet were the only change observed. After a second 6-month period, subnormal plasma glucose levels, at least 4-fold decreased plasma insulin and up to 2-fold decreased plasma IAPP levels were present in all hamsters. Remarkably, both in azaserine-treated rats on high-fat and in BOP-treated hamsters, decreased insulin levels and elevated IAPP/insulin ratios are not associated with hyperglycaemia. In contrast to humans with pancreatic cancer, IAPP over-production and hyperglycaemia do not develop in rats and hamsters with (pre-)neoplastic pancreatic lesions.
 ...
PMID:Pancreatic cancer in rats and hamsters does not induce IAPP-related hyperglycaemia. 925 4

We studied whether repeated boluses of sucrose or diets containing carbohydrates with a variable glycemic index (GI) affect intestinal carcinogenesis in rats. Male F344 rats were treated twice (1 wk apart) with 15 mg/kg sc azoxymethane (AOM) and then divided into four experimental dietary groups with different carbohydrate composition and administration schedules: the sucrose group was fed 44% (wt/wt) sucrose (GI = 65), the bolus group was fed sucrose as carbohydrate and 43 boluses of sucrose (10-15 g/kg) at various time intervals, the pasta group was fed pasta [77% (wt/wt) cooked pasta, GI = 55], and the glucose group was fed 44% (wt/wt) glucose (GI = 97). All nutrients, including carbohydrates, were provided in similar amount to the different groups. The experiment was terminated between Day 230 and Day 245 after AOM administration. At this time the pasta group had significantly higher cecal short-chain fatty acids than the other groups. Intestinal adenomas and cancers occurred with the same frequency in the bolus, sucrose, and glucose groups. On the contrary, we observed a significant decrease (p = 0.03) in the cumulative incidence of intestinal adenomas, but not adenocarcinomas, in the pasta group compared with the sucrose group (intestinal adenoma incidence in the pasta group was 31% compared with 63% in the sucrose group, 46% in the bolus group, and 37% in the glucose group). In conclusion, these results do not support the hypothesis that sucrose boluses or carbohydrates with a high GI stimulate colon carcinogenesis, but they indicate that foods such as pasta may exert a protective effect.
 ...
PMID:Modification of azoxymethane intestinal carcinogenesis in rats by feeding sucrose boluses, pasta, and glucose. 929 Jan 20

McKeown-Eyssen and Giovannucci recently proposed that the etiology of insulin resistance (IR) and colorectal cancer (CRC) are related. They suggested that diets high in fat and energy and low in complex carbohydrates and a sedentary life-style lead to IR and that the associated hyperinsulinemia, hypertriglyceridemia, and glycemia lead to increased CRC risk through the growth-promoting effect of insulin or the increased availability of energy. We reasoned that if diet affects colon carcinogenesis through its effect on IR, evidence of colon cancer promotion would be preceded by evidence of IR. To test this expectation, we compared the effects of a high-fat (HF, 59% energy) diet and a low-fat (LF, 11% energy) diet on indirect measures of IR and promotion in azoxymethane-initiated F344 rats. Promotion was assessed as growth of aberrant crypt foci (ACF) at 100 days after initiation. The HF diet increased ACF size 1.4 times (95% confidence interval = 1.30-1.58) that of the LF diet. The HF diet also led to impaired oral glucose tolerance tests measured at 4, 32, 60, and 88 days and characterized by an average increased glucose concentration of 0.78 +/- 0.17 mmol/l (p < 0.001). It also resulted in an impaired intravenous glucose tolerance test and elevated levels of serum insulin after a glucose gavage. We concluded that with this model a high-fat diet leads to evidence of IR before it is possible to demonstrate CRC promotion, thus providing support, necessary but not sufficient, for the causal hypothesis linking IR and CRC. Possible mechanisms linking diet, IR, and promotion are considered.
 ...
PMID:Insulin resistance and promotion of aberrant crypt foci in the colons of rats on a high-fat diet. 938 87

We reported recently that weight cycling significantly increased the incidence of mammary cancer in virgin female rats that were pretreated with N-methyl-N-nitrosourea. The present study investigated the effect of weight cycling on mammary epithelial cell proliferation and its relationship to changes in plasma insulin, estrogen, progesterone and urinary corticosterone in 30 female virgin Sprague-Dawley rats. Animals were fed a modified AIN-76A diet containing 24.6% corn oil by weight. Weight-cycled (WC) rats were food restricted daily by either 33% or 50% of non-restricted controls for 1 week followed by 3 weeks compensatory refeeding and weight recovery over 18 weeks or 4.5 weight cycles. WC rats consumed 6-10% less food than controls (P = 0.01) but showed a 71-89% greater efficiency of food utilization for growth (P < 0.0001) than controls. There were no differences in total weight gain during treatment. Mammary lobuloalveolar and ductal cell proliferation of WC rats, measured by 5-bromo-2'deoxyuridine labelling, increased in a dose-response fashion, P = 0.03, P = 0.06 respectively in comparison to controls. Energy and substrate utilization measured by indirect calorimetry indicated WC animals expended less energy (P = 0.005) and utilized less glucose (P = 0.0001) and protein (P = 0.006) during restriction, and less lipid during recovery (P = 0.05) than controls. There were no significant differences in hormone levels between groups. Multiple regression analysis with plasma insulin, estrogen, progesterone and urinary corticosterone as independent variables (r = 0.947, r2 = 0.897, P = 0.003) showed that plasma insulin was the only significant predictor (P < 0.01) of mammary cell proliferation. In accord with this observation, tyrosine-phosphorylated activation of insulin receptor substrate-1, detected by immunoprecipitation and Western immunoblot analysis in mammary tumors of WC rats from our previous study, was 3-5 times greater than in non-restricted controls (P < 0.01). Present findings suggest that weight cycling in rats increases risk of breast cancer development via insulin stimulated mammary cell proliferation.
Carcinogenesis 1997 Nov
PMID:Cyclic food restriction, insulin and mammary cell proliferation in the rat. 939 31

Hydroquinone, an intermediate used in the chemical industry and a metabolite of benzene, is a nephrocarcinogen in the 2-year National Toxicology Program bioassay in male Fischer 344 rats. Current evidence suggests that certain chemicals may induce carcinogenesis by a mechanism involving cytotoxicity, followed by sustained regenerative hyperplasia and ultimately tumor formation. Glutathione (GSH) conjugates of a variety of hydroquinones are potent nephrotoxicants, and we now report on the effect of hydroquinone and 2,3,5-(tris-glutathion-S-yl)hydroquinone, on site-selective cytotoxicity and cell proliferation in rat kidney. Male Fischer 344 rats (160-200 g) were treated with hydroquinone (1.8 mmol/kg or 4.5 mmol/kg, p.o.) or 2,3,5-(tris-glutathion-S-yl)hydroquinone (7.5 micromol/kg; 1.2-1.5 micromol/rat, i.v.), and blood urea nitrogen (BUN), urinary gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase (ALP), glutathione-S-transferase (GST) and glucose were measured as indices of nephrotoxicity. Hydroquinone (1.8 mmol/kg, p.o.) is nephrotoxic in some rats, but not others, but cell proliferation (BrDU incorporation) in proximal tubular cells of the S3M region correlates with the degree of toxicity in individual rats. At 4.5 mmol/kg, hydroquinone causes significant increases in the urinary excretion of gamma-GT, ALP and GST. Pretreatment of rats with acivicin prevents hydroquinone-mediated nephrotoxicity, indicating that toxicity is dependent on the formation of metabolites that require processing by gamma-GT. Consistent with this view, 2,3,5-(tris-glutathion-S-yl)hydroquinone, a metabolite of hydroquinone, causes increases in BUN, urinary gamma-GT and ALP, all of which are maximal 12 h after administration of 2,3,5-(tris-glutathion-S-yl)hydroquinone. In contrast, the maximal excretion of GST and glucose occurs after 24 h. By 72 h, BUN and glucose concentrations return to control levels, while gamma-GT, ALP and GST remain slightly elevated. Examination of kidney slices by light microscopy revealed the presence of tubular necrosis in the S3M segment of the proximal tubule, extending into the medullary rays. Cell proliferation rates in this region were 2.4, 6.9, 15.3 and 14.3% after 12, 24, 48 and 72 h, respectively, compared to 0.8-2.4% in vehicle controls. Together with the metabolic data, the results indicate a role for hydroquinone-thioether metabolites in hydroquinone toxicity and carcinogenicity.
Carcinogenesis 1997 Dec
PMID:Cytotoxicity and cell-proliferation induced by the nephrocarcinogen hydroquinone and its nephrotoxic metabolite 2,3,5-(tris-glutathion-S-yl)hydroquinone. 945 Apr 87

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.
Carcinogenesis 1998 Sep
PMID:Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy. 977 41

Energy metabolism of human colon cancer in vivo relies predominantly on glucose. Although studies have revealed increased expression of Glut1 mRNA in colon cancer, Glut1 protein (Glut1) expression in the large intestine and its significance are still unknown. The objective of this work was to determine whether Glut1 is present in human colorectal neoplasms and whether that presence is of biological significance. Formalin-fixed, paraffin-embedded tissue sections of 53 colonic adenocarcinomas, 82 adenomas, 46 hyperplastic polyps, and 38 normal colon samples were immunostained with the anti-Glut1 antibody MYM. The localization was carried out using the avidin-biotin immunoperoxidase technique. No Glut1 immunoreactivity was present in normal colonic mucosa or in hyperplastic polyps, whereas 8 (10%) of 82 adenomas showed such immunoreactivity. The frequency of Glut1 expression in adenomas increased with villous morphology and with the size of the adenoma. Forty-four (83%) of 53 colorectal adenocarcinomas expressed Glut1, and, of these, tumors in which >50% of the cancer cells expressed Glut1 had a significantly higher incidence of metastasis to the lymph nodes (P = 0.0001). It is concluded that (a) Glut1 is expressed as a late event in the carcinogenesis process in human colorectal cancer, and (b) expression of Glut1 in a high proportion of cancer cells is associated with a high incidence of lymph node metastases.
 ...
PMID:Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. 981 81


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