Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiologic studies indicate strongly that aspirin use reduces the risk of colorectal cancer and adenoma by approximately 40 to 50%. Perhaps up to ten years of use may be required before a benefit is apparent in colorectal cancer. The chemo-preventive actions of aspirin and other non-steroidal anti-inflammatory agents (NSAIDs) in colorectal carcinogenesis are also supported by animal studies, and by intervention studies that demonstrate that the anti-inflammatory agent sulindac causes regression of adenomas in familial adenomatous polyposis. Despite this evidence, the clinical implications are not clear because of increased gastro-intestinal irritation and bleeding episodes related to chronic aspirin use. Emerging evidence suggests that the anti-tumor properties of NSAIDs may be related primarily to the inhibition of cyclooxygenase-2 (COX-2), one of the two isoenzymes of the COX enzyme family. If confirmed, a new generation of selective COX-2 inhibitors may retain some of the chemo-preventive properties of NSAIDs with fewer side-effects. Firm recommendations regarding the use of aspirin or other NSAIDs to prevent colorectal cancer must await further research. For now, the decision must lie with the patient, in consultation with his or her healthcare provider, after a careful weighing of all potential risks and benefits.
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PMID:The prevention of colorectal cancer by aspirin use. 1047 28

Two isoforms of prostaglandin H synthase (PTGS = COX) are key enzymes in prostaglandin synthesis and primary targets for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Use of aspirin or other NSAIDs is associated with a lower risk and reduced recurrence of colorectal adenomas, established precursors of adenocarcinoma. This study investigated risk of colorectal adenomatous and hyperplastic polyps associated with several polymorphisms in the coding region of PTGS1. Within the Minnesota polyp case-control study, patients with colorectal adenomatous (n = 521) or hyperplastic (n = 194) polyps and n = 621 polyp-free controls were genotyped for four PTGS1 polymorphisms (R8W, L15-L16del, P17L, L237M); these had been predicted to affect protein function based on sequence-homology software. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed. Whereas there was no appreciable difference in adenoma or hyperplastic polyp risk associated with R8W, P17L, and L237M, an increased risk was observed for individuals heterozygous for the L15-L16del polymorphism (OR = 3.6, 95% CI 1.2-11.2). The variant L15-L16del allele appeared to be associated with a stronger increase in adenoma risk among nonusers of aspirin/other NSAIDs. The reduced risk observed with aspirin/other NSAID use was limited to those wild type for P17L [PP users: OR = 0.6 (0.5-0.8) versus PP nonusers: 1.0 (referent) (P interaction = 0.03)]. To our knowledge, this study represents the first investigation of polymorphisms in PTGS1 and risk of colorectal polyps. The L15-L16del variant allele may result in an increased risk of colorectal adenomas, whereas P17L may be relevant to the pharmacogenetics of aspirin. These preliminary findings require confirmation in larger studies of colorectal neoplasia.
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PMID:Polymorphisms in PTGS1 (=COX-1) and risk of colorectal polyps. 1515 24

Fatty acid hydroperoxides arise from unsaturated fatty acids in the presence of oxygen and elevated temperature during processing of food. Here we have studied their effects on gene expression in colorectal tumor cells using linoleic acid hydroperoxide (LOOH) as a model compound. Its addition to the medium of LT97 human adenoma cells and SW480 human carcinoma cells enhanced the production of intracellular hydrogen peroxide. Furthermore, in both cell lines, increases in VEGF mRNA and protein were observed. Unoxidized linoleic acid had little or no activity. Concomitantly, COX-2 expression was up-regulated. In the LT97 cells, the COX inhibitors SC58560 and SC58236 completely prevented the VEGF induction, suggesting that the effect was dependent on prostaglandin synthesis. In vivo prostaglandin-mediated induction of VEGF secretion is known to be essential for the growth of adenomatous polyps and their progression to carcinomas. Therefore, our results for the first time implicate dietary lipid hydroperoxide as a key risk factor in colon carcinogenesis.
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PMID:Dietary lipid hydroperoxides induce expression of vascular endothelial growth factor (VEGF) in human colorectal tumor cells. 1552 6

Nonsteroidal antiinflammatory drugs (NSAIDs) are postulated to protect against colorectal cancer and adenomas at least in part by a cyclooxygenase (COX-mediated mechanism. The results reported herein address the questions of what factors are associated with expression (relative messenger RNA levels) of COX-1 and COX-2 in colorectal adenomas and whether there is heterogeneity in the protective effect of NSAIDs by levels of COX expression. Paraffin-embedded tissue samples and data describing selected risk factors were obtained from cases enrolled in a case-control study of colorectal adenomatous polyps. RNA was isolated from paraffin-embedded specimens. Samples of complementary DNA were quantified using a fluorescence-based real-time detection method. We tested for differences in levels of COX expression among selected subgroups of cases using a standard Student t test. Odds ratios for the effects of NSAID variables were calculated using unconditional logistic regression in order to make use of all available data on COX expression. Results suggest that use of NSAIDs is associated with lower levels of COX-2 expression and that the protective effect of NSAIDs on polyp occurrence is stronger in the subgroup of cases with higher expression of COX-2 and a higher COX-2/COX-1 ratio. The results suggest that at least part of the protective effect of NSAIDs on the risk of colorectal adenoma involves a COX-mediated pathway.
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PMID:A molecular/epidemiologic analysis of expression of cyclooxygenases 1 and 2, use of nonsteroidal antiinflammatory drugs, and risk of colorectal adenoma. 1580 32

Overexpression of cyclooxygenase-2 (COX-2) is observed early in colon cancer. Treatments with COX-2-specific NSAIDs have been shown to reduce polyp size and polyp number in FAP patients with a predisposition to colorectal adenoma and cancer. However, the use of COX-2-specific NSAIDs in colon cancer patients has recently revealed increased cardiovascular risks. These harmful side effects may be the result of COX-dependent and/or COX-independent mechanisms. RNA interference (RNAi) is a method of post-transcriptional gene silencing intrinsic to cells. This study employed RNAi to specifically knockdown endogenous COX-2 expression in the HT-29 colon cancer cell line, and to observe the apoptotic response as well as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression levels. Following treatment with a COX-2 siRNA, we demonstrated a significant knockdown at the protein level of 57% as compared to a non-silencing siRNA control. Protein results were corroborated by concurrent decrease in COX-2 mRNA levels following the same treatment regimen. Despite previous studies using NSAID treatment to implicate COX-2 involvement in apoptosis, we did not observe any alteration in Bcl-2 expression and Caspase-3 activation following COX-2 knockdown in these cells. 15-PGDH, a physiological antagonist of COX-2 in its catabolism of PGE2, showed a modest but significant induction in response to COX-2 knockdown. The precise role of COX-2 in apoptosis and PGE2 regulation remains unclear; however, having shown that down-regulation of endogenous levels of COX-2 can be achieved in colon cancer by RNAi, this strategy should prove to be a valuable tool in revealing the specific function of COX-2 in tumourigenesis.
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PMID:Cyclooxygenase-2 knockdown by RNA interference in colon cancer. 1639 11

High consumption of dietary fat promotes colon carcinogenesis. While this effect is well known the underlying mechanism is not understood. Fatty acid hydroperoxides (LOOH) arise from unsaturated fatty acids in the presence of oxygen and elevated temperature during food processing. An approach was made starting from the assumption that LOOH are present in dietary fats as a result of boiling. LOOH undergoes homolytic cleavage in the presence of iron. We studied their effects on gene expression in colorectal tumour cells using linoleic acid hydroperoxide (LOOH) as model compound. Addition to the medium of LT97 adenoma and SW480 carcinoma cells enhanced the production of hydrogen peroxide. Both cell lines were observed to increase VEGF and COX-II expression based on mRNA. Expression of VEGF was inhibited by caroverine and ubiquinon.
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PMID:Ubiquinol and the papaverine derivative caroverine prevent the expression of tumour- promoting factors in adenoma and carcinoma colon cancer cells induced by dietary fat. 1687 33

The inducible prostaglandin synthase isoform cyclooxygenase-2 (COX-2) is overexpressed in approximately 40% of human breast carcinomas and in precancerous breast lesions, particularly in association with overexpression of human epidermal growth factor receptor 2 (HER2/neu). Experimental breast cancer can be suppressed by pharmacologic inhibition or genetic ablation of Cox-2, suggesting potential clinical utility of COX-2 inhibitors with respect to breast cancer. Importantly, several clinical trials have found reduced colorectal adenoma formation in individuals administered selective COX-2 inhibitors. However, such trials also identified increased cardiovascular risk associated with COX-2 inhibitor use. The goal of this research was to test whether improved chemopreventive efficacy could be achieved by combining submaximal doses of a selective COX-2 inhibitor and a retinoid X receptor-selective retinoid (rexinoid). The rate of HER2/neu-induced mammary tumor formation was substantially delayed by coadministration of the COX-2 inhibitor celecoxib (500 ppm in diet) and the rexinoid LGD1069 (10 mg/kg body weight; oral gavage) to MMTV/neu mice. Median time to tumor formation was increased from 304 to >600 days (P < 0.0001). The combination was substantially more effective than either drug individually. Similarly, potent suppression of aromatase activity was observed in mammary tissues from the combination cohort (44% of control; P < 0.001). Regulation of aromatase expression and activity by COX-derived prostaglandins is well established. Interestingly however, single agent LGD1069 significantly reduced mammary aromatase activity (71% of control; P < 0.001) without modulating eicosanoid levels. Our data show that simultaneous blockade of COX/prostaglandin signaling and retinoid X receptor-dependent transcription confers potent anticancer efficacy, suggesting a novel avenue for clinical evaluation.
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PMID:Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid. 1913 58

Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11betaHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11betaHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity.
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PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. 1934 44

The Silent Corticotroph Adenoma (SCA) is a pituitary adenoma variant characterized by the immunoreactivity for adrenocorticotropic hormone (ACTH) and related peptides, without the clinical signs of Cushing's disease. SCA has been postulated to either secrete structurally abnormal ACTH that is inactive but detectable by immunohistochemistry or radioimmunoassay, or to secrete ACTH intermittently or at low levels continuously. Excess of ACTH has been associated to type II muscle atrophy. We describe a case of type II muscle fibers atrophy associated with silent corticotroph adenoma in a dog. The dog showed moderate to severe proximal muscle wasting and weakness with normal levels of muscle-associated enzymes. In the limb muscle biopsies, type II fibers were uniformly smaller than type I fibers. In temporalis muscles, there were few atrophic fibers, and several irregular areas of loss of enzymatic activity observed in NADH, SDH and COX stains. The tumour showed a trabecular growth pattern and immunohistochemical analysis demonstrated the presence of cytoplasmic immunoreactivity for ACTH. The muscle atrophy was considered to be related to an excess of inactive ACTH. Studying spontaneous occurring rare diseases in animals could help to understand the mechanism of similar diseases in human has well.
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PMID:Type II muscle fibers atrophy associated with silent corticotroph adenoma in a dog. 2107 46

Colorectal cancer (CRC) is one of the leading causes of mortality in the western world. It is widely accepted that neoplasms such as colonic polyps are precursors to CRC formation; with the polyp-adenoma-carcinoma sequences well described in medical literature [1, 2]. It has been shown that Aspirin and other non-steroid anti-inflammatory drugs (NSAID) have a negative effect on polyp and cancer formation. This review aims to describe some of the mechanism behind the chemoprotective properties of aspirin; COX 2 inhibition, regulation of proliferation and apoptosis and effects on the immune system and also the current evidence that supports its use as a chemoprevention agent against CRC. We will also aim to explore the side effects with the use of aspirin and the pitfalls of using aspirin routinely for primary prophylaxis against CRC.
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PMID:Aspirin as a chemoprevention agent for colorectal cancer. 2249 84


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