[Chemoprevention for Familial Adenomatous Polyposis].

Colorectal cancer (CRC) is the second most common cancer in Japan. Primary cancer prevention is especially desired for hereditary CRC patients, owing to the high incidence of cancer in these patients. Prophylactic total proctocolectomy is generally accepted for young FAP patients; however, this procedure may reduce their QOL. If we could obtain effective chemopreventive drugs for FAP patients, prophylactic surgery could be postponed until the patients are older, or be avoided altogether. Thus, such drugs would bring large benefits to FAP patients. In this review, the history of chemopreventive drug development for FAP and the future prospects of chemopreventive drugs are described.

[Colorectal neo- and dysplasia in acromegaly].

Colorectal disorders can be not only an independent disease, but also manifestation of acromegaly--a neuroendocrine disease which is characterized by chronic pathological hypersecretion of the growth hormone (GH) and the increased concentration of insulino-like growth factor type 1 (IGF-1). In clinical recommendations on diagnosis and treatment of acromegaly, colonic polyps are marked as one of most pathognomonic manifestations of acromegaly. Prevalence of coloni polyps in acromegalic is 2,5-3 times higher than in the general population. Moreover, frequency of diverticula and dolichocolon is increased in patients with acromegaly compared with general population (in 3,6 and 12 times, accordingly). Colorectal cancer incidence with a tendency to more aggressive current is also increased (by 4,4 times). When these colonic diseases is diagnosed, especially in patients of young age, it is necessary to define the IGF-1 blood level as the first stage of acromegaly identification. If diagnosis of acromegaly is confirmed, gastroenterologist with endocrinologist together should direct treatment on correction of intestinal pathology as well as on achievement of the biochemical control over acromegaly.

Theoretical basis validation and oxidative stress markers for cancer prevention clinical trials of aspirin.

Aspirin, a nonsteroidal anti-inflammatory drug, has been proven effective in a clinical trial of carcinogenesis blockade. However, various modes of action have been reported for these effects. Thus, in this study, we aimed to present reasonable mode of actions as a proof of concept for human trials, especially trials for patients with familial adenomatous polyposis (FAP). Aspirin treatment at 1000 ppm inhibited intestinal tumorigenesis in FAP model Min mice. As a mode of action, aspirin regulated ß-catenin signaling, inflammation, and oxidative stress both in vivo and in vitro. Furthermore, we examined novel markers predictive of aspirin treatment based on liquid biopsy. Here, we demonstrated that aspirin reduced the levels of reactive carbonyl species in the serum of Min mice. These data are expected to be of use for proof of concept of aspirin human trials and implied for the prediction of aspirin efficacy.

Celecoxib Colorectal Bioavailability and Chemopreventive Response in Patients with Familial Adenomatous Polyposis.

Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven patients with FAP completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-S-hydroxyoctadecadienoic acid (13-HODE), 15-HETE, 12-HETE, and LTB4 levels by LC/MS-MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in patients with FAP. PREVENTION RELEVANCE: This study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in patients with FAP. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in patients with FAP. See related Spotlight, p. 205.

[Prevention of carcinogenesis in familial tumors].

This report reviews the state of the art of cancer prevention of familial colorectal cancer (familial adenomatous polyposis, hereditary non-polyposis colorectal cancer). A large number of clinical trials have been performed using sulindac, a non-steroidal anti-inflammatory drug (NSAID). Sulindac reduces the size and number of large bowel polyps. However, as yet, it cannot be used for this indication in the clinical setting, because of the frequent occurrence of serious gastrointestinal side effects, and there are a number of cases in which aggressive tumors developed despite a reduction in the size of polyps. Studies on COX-2 selective inhibitors, with minimal side effects on the digestive tract, are showing promising results. In addition to NSAIDs, clinical trials have been performed using vitamins and dietary components. These show minimal side effects, but their efficacy is still insufficient for clinical use, and further studies are anticipated.

New avenues for the prevention of colorectal cancer: targeting cyclo-oxygenase-2 activity.

Carcinoma of the colon and/or rectum represents the second most common gastrointestinal malignancy worldwide. Despite this prevalence, current therapeutic regimens remain largely ineffectual, particularly when the disease is diagnosed at an advanced stage. Recent work in the field of colorectal cancer has established that a chronic intake of non steroidal anti-inflammatory drugs can reduce the risk of developing colorectal cancer. Although the precise mechanism(s) by which these drugs inhibit tumour growth is not completely understood, it is likely that at least a part of their anti-tumorigenic effects results from an inhibition of the cyclo-oxygenase-2 enzyme. This chapter will focus on this emerging research area and the promise it brings for identifying new strategies for the prevention of colorectal cancer.

Cyclooxygenase, NSAIDs, and colorectal cancer.

Prevention of human diseases has become a major focus of biomedical investigators around the world. Our current screening and treatment regimens for colorectal cancer are not effective, as indicated by the fact that this disease is the second leading cause of death from cancer in the United States. Recently published reports indicate that continuous use of aspirin reduces the relative risk of colorectal cancer by about 50%. Other work demonstrates that NSAIDs cause regression of adenomas in patients with familial adenomatous polyposis and prevent the development of colon tumors in carcinogen-treated animals. This review is a summary of the literature and includes an analysis of recent reports indicating the potential molecular basis for the chemoprotective effects of NSAIDs.

Nonsteroidal anti-inflammatory drugs, COX-2 and colorectal cancer.

Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of colorectal cancer. Moreover, the NSAID sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. The mechanisms of these effects of NSAIDs are not known but several lines of evidence suggest the involvement of the inhibition of the inducible isoform of prostaglandin H synthase (known as COX-2). Specific COX-2 inhibitors, showing an improved profile of gastrointestinal safety vis-à-vis conventional NSAIDs, provide interesting tools to probe the COX-2 dependence of the apparent protection against colorectal cancer associated with the use of NSAIDs.

[Presymptomatic detection of familial colonic polyposis]. / Dépistage présymptomatique de la polypose colique familiale.

In familial adenomatous polyposis coli (APC) it is possible to detect APC carriers either by research of bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE) or by genetic diagnosis (APC gene is localized in 5q21). These detections were performed in 33 patients of four families with the same positivity for genetic typing (11 patients) or for CHRPE (11 patients) which thus avoided annual coloscopy.

[Effects of nonsteroidal anti-inflammatory drugs (NSAID) on colorectal polyps in patients with familial adenomatous polyposis: a review of clinical studies].

Experimental animal studies have demonstrated a protective effect of NSAIDs against intestinal tumorigenesis due to chemical carcinogens. Many epidemiological studies have also shown that regular aspirin use is associated with reduction of the risk of colorectal cancer. In familial adenomatous polyposis, numerous clinical studies have reported that sulindac and indomethacin are effective in reducing colorectal polyps. However, their effects are incomplete and they may cause severe toxicity. Therefore, they are unlikely to replace colectomy as primary treatment. Nevertheless, their unique effects on colorectal tumorigenesis warrant further basic and clinical research on NSAIDs, including COX-2-selective inhibitors.

[Postoperative management of the preserved rectal segment in patients with familial polyposis: the use of 5-fluorouracil suppositories and green tea extract to inhibit tumor growth].

We report the clinical details of seven patients with familial polyposis. They underwent subtotal colectomy with ileorectostomy, and were treated with 5-fluorouracil suppositories and green tea extract after surgery. Some regression of the polyps in the preserved rectal segment was observed, and no rectal cancer developed in any of these patients.

Aspirin and the prevention of colorectal cancer.

A large body of evidence from basic science, epidemiologic observations and population-based studies demonstrates that aspirin, as well as other non-steroidal anti-inflammatory drugs, has a chemopreventive effect on several cancer types and, more specifically, in CRC. This protective effect includes prevention of adenoma recurrence and reduction of CRC incidence and mortality. Although the protective effect appears to depend on the dose and the drug, the most important factor is the duration of exposure. However, the lowest effective dose, treatment duration, specific target populations, and effects on survival have not been defined yet. More important, data on the risk-benefit profile for cancer prevention are insufficient and, accordingly, no definitive recommendation can be made at present. In this article, besides reviewing current knowledge of the mechanisms involved in aspirin-based CRC chemoprevention, we will be focused on randomized controlled studies assessing its efficacy in high-, moderate- and average-risk populations.

Is COX-2 a 'collateral' target in cancer prevention?

NSAIDs (non-steroidal anti-inflammatory drugs) prevent colon and other cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug-developmental work focusing on COX (cyclo-oxygenase) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, one COX-2 inhibitor has been withdrawn from the market because of cardiovascular side effects, and there are concerns about a class effect. Evidence suggests that COX-2 may not be the only, or the ideal, target for cancer prevention; for example, COX-2 is not expressed in human aberrant crypt foci, the earliest recognizable pre-malignant lesion in the colon; COX-2 is expressed in less than half of the adenomas; in vitro data show that NSAIDs do not require the presence of COX-2 to prevent cancer; in familial adenomatous polyposis, the COX-2 inhibitor, celecoxib, had a modest effect, which was weaker than that of a traditional NSAID; and COX-2-specific inhibitors have several COX-2-independent activities, which may account for part of their cancer-preventive properties. The multiple COX-2-independent targets, and the limitations of COX-2 inhibitors, suggest the need to explore targets other than COX-2.

The role of arachidonic acid regulatory enzymes in colorectal disease.

PURPOSE: Nonsteroidal anti-inflammatory drugs have a wide ranging effect on diseases of the colon and rectum. Interestingly, nonsteroidal anti-inflammatory drugs seem to play a beneficial role in colorectal cancer chemoprevention and adenoma regression, but may have a deleterious effect in inflammatory bowel disease. Prostaglandin inhibition is central to both the beneficial and toxic effects of this class of drugs. Arachidonic acid metabolism is essential to prostaglandin synthesis. METHODS: A Medline search using "nonsteroidal anti-inflammatory drugs," "colon cancer," "inflammatory bowel disease," "colitis," "COX inhibitors," "arachidonic acid," and "chemoprevention" as key words was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work. RESULTS: Based on numerous studies, nonsteroidal anti-inflammatory drugs have a beneficial role in colon cancer and colonic adenomas. However, they have been reported to have a deleterious effect on the colon in inflammatory bowel disease and have been shown to cause colitis. Nonsteroidal anti-inflammatory drugs work via multiple pathways, some well defined, and others unknown. CONCLUSIONS: In the new millennium, nonsteroidal anti-inflammatory drugs may be used for chemoprevention of colorectal and other cancers. In addition, they may be used in combination with surgery and chemotherapy to primarily treat colorectal carcinoma. Undoubtedly, the use of novel cyclooxygenase inhibitors with less of a toxicity profile will allow more widespread use of nonsteroidal anti-inflammatory drugs for a variety of diseases. The future of this class of drugs is promising.

Chemoprevention of carcinogenesis in familial tumors.

Among familial cancers, chemoprevention has been studied for familial adenomatous polyposis, hereditary nonpolyposis colorectal cancers, and familial breast cancers. This report reviews the studies on chemoprevention in familial adenomatous polyposis. A large number of clinical trials have been performed using sulindac, a non-steroidal anti-inflammatory drug (NSAID). Sulindac reduces the size and number of large-bowel polyps. However, as yet, it cannot be used for this indication in the clinical setting, because of the frequent occurrence of serious gastrointestinal side effects, and there are a number of patients in whom aggressive tumors developed despite a reduction in the size of polyps. Studies of cyclooxygenase-2 (COX-2) selective inhibitors, with minimal side effects on the digestive tract, are showing promising results. In addition to NSAIDs, clinical trials have been performed using vitamins and dietary components. These show minimal side effects, but their efficacy is still insufficient for clinical use, and further studies are anticipated.