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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological and animal studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce colon cancer risk. NSAIDs nonselectively inhibit both the constitutive cyclooxygenase (COX) 1 associated with side effects and the desired therapeutic target COX-2, which is induced in inflammation and neoplasia. We used the adenomatous polyposis coli (Apc) mutant Min mouse model to determine whether the selective COX-2 inhibitor celecoxib is effective for adenoma prevention and/or regression, and whether it might be safer than the nonselective NSAID previously shown to be most effective in this model, piroxicam. Min mice (n = 120) were randomized to treatment with celecoxib (0, 150, 500, or 1500 ppm celecoxib mixed in the diet) or piroxicam. To distinguish prevention from regression effects, groups were treated either "early" (before adenomas develop) or "late" (after most adenomas are established). Celecoxib caused dramatic reductions in both the multiplicity and size of tumors in a dose-dependent manner (P < 0.01). Early treatment with 1500 ppm of celecoxib was effective for prevention, decreasing tumor multiplicity to 29% and tumor size to only 17% of controls (P < 0.01). Late treatment demonstrated regression effects, reducing tumor multiplicity and size by about half. In contrast to the significant toxicity of piroxicam, which caused ulcers complicated by perforation and bleeding, celecoxib caused no gastrointestinal side effects and did not inhibit platelet thromboxane B2 at plasma drug levels similar to those obtained in early clinical trials in humans. These results provide the first evidence that selective inhibitors of COX-2 are safe and effective for the prevention and regression of adenomas in a mouse model of adenomatous polyposis and strongly support ongoing clinical trials in humans with the same syndrome. The broader population of patients with common sporadic adenomas that have somatic mutations of the same gene (APC) may also benefit from this treatment approach.
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PMID:The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. 1101 26

Celecoxib, a cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug, is a new anticarcinogenic agent. Its antitumor effects depend on the one hand on its COX-2-inhibiting potency, but on the other hand on COX-2-independent mechanisms, which until now have not been fully understood. Here, we investigated whether celecoxib has an impact on the APC/beta-catenin pathway, which has been shown to play a pivotal role in the development of various cancers, especially of the colon. After only 2 h of treatment of human Caco-2 colon carcinoma cells with 100 muM celecoxib, we observed a rapid translocation of beta-catenin from its predominant membrane localization to the cytoplasm. Inhibition of the glycogen-synthase-kinase-3beta (GSK-3beta) by LiCl prevented this celecoxib-induced translocation, suggesting that phosphorylation of beta-catenin by the GSK-3beta kinase was essential for this release. Furthermore, the cytosolic accumulation was accompanied by a rapid increase of beta-catenin in the nuclei, starting already 30 min after celecoxib treatment. The DNA binding activity of beta-catenin time dependently decreased 2 h after celecoxib treatment. After this cellular reorganization, we observed a caspase- and proteasome-dependent degradation of beta-catenin after 8 h of drug incubation. Celecoxib-induced beta-catenin degradation was also observed in various other tumor cell lines (HCT-116, MCF-7, and LNCAP) but was not seen after treatment of Caco-2 cells with either the anticarcinogenic nonsteroidal anti-inflammatory drug R-flurbiprofen or the highly COX-2-selective inhibitor rofecoxib. These findings indicate that the anticarcinogenic effects of celecoxib can be explained, at least partly, by an extensive degradation of beta-catenin in human colon carcinoma cells.
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PMID:Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. 1594 92

(1) Familial adenomatous polyposis is a genetic disorder associated with multiple adenomatous colorectal polyps that invariably progress to colorectal cancer. Gastroduodenal polyposis and extra-gastrointestinal desmoid tumours are other major sources of morbidity in these patients. (2) The current strategy used to prevent colorectal cancer in patients with APC gene mutations consists of yearly monitoring starting in adolescence, and prophylactic colectomy in early adulthood if polyposis occurs. (3) On the basis of pathophysiological, experimental and epidemiological evidence, some specialists have postulated that certain nonsteroidal antiinflammatory drugs (NSAIDs) might have a preventive effect on colorectal adenomas and cancer. (4) Aspirin and sulindac were tested for the prevention of polyps in patients with familial adenomatous polyposis, with uncertain results and weak evidence of effectiveness. (5) Celecoxib was tested in a comparative randomised double-blind trial lasting 6 months. It involved 77 patients with familial polyposis and colorectal polyps, and 6 patients with only duodenal polyps. On the basis of composite endoscopic criteria, a celecoxib dose of 800 mg/day (but not 200 mg/day) reduced the number and surface area of adenomatous colorectal polyps in patients with familial adenomatous polyposis. It is not known whether celecoxib also reduced the risk of colorectal cancer. A global qualitative analysis suggested that celecoxib was also effective in reducing duodenal polyps. (6) Nearly one-third of patients receiving celecoxib 800 mg/day in this trial developed rectal bleeding. Another preventive trial was stopped when an excess of cardiovascular events was found in patients taking celecoxib. (7) The long-term risk-benefit balance of celecoxib 800 mg/day is not known nor whether efficacy persists after treatment discontinuation. (8) In practice, it is better not to use celecoxib to prevent colorectal cancer: its efficacy has not been demonstrated, even in familial polyposis, and it carries a major risk of bleeding and cardiovascular events.
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PMID:Celecoxib: new indication. Colorectal cancer: no preventive benefit. 1654 99

Non-steroidal antirheumatics (NSA) belong to the most often prescribed drugs. Certain observation studies indicate that they are used by 20 to 30% of population of developed countries. The most common NSA's adverse effects are gastrointestinal complications. Coxibs have been developed as an alternative to conventional non-selective NSA; with similar efficacy, they should reduce the risk of development of gastrointestinal complications. In the few last years, possible toxicity of coxibs and other non-steroidal antirheumatics has been widely discussed. The VIGOR study, which was performed 6 years ago, showed five times higher incidence of nonfatal myocardial infarction in patients with rofecoxib therapy as compared with naproxen. Afterwards, there was much debate about rofecoxib, and coxibs in general, whose cardiotoxicity was supported and confuted at the same time. Possible cardioprotective effect of naproxen was discussed too. Later on, results of the APPROVE study (Adenoma Polyp Prevention on Vioxx) made Merck & Co., Inc. withdraw rofecoxib from all markets voluntarily. In the end of 2004, three controversial studies on celecoxib were published. Although the first study (Adenoma Prevention with Celecoxib study, APC) showed higher cardiovascular risk of celecoxib, the second study (Prevention of Adenomatosus Polyps, PreSAP) did not verify these results. Surprisingly, the third study (Alzheimer Disease and Prevention Trial, ADAPT) proved 50% increase of the risk of cardiovascular (CV) toxicity of naproxen. In the last year, researchers have tried to decide whether CV toxicity is a class effect of coxib group or a class effect of all NSA. Many observation studies proved higher CV risk both of coxibs (particularly rofecoxib) and non-selective NSA including naproxen. These new findings moved the American FDA (Food and Drug Administration) to publish guidance concerning higher CV risk of all coxibs and NSA. For the time being, the EMEA (European Agency for Evaluation of Medicinal Products) does not change its attitude to NSA; coxibs are contraindicated in patients with ischemic heart disease, cerebrovascular disease and peripheral artery disease; they should be used with caution in high-risk patients. Final assessment of the problems of CV toxicity of NSA and coxibs will be a case of a long-term randomized study focused on the incidence of cardiovascular adverse effects.
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PMID:[Problems of cardiovascular toxicity of coxibs and non-selective NSA]. 1696 8

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.
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PMID:Chemoprevention with special reference to inherited colorectal cancer. 1768 Mar 50

CRC development is a multi-step process that spans 10 to 15 years, thereby providing an opportunity for early detection and even prevention. The poor survival rate of advanced CRC has prompted the emphasis on prevention of this disease. CRC screening and removal of adenomas is an effective intervention, and is the cornerstone of prevention. However, screening efforts have had limited impact due to less than optimal compliance with guidelines. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel, thus interfering with the multi-step progessing from adenoma to carcinoma. This effect is of particular importance to individuals with a hereditary prediposition to colorectal neoplasia and to those who are especially susceptile to the environmental causes of CRC. NSAIDs have drawn the most attention as chemoprevention agents. Sulindac and celecoxib are effective in promoting poly regression in high risk individuals with Familial Adenomatous Polyposis (FAP). In the more common sporadic setting the APROVe (refecoxib), APC and PreSAP (Celecoxib) trials have shown a significant reduction in adenoma recurrence but important concerns exist regarding cardiovascular toxicity associated with selective COX-2 inhibitors. These landmark studies are very important, as they provide a proof of concept that we can prevent high risk adenomas that can lead to CRC development. The ideal chemopreventive agent remains to be discovered with great emphasis on need not to harm. Possibly, combinations of agents will maximize effectiveness while limiting drug toxicity. Finally, personalized approaches will include the ability to predict risk and toxicity.
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PMID:Chemoprevention of colorectal neoplasia: the potential for personalized medicine. 1878 38

The COX-2 inhibitor Celecoxib, tested in phase III trials for the prevention of sporadic colon adenomas, reduced the appearance of new adenomas, but was unable to affect the incidence of colon cancer. Moreover the 5years follow-up showed that patients discontinuing Celecoxib treatment had an increased incidence of adenomas as compared to the placebo arm. In the APC(min/+) mouse model short term treatment with Celecoxib reduced gut adenomas, but a prolonged administration of the drug induced fibroblast activation and intestinal fibrosis with a final tumor burden. The way Celecoxib could directly activate human colon myofibroblasts (MF) has not yet been investigated. We found that MF are activated by non toxic doses of Celecoxib. Celecoxib induces erk1-2 and Akt phosphorylation within 5'. This short term activation is apparently insufficient to cause phenotypic changes, but the contemporary triggering of EGFR causes an impressive synergic effect inducing MF proliferation and the neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist involved in colon cancer progression. As a confirm to these observations, the erk inhibitor U0126 and the EGFR inhibitors Tyrphostin and Cetuximab were able to contrast AREG induction. Our data provide evidence that Celecoxib directly activates MF empowering EGFR signaling. According to these results the association with EGFR (or erk1-2) inhibitors could abolish the off-target activity of Celecoxib, possibly extending the potential of this drug for colon cancer prevention.
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PMID:Celecoxib induces proliferation and Amphiregulin production in colon subepithelial myofibroblasts, activating erk1-2 signaling in synergy with EGFR. 2301 81