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)

A concise review of the literature that evaluates the risk of colorectal cancer among NSAID users has been presented. Animal studies document a protective effect of NSAIDs in preventing colorectal cancers in carcinogen-induced (AOM) models and in Min mice. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that these agents must be acting early in the adenoma-to-carcinoma sequence. Treatment of FAP patients with NSAIDs causes regression of adenomas that were already present before initiation of therapy. Many epidemiologic studies have examined the relationship between aspirin use and colorectal cancer. Most show a marked decrease in the relative risk (40% to 50%) of this tumor among continuous aspirin users. The appropriate dose and duration of aspirin treatment needed for optimal results are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is inhibition of cyclooxygenase. Presently, whether inhibition of COX-1 or COX-2 is required for the protective effect of aspirin and other NSAIDs is unclear. The authors and others have demonstrated that COX-2 is up-regulated from 2 to 50 fold in 85% to 90% of colorectal adenocarcinomas, making the COX-2 enzyme a more likely target. The authors have also reported a dramatic increase in COX-2 expression in colon tumors that develop in rats after AOM treatment. Drugs are currently being developed that preferentially inhibit either COX-1 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, these newly developed, selective NSAIDs may play a role in future chemoprevention strategies.
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PMID:Nonsteroidal anti-inflammatory drugs, eicosanoids, and colorectal cancer prevention. 896 Aug 92

The existence of two distinct isoforms of cyclooxygenase (COX), which convert arachidonic acid to prostanoids, is now well established. COX-1, which is constitutively expressed in many tissues (including the gastrointestinal tract, platelets, and kidney) is responsible for producing prostanoids that regulate normal housekeeping or physiologic functions. In contrast, COX-2 is the inducible form responsible for the production of prostanoids in response to a variety of evoking stimuli in different tissues and for mediation of inflammation and pain in certain diseases. Since the identification of COX-2, a great deal of research has been devoted to elucidating and understanding its molecular and physiologic characteristics. As a result of research into the differences between COX-1 and COX-2, new insights into the role of each isoform in normal homeostasis and in their responses to exogenous stimuli have emerged. Besides its induction in cells at inflammatory sites, COX-2 is known to be induced in the kidney in response to sodium depletion or in hyperfiltration states; in postsynaptic excitatory neurons in the brain after electroconvulsive stimulation, in the ovary and uterus during ovulation and implantation; in intestinal epithelium after bacterial infection; as well as in colon adenoma and carcinoma cells. These findings, largely from animal studies, have suggested a broader spectrum of biologic activity of COX-2 and potential alterations of specific physiologic or protective mechanisms by inhibition of COX-2, as well as potential new clinical targets of therapy with COX-2 inhibitors. As COX-2 appears to play an important role in pathologic processes other than pain and inflammation, ongoing research is investigating the potential utility of COX-2 inhibitors in other conditions, such as colonic polyposis, colorectal cancer, and Alzheimer's disease.
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PMID:Specific COX-2 inhibitors in arthritis, oncology, and beyond: where is the science headed? 1022 37

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumor cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulindac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC58560 on tumor cell growth in relation to COX-2 expression and prostaglandin production. To establish the role of COX-2 in NSAID action, we constructed clones expressing different levels of COX-2 from SW480 cells. All five compounds inhibited DNA synthesis and/or induced apoptosis, each with a characteristic pattern. ID(50)s were very similar in all the cell lines and were independent of COX expression, except for the COX-1 inhibitor SC58560, which was least effective in HT29/HI1, the cell line expressing the highest level of COX-1 (ID(50) 70 microM; in other cells lines the ID(50) was 15 microM). For all other compounds ID(50) concentrations varied less than two-fold: 25-40, 40-90 and 150 microM for SC236, sulindac sulfide and sulindac sulfone, respectively. SC58125 was the weakest inhibitor, never causing >50% cell loss. All compounds modulated expression of Bcl-2 and Bak and activated caspase 3. Overexpression of COX-2 in SW480 cells protected them against induction of apoptosis by sulindac sulfide. The effect was restricted to clones producing high levels of prostaglandin E(2). In summary, our data indicate that both COX-dependent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicating that the therapeutic effect of NSAIDs cannot be explained by a direct effect of NSAIDs on the epithelial cells alone. For therapeutic purposes, compounds using different targets could be used to minimize side effects while optimizing therapeutic effect.
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PMID:Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors. 1115 36

Colorectal cancer is an excellent model for studying cancer prevention by means of secondary (e.g., polypectomy to remove a precursor adenoma) and primary (chemoprevention) strategies. Evidence has shown that regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have a reduction in risk of colorectal cancer. A possible mechanism of this benefit is decreased prostaglandin production, which is achieved through inhibition of cyclooxygenase (COX) activity, and possibly other pathways. Two isoforms of COX--COX-1 and COX-2--have been identified. COX-2 is expressed in colorectal adenomas and carcinomas, both in humans and rodents. Inhibition of COX-2 has been shown to decrease the incidence of carcinogen-induced neoplasia in rats and to lower the incidence of adenomas in murine models. Several COX-2 inhibitors, with the potential for less toxicity than that associated with traditional NSAIDs, are under development. This paper reviews potential chemoprevention of colorectal cancer using COX-2 inhibitors in patients at increased risk, e.g., patients with familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and sporadic adenomas. Included are the rationale for use of such agents, results of a study showing a significant reduction in adenoma burden in familial adenomatous polyposis patients who received the selective COX-2 inhibitor celecoxib (Celebrex), and the design of other ongoing or planned clinical trials.
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PMID:COX-2 inhibition in clinical cancer prevention. 1130 36

The effects of indomethacin on A/J mice were investigated. The non-steroidal antiinflammatory drug (NSAID) indomethacin reduced significantly the number of lung adenomas 3, 4 or 8 months after urethane injection by 28, 30 and 29% respectively. The density of apoptotic cell bodies increased 2.9-fold in the lung adenomas of A/J mice treated with indomethacin. By immunocytochemistry, COX-2 immunoreactivity was present in the cytosol of lung adenomas, and in epithelial cells lining the bronchioli and bronchus as well as type 2 alveolar cells. COX-1 immunostaining was similar to that of COX-2 in the lungs of urethane-injected mice treated with or without indomethacin. By RT-PCR, COX-1 and COX-2 PCR products were present in mouse lung adenomas, alveoli and bronchioli. These results suggest that indomethacin may inhibit COX-1 and COX-2 in the A/J mouse lung resulting in reduced adenoma formation.
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PMID:Indomethacin reduces lung adenoma number in A/J mice. 1149 55

It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases maybe avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2. Epidemiological studies showed a lower risk of developing cancer of the colon, breast, esophagus, and stomach following the ingestion of NSAIDs. The use of NSAIDs in low dose was associated with a statistically significant decrease in the risk of adenomatous polyps and of overt colon cancer. The regressive effects of sulindac on foci of aberrant crypts in the colon (considered to be precursors of adenoma), and on adenocarcinoma of the colon, are of particular interest because this NSAID does not have an inhibitory effect on COX. This may support the view that the antineoplastic effect of NSAIDs may also be due to a mechanism other than COX-2 inhibition. In breast cancer, large cohort studies reported a 40 to 50% reduced risk of developing cancer, a smaller size of the primary tumor, and a reduction in the number of involved axillary lymph nodes. Similar findings have been reported in the esophagus and stomach, but not in gastric cardia adenocarcinoma. The recent development of selective COX-2 inhibitors resulted in better clinical tolerance than that associated with NSAIDs in general, with the absence of gastrointestinal side effects known to occur after the inhibition of COX-1. Encouraging results have been obtained with these new agents in familial adenomatous polyposis, colon, breast, and prostate cancer.
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PMID:Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks. 1208 6

In the third millennium, preventive medicine is becoming a cornerstone in our concept of health. Colorectal cancer (CRC) prevention, in particular, has become an important goal for health providers, physicians and the general public. CRC fits the criteria of a disease suitable for chemopreventive interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths expected, worldwide, in 2004. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 15-20 years, providing a window of opportunity for effective interventions and prevention. A pre-malignant precursor lesion (i.e. adenoma) usually precedes cancer, and helps to identify a subset of the population that is at increased risk of harbouring and developing cancer. Science and technology have evolved to a point where we are able to use our knowledge of cancer biology to identify individuals at risk and interrupt the process of malignant transformation at the level of the pre-cancerous lesion. Recent progress in molecular biology and pharmacology enhances the likelihood that cancer prevention will increasingly rely on chemoprevention. Chemoprevention, a new emerging science, means the use of agents to inhibit, delay or reverse carcinogenesis. Recent observations suggest a number of potential targets for chemoprevention. Many agents have potential benefit but only modest chemopreventive efficacy in clinical trials. There is much evidence suggesting an inverse relationship between aspirin or non-steroidal anti-inflammatory drug (NSAID) consumption and CRC incidence and mortality. However, NSAID consumption is not problem-free; 1997 data show 107,000 hospitalisations and 16,500 deaths due to NSAID consumption in the U.S. alone. Therefore, although chemoprevention of CRC is already possible, drugs that have more acceptable side-effect profiles than the currently available NSAIDs are required. Cyclo-oxygenase (COX)-2-specific inhibitors, which have an improved safety profile compared to traditional NSAIDs that inhibit both the COX-1 and COX-2 enzymes, seem to be well-suited drug candidates for CRC prevention. The inhibition of the growth of pre-cancerous and cancerous cells without affecting normal cells is the ultimate aim of cancer treatment and is of particular importance in chemoprevention studies, which may be long term in nature, involving healthy subjects and minimal toxicity. Cancer prevention is certain to be a significant focus of research and intervention in the coming years, propelled by the realisation that we will be able to identify both individuals susceptible to specific cancers as well as the molecular targets that can alter or stop the carcinogenesis process. Pharmacology and genetics are collaborating to develop new chemoprevention agents designed to affect molecular targets linked to specific premalignant or predisposing conditions.
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PMID:Chemoprevention of colorectal cancer: ready for routine use? 1564 92

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

In the third millennium preventive medicine is becoming a corner stone in our concept of health. Colorectal cancer (CRC) prevention, in particular, has become an important goal for health providers, physicians and the general public. CRC fits the criteria of a disease suitable for chemopreventive interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths expected, worldwide, in 2004. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 15-20 years, providing a window of opportunity for effective interventions and prevention. A pre-malignant precursor lesion (i.e., adenoma) usually precedes cancer, and helps to identify a subset of the population that is at increased risk of harbouring and developing cancer. Science and technology have evolved to a point where we are able to use our knowledge of cancer biology to identify individuals at risk and interrupt the process of malignant transformation at the level of the pre-cancerous lesion. Recent progress in molecular biology and pharmacology enhances the likelihood that cancer prevention will increasingly rely on chemoprevention. Chemoprevention, a new emerging science, means the use of agents to inhibit, delay or reverse carcinogenesis. Recent observations suggest a number of potential targets for chemoprevention. Many agents have potential benefit, but only modest chemopreventive efficacy in clinical trials. There is much evidence suggesting an inverse relationship between aspirin or NSAIDs consumption and CRC incidence and mortality. However, NSAID consumption is not problem-free, as 1997 data showed 107,000 hospitalisations and 16,500 deaths due to NSAIDs consumption in the US alone. Therefore, although chemoprevention of CRC is already possible, drugs that have more acceptable side-effect profiles than the currently available NSAIDs are required. COX-2-specific inhibitors, which have an improved safety profile, as compared to traditional NSAIDs that inhibit both the COX-1 and COX-2 enzymes, seem to be well suited drug candidates for CRC prevention. The inhibition of the growth of pre-cancerous and cancerous cells without affecting normal cells is the ultimate aim of cancer treatment and is of particular importance in chemoprevention studies, which may be long term in nature, involve healthy subjects and minimal toxicity. Cancer prevention is certain to be a significant focus of research and intervention in the coming years, propelled by the realization that we will be able to identify both individuals susceptible to specific cancers as well as the molecular targets that can alter or stop the carcinogenesis process. Pharmacology and genetics are collaborating to develop new chemoprevention agents designed to affect molecular targets linked to specific pre-malignant or predisposing conditions.
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PMID:Chemoprevention of colorectal cancer: ready for routine use? 1597 46

While brown rice is a staple dietary constituent in Asia, rice consumed in the Western world is generally white, obtained from brown rice by removal of the bran. Rice bran contains the flavone tricin, which has been shown to inhibit colon cancer cell growth. We tested the hypothesis that tricin interferes with adenoma formation in the Apc(Min) mouse. Mice received tricin (0.2%) in their American Institute of Nutrition 93G diet throughout their postweaning life span (4-18 weeks). Consumption of tricin reduced numbers of intestinal adenomas by 33% (P < 0.05) compared with mice on control diet. We explored whether tricin may exert its effect via inhibition of cyclooxygenase (COX) enzymes. Its effect on COX activity was assessed in purified enzyme preparations in vitro and its ability to reduce prostaglandin E(2) (PGE(2)) levels in human colon-derived human colon epithelial cell (HCEC) and HCA-7 cells in vitro and in Apc(Min) mice in vivo. Tricin inhibited activity of purified COX-1 and COX-2 enzyme preparations with IC(50) values of approximately 1 micromol/L. At 5 micromol/L, it reduced PGE(2) production in HCEC or HCA-7 cells by 36% (P < 0.01) and 35% (P < 0.05), respectively. COX-2 expression was reduced by tricin weakly in HCEC and unaffected in HCA-7 cells. PGE(2) levels in the small intestinal mucosa and blood of Apc(Min) mice that had received tricin were reduced by 34% (P < 0.01) and 40% (P < 0.05), respectively, compared with control mice. The results suggest that tricin should be further evaluated as a putative colorectal cancer chemopreventive agent.
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PMID:The rice bran constituent tricin potently inhibits cyclooxygenase enzymes and interferes with intestinal carcinogenesis in ApcMin mice. 1617 19


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