Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biologically significant levels of IL-2 activity were produced by isolated lamina propria mononuclear cells (LPMC) from normal intestine (n = 12), cancer-bearing colons (n = 35) and inflammatory bowel disease (IBD) affected tissue (n = 12). The levels of IL-2 produced were similar for all three sources of LPMC (normal 252 +/- 48 U/ml, IBD-affected mucosa 197 +/- 42 U/ml and colon cancer 285 +/- 43 U/ml). These levels were significantly greater than those produced by peripheral blood mononuclear cells (20 +/- 5 U/ml, P less than 0.01) on a per cell basis. In mucosa from cancer-bearing colons the amount of IL-2 produced by LPMC was unaffected by the invasiveness of the colon cancer. LPMC IL-2 production was markedly suppressed by drugs used in IBD therapy. 5-Aminosalicylic acid (5-ASA) reduced activity in a dose-dependent fashion. At a dose equivalent to the faecal therapeutic level of 0.5 mg/ml activity, IL-2 production by LPMC was suppressed to 3.4% of controls. Similarly, exposure of LPMC to cyclosporin A (CyA) and hydrocortisone (HC) at therapeutic levels reduced IL-2 activity to less than 1% of controls. The major producers of IL-2 activity were shown to be CD3+ T lymphocytes and those bearing the activation markers IL-2R and TFR. Suppression of mucosal IL-2 production represents an important therapeutic mechanism of drugs used in the management of IBD including HC, 5-ASA and CyA. These results suggest that mucosal T cells produce appreciable levels of IL-2 activity that may be important in maintaining immune homeostasis in the normal intestine, provide anti-neoplastic cytotoxic activity and contribute to the inflammatory events that characterize the mucosal lesions of IBD.
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PMID:IL-2 production by intestinal lamina propria cells in normal inflamed and cancer-bearing colons. 156

One-stage subtotal colectomy of an acutely obstructed left colon would improve quality of life while shortening the length of hospitalization. Prohibitive mortality rates, however, are ascribed to such an approach. Analyzing the Senior Author's experience we compared the one-stage approach versus the multi-stage resections concerning operative mortality and morbidity rates and the duration of hospitalization. Forty-nine of 291 (17%) large bowel cancers presented acute left-sided obstruction requiring emergency surgery. Colostomy alone was performed in 18 (37%), multi-stage colectomy in 20 (41%, Group A) and one-stage subtotal colectomy in 11 (22%, Group B, all of them after 1979), the years under scrutiny being from 1973 through Sept. 1990. Both groups were comparable in age and sex distribution, TNM staging and ASA classification. Operative mortality and morbidity rates were 10% and 30% in Group A, 9% and 18% in Group B, respectively. The average length of hospitalization was 21.25 days (14-30) in Group A, 9.18 days (7-14) in Group B. Whenever an experienced surgical team is available and in the absence of contra-indications (local factors precluding a swift dissection, hemodynamic instability, gangrenous bowel) a one-stage subtotal colectomy, taking advantage of a better healing ileo-sigmoid or ileo-rectal anastomosis, carries acceptable mortality and morbidity rates while enhancing the quality of life and shortening the length of hospitalization. It should be considered the choice procedure, provided selection requirements and technical demands are met. An evaluation of the Senior Author's team experience (1973-90) in the management of acutely obstructing left colon cancer (49/291 or 17%) provides information on multi-stage resections and one-stage subtotal colectomy (Group A and B) as regards operative mortality (10% in Group A, 9% in Group B) as well as length of hospitalization (21 days in Group A, 9 days in Group B).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Surgical management of acute, malignant obstruction of the left colon with colostomy]. 178 65

Epidemiological studies have suggested that increased intake of calcium (Ca) or aspirin (ASA) is associated with a reduced risk for colon cancer. To delineate a possible mechanism of action, the present study used male F344 rats in an azoxymethane (AOM)-induced colon tumor model to study the single and interactive effects of Ca and ASA on cholic acid-promoted experimental colon carcinogenesis. Following initiation with AOM, a promotion diet containing 0.5% cholic acid was fed for 34 weeks until the adenoma development stage. Cholic acid was used as a surrogate for high-fat diets and to promote carcinogenesis. Diets were supplemented with CaCO3 (2% Ca by weight), 250 p.p.m. ASA, or both. After 34 weeks, the diets were switched during the progression stage and rats were killed at week 51. Several intermediate endpoints were examined during the course of AOM carcinogenesis to determine their reliability as predictors of colon cancer risk. Intermediate endpoints included colon crypt height measurement, colon mucosal ornithine decarboxylase (ODC) and colon mucosal protein kinase C (PKC) activities. The biomarkers were examined at the beginning of the study at 2 weeks, and thereafter at 5, 15, 30 and 40 weeks of dietary treatment. Animals were necropsied at week 51 and tumor incidence and numbers were analyzed for correlation with biomarkers. Survival was highest in the group fed CaCO3 during the promotion stage and tumor burden was lowest in groups fed CaCO3 during this stage. Supplementation during the progression stage was ineffective. The cholic acid promotion model resulted in increased ODC which was inhibited by intervention during the promotion stage with Ca, but not ASA. PKC was also activated by cholic acid feeding, and this effect was modulated by intervention in the promotional stage with Ca or ASA. Colon tumor incidence and burden was increased by cholic acid promotion and decreased by Ca, but not affected by ASA. In summary, Ca is a more effective chemopreventive agent in cholic acid-promoted colon carcinogenesis than ASA, impacting both incidence and tumor number. Colonic ODC, but not PKC may be a suitable predictor of risk and response in chemoprevention trials for colon cancer.
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PMID:Chemopreventive effects of calcium but not aspirin supplementation in cholic acid-promoted colon carcinogenesis: correlation with intermediate endpoints. 772 52

A retrospective analysis was carried out on 56 pts., (37 M, 19 F), mean age 64 yrs., operated for moderate to severe obstruction due to left colon carcinoma. Clinical and pathological features, treatment and results were compared with those of 108 pts. with left colon cancer who underwent elective surgery. Mean duration of obstructive symptoms was 5.3 days and mean delay between admission and operation was 1.15 days. Site and nature of the obstruction were assessed pre-operatively in 80.3% of the pts. Distribution of tumor localization was similar in the two groups. ASA risk was statistically higher in pts. with obstruction. Staging according to the Astler-Coller (mod. 1978) classification, showed a greater incidence of more advanced stages in the obstructing tumors. In the group with obstruction a three stage surgery was carried out in 18 pts. (32.1%), a two stage in 6 (10.7%), a primary resection in 6 (10.7%) and a decompressive colostomy in 26 (46.5%). Radicality and resectability rates were 50% and 53.6% vs 69.4% and 82.4% in elective surgery. Mean post-operative stay was 42 and 21 days respectively in the two groups. Overall post-operative death rate was 19.6% vs 9.2%, and 3.3% vs 7.8% after resective surgery. Post-operative complications accounted for 21.4% vs 21.3%. 5-year survival rate after curative surgery was 47.8% vs 76.8%. On the basis of their results and on Literature reports the Authors suggest a reevaluation of a staged surgical treatment for obstructing left colon cancer based on primary decompression following an E.L. when needed. Consequent resection and intestinal reconstruction should be performed after 2-3 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Surgery of the obstructive complication of carcinoma of the left colon. The clinical problems and the authors' personal experience with 56 surgical cases]. 784 71

Aspirin and other NSAIDs reduce the incidence of and mortality from colon cancer, but their mechanism of action remains unknown. We evaluated the effect of aspirin (ASA) and three other structurally unrelated NSAIDs (indomethacin, naproxen, and piroxicam) on cell proliferation, cell cycle phase distribution, and the development of apoptosis in HT-29 colon adenocarcinoma cells in vitro. All of the NSAIDs examined reduced the proliferation and altered the morphology of these cells in a time- and concentration-dependent manner. In addition, they altered the cell cycle phase distribution of these cells. They increased the proportion of cells in the G0/G1 phase and reduced the proportion in the S phase of the cell cycle. ASA and indomethacin also reduced the percentage of cells in the G2/M phase, whereas naproxen and piroxicam did not. Parallel to their effect on cell cycle, ASA and indomethacin also reduced the levels of p34cdc2 and p33cdk2, two cyclin-dependent kinases that are important for cell cycle progression. Finally, all the NSAIDs analyzed, except ASA, induced apoptosis in these cells. There as a rough correlation between the relative potency of these compounds in inducing apoptosis and their effectiveness in retarding cell proliferation. Our findings indicate that NSAIDs can reduce the proliferation of HT-29 colon cancer cells in vitro. In addition, they cause cell cycle quiescence and apoptosis, both of which could account for their anti-proliferative effect. These findings suggest possible mechanisms for the cancer preventive effects of these compounds in humans.
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PMID:Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: effects on cell cycle and apoptosis. 854 62

Aspirin (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal tumorigenesis. Apoptosis is a critical determinant of tissue mass homeostasis and may play a role in carcinogenesis. We studied the effect of ASA on the survival of a human colon cancer cell line using more sensitive methods than we had applied previously. ASA induced apoptosis in HT-29 colon adenocarcinoma cells at concentrations > or =1 mM as established by: (a) morphological changes consistent with apoptosis in cells examined by fluorescence microscopy and semi-thin cell sections, and (b) DNA strand breaks: 45% of the cells were TdT-mediated dUTP nick end labeling (TUNEL) positive at 3 mM at 72 hr, and 70% were positive by the comet assay. Electron microscopy also confirmed the induction of apoptosis by ASA. ASA-induced apoptosis was not associated with: (a) a ladder pattern on genomic DNA electrophoresis, or (b) a subdiploid peak on flow cytometry. Apoptotic bodies were virtually absent on standard morphological assessments and only a few were detected on semi-thin sections. For the above reasons, this apoptosis induced by ASA is "atypical," and the unusual features of ASA-induced apoptosis, besides their taxonomic value, may offer clues to the mechanisms that control the process of apoptosis or perhaps the cancer chemopreventive properties of this compound. These findings demonstrate that ASA induces apoptosis in human colon cancer cells, bolstering the hypothesis that apoptosis may be a mechanism by which NSAIDs inhibit colon carcinogenesis. These findings should be examined in animal and/or clinical research studies in vivo.
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PMID:Effect of aspirin on induction of apoptosis in HT-29 human colon adenocarcinoma cells. 941 30

Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin have been shown to suppress colon carcinogenesis and in some cases reduce the size of colorectal polyps. Balsalazide disodium (BSZ) is a colon-specific prodrug of the salicylate, 5-aminosalicylic acid. The aim of the present study was to test the chemopreventive activity of BSZ in two established animal models of colon tumorigenesis, azoxymethane-induced aberrant crypt formation in the rat and intestinal tumor formation in the B6-Min/+ mouse. Aberrant crypt foci (ACF) were induced in Fischer 344 rats via 2 subcutaneous injections of azoxymethane (20 mg/kg). BSZ was supplied in the drinking water for 8 weeks and ACF quantitated. B6-Min/+ mice were treated from 55 days of age for 90 days and intestinal tumors scored for number, size and location. BSZ treatment of AOM-injected rats reduced ACF formation in a dose-dependent manner by 60% with the greatest effect observed on ACF with 4 or more crypts. In B6-Min/+ mice a dose-dependent reduction of intestinal tumor number was observed which reached 80% in the distal small intestine and colon. A preliminary mechanistic study in cultured human colon cancer cells showed that both BSZ and 5-ASA inhibited colon cancer cell proliferation in vitro. However, 5-ASA but not BSZ produced changes consistent with the induction of apoptosis. BSZ produces a dose-dependent chemopreventive effect on colon carcinogenesis. A possible mechanism is consistent with the inhibition of cellular proliferation and the induction of apoptosis.
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PMID:Chemoprevention of colon cancer carcinogenesis by balsalazide: inhibition of azoxymethane-induced aberrant crypt formation in the rat colon and intestinal tumor formation in the B6-Min/+ mouse. 1085 36

Bile acids enhance colon carcinogenesis in animal models, whereas ursodeoxycholic acid (UDCA) suppresses it. Nonsteroid anti-inflammatory drugs prevent colon cancer development in animals and humans. The aim of the present study was to explore the inhibitory effect of UDCA conjugate with 5-aminosalicylic acid (5-ASA), UDCA-5-ASA conjugate (UDCA-5-ASA), against colon carcinogenesis in rats. One-hundred-and-twenty-nine 7-week-old F344 rats received an intrarectal instillation of 2 mg of N-methylnitrosourea 3 times a week for 3 weeks, and were fed a 0% (control), 0.11% or 0.02% UDCA-5-ASA-, 0.08% UDCA- or 0.03% 5-ASA-supplemented diet for the next 27 weeks. The test diets contained an equimolar amount of a test agent, 2.0 mmol/kg diet, except for the 0.02% UDCA-5-ASA diet. The tumor incidence and the mean number of tumors/rat at week 30 were significantly lower and smaller in the UDCA-5-ASA diet groups, 48% and 0.7 in both, and marginally lower in the UDCA and 5-ASA diet groups, 56% and 0.9, and 64% and 0.8, compared to the control group, 83% and 1.3. All the tumors were polypoid in shape, and most of them were differentiated adenocarcinomas restricted to the mucosa or submucosa. An analysis by HPLC for bile acids and 5-ASA in the feces and serum collected at week 30 showed that one-half of ingested UDCA-5-ASA was cleaved into UDCA and 5-ASA in the colon. Thus, the two moieties may have independently affected the promotion stage of carcinogenesis.
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PMID:Chemoprevention of N-methylnitrosourea-induced colon carcinogenesis by ursodeoxycholic acid-5-aminosalicylic acid conjugate in F344 rats. 1185 77

Dysregulation of the Wnt pathway and altered Beta-catenin expression are central early events in colorectal carcinogenesis. We studied the ortho, meta, and para (o-, m-, and p-) positional isomers of NO-donating aspirin (NO-ASA), a chemopreventive agent against colon cancer, for their effect on Beta-catenin/T cell factor (TCF) signaling. In human SW480 colon carcinoma cells, cell-growth inhibition by NO-ASA [IC50 values for p-, o-, and m- were 48.1 +/- 4.3 (mean +/-SEM), 60.4 +/- 2.1, and 900 +/-50 microM, respectively] was accompanied by significant inhibition of Beta-catenin signaling. We determined Beta-catenin-dependent TCF-4 transcriptional activity by measuring the activity of the luciferase gene placed under the control of TCF-4 regulatory sequences. The IC50 values for Beta-catenin/TCF-4-signaling inhibition by NO-ASA were: o-, 2.6 +/- 0.4; m-, 15 +/- 5; p-, 1.1 +/- 0.1 microM; and for ASA, >5,000 microM. Total or nuclear levels of Beta-catenin and its distribution in the cell were not altered by NO-ASA, as judged by protein expression levels and semiquantitative immunofluorescence analysis. NO-ASA disrupted the association of Beta-catenin and TCF-4 in the nucleus, whereas ASA did not affect it. NO-ASA reduced the expression of cyclin D1, a downstream target gene that plays an important role in colon carcinogenesis. In contrast, a structural analog of NO-ASA lacking the -NO2 moiety did not affect TCF-4 transcriptional activity. Thus, NO-ASA inhibits Beta-catenin-mediated TCF activity by preventing the formation of the Beta-catenin/TCF-4 complex. This effect, occurring at NO-ASA concentrations far below those required to inhibit cell growth, may be a critical early event in the chemopreventive activity of NO-ASA against colon cancer.
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PMID:Nitric oxide-donating aspirin inhibits beta-catenin/T cell factor (TCF) signaling in SW480 colon cancer cells by disrupting the nuclear beta-catenin-TCF association. 1456 53

Nitric oxide (NO)-releasing aspirin (ASA), consisting of a traditional ASA molecule to which a NO-donating moiety is covalently bound, is a promising colon cancer chemopreventive agent. NO-ASA inhibits colon cancer cell growth more potently than ASA by inhibiting cell proliferation and enhancing cell killing. We examined in cultured human colon cancer cells the effect of NO-ASA on the beta-catenin/T-cell factor signaling pathway, nuclear factor-kappaB, and NO synthase 2 and on cyclooxygenase (COX) expression, all presumed to participate in colon carcinogenesis. Besides inhibiting cell growth, NO-ASA inhibited the beta-catenin/T-cell factor signaling pathway (IC(50), 1.1 microM), nuclear factor-kappaB DNA binding (IC(50), 7.5 microM), and NO synthase 2 expression (IC(50), 2 microM). Interestingly, NO-ASA induced COX-2 expression, although it had no effect on COX-1. COX-2 induction was accompanied by increased prostaglandin E(2) production. These effects occurred at NO-ASA concentrations below or near its IC(50) for cell growth (IC(50), 2-50 microM). The metabolism of NO-ASA by these cells is characterized by a rapid deacetylation step and the formation of a conjugate with glutathione. NO-ASA had no effect on intracellular cyclic GMP concentrations. We propose a model incorporating the pleiotropic effects of NO-ASA on cell signaling and postulate that collectively these effects may contribute to its strong chemopreventive effect.
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PMID:Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition: implications for chemoprevention. 1463 77


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