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R W Burt

Publications and source records attributed to R W Burt.

At least 19 recordsLinked to original sources
PubMed1997

Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac, have cancer chemopreventive properties by a mechanism that has been suggested to involve cyclooxygenase inhibition and reduction of prostaglandin (PGE2) levels in the target tissue. To test this hypothesis, we studied the effect of dietary sulindac sulfone (500-2000 ppm), a metabolite of sulindac reported to lack cyclooxygenase inhibitory activity, on tumor formation and PGE2 levels in the azoxymethane model of colon carcinogenesis. Rats treated with sulindac at 400 ppm and piroxicam at 150 ppm were used as positive controls. Rats received two s.c. injections of azoxymethane (15 mg/kg) for 2 weeks and were fed either experimental or control diets until necropsy. After 31 weeks of sulfone treatment, a dose-related increase in sulfone levels in both serum and cecal contents was measured; there was no evidence of metabolic conversion to sulindac or other metabolites. Rats treated with sulfone at 1000 and 2000 ppm, sulindac, and piroxicam had significantly fewer colonic adenomas and carcinomas compared with rats fed control diet as measured by tumor incidence, multiplicity, and tumor burden. Sulfone-treated rats also showed a dose-response relationship for inhibiting all tumor parameters. Colons from rats treated with sulindac or piroxicam contained PGE2 levels that ranged from approximately 16-49% of control levels. PGE2 levels in rats treated with sulfone up to 2000 ppm ranged from 78-118% of control levels. Moreover, the effects of sulindac sulfone on various enzymes responsible for regulating prostaglandin levels were evaluated. No significant inhibitory effects were observed for cyclooxygenase, lipoxygenase, or phospholipase A2. These results suggest that reduction of prostaglandin levels in the target tissue may not be necessary for the chemopreventive properties of sulindac.

Animals↗
PubMed1997

Cerebral vascular reactivity assessed with acetazolamide single photon emission computer tomography scans before and after carotid endarterectomy.

BACKGROUND AND METHODS: In 64 patients, cerebral perfusion and vascular reactivity were assessed before and after carotid endarterectomy (CEA) using acetazolamide (ACZ)-enhanced single photon emission computer tomography (SPECT). Twenty-five patients were asymptomatic, whereas the remainder were symptomatic. Sixty-one patients had a > or = 70% ipsilateral internal carotid artery stenosis. RESULTS: Fifty SPECT scans revealed decreased vascular reactivity. Twenty-three showed infarcts. Fourteen patients had normal studies. Twenty of the SPECT scans of asymptomatic patients demonstrated poor vascular reactivity. After CEA, 39 patients had improved ipsilateral vasoreactivity. In 12 patients, contralateral improvement was also found. CONCLUSION: ACZ-enhanced SPECT scans, by assessing cerebral perfusion and vascular reactivity, may help to identify patients at risk of stroke should perfusion further diminish. Postoperative studies confirm improvement in vascular reactivity. ACZ-enhanced SPECT scans may provide objective evidence for the selection of patients with a high-grade asymptomatic carotid stenosis for CEA.

Acetazolamide↗
PubMed1997

Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli.

Gastric adenocarcinoma has been previously recognized as a potential complication of familial adenomatous polyposis coli (APC) and attenuated forms of APC (AAPC). This tumor has only been reported to originate from adenomatous polyps of the gastric mucosa in these clinical conditions. There have been no previous case reports of gastric adenocarcinoma arising from the more commonly found fundic gland polyps associated with AAPC or APC. We report the first definitive case of gastric adenocarcinoma arising from a hyperplastic polyp of the fundis of a patient with AAPC.

Adenocarcinoma↗
PubMed1997

Screening of patients with a positive family history of colorectal cancer.

A positive family history is one of the most common risk factors for colon cancer. The risk varies from moderately increased when a first-degree relative has colon cancer to high when a first-degree relative is diagnosed at an age less than 50 years or there are two first-degree relatives with large bowel malignancy. The risk of colon cancer is extreme in the rare colon cancer syndromes of familial adenomatous polyposis and hereditary nonpolyposis colon cancer. The extensive characterization of familial occurrence of colon cancer has led to specific screening strategies for each of these levels of familial risk.

Adenomatous Polyposis Coli↗
PubMed1996

Genetic heterogeneity and unmapped genes for colorectal cancer.

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.

Adult↗
PubMed1996

Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated adenomatous polyposis coli.

Mutation of Pla2g2a, a secretory phospholipase A(2) gene, dramatically increases the number of intestinal polyps that develop in the multiple intestinal neoplasia (Min) mouse, a murine model for adenomatous polyposis coli in humans. We tested the hypothesis that mutation of the human homologue(s) of this gene might be responsible for the more severe phenotype (hundreds of polyps) seen in a subset of individuals with attenuated adenomatous polyposis coli (AAPC). DNA sequence analysis demonstrated that alterations of PLA2G2A, as well as related genes PLA2G2C and PLA2G5, were evenly distributed between three classes of AAPC subjects: those with small, intermediate, and large numbers of adenomatous colonic polyps. Among 67 additional unrelated AAPC subjects, a stop mutation in PLA2G2C did not correlate with an increased burden of adenomatous polyps. Therefore, mutation of the human homologue(s) of murine Pla2g2a does not appear to be responsible for phenotypic variation among subjects with AAPC.

Adenomatous Polyposis Coli↗
PubMed1996

Familial risk and colon cancer.

Familial occurrence in excess of that expected by chance is common among cases of colon cancer. Only a small fraction of these familial cases arise from well-described syndromes. There are epidemiologic, colonoscopic, genealogic data base and large prospective studies that characterize the familial occurrence and risk for common colon cancer. Kindred studies suggest that common familial occurrence arises from inherited susceptibility of a mild to moderate magnitude. The responsible genes are yet to be identified, though a number of candidate genes have been suggested. Clinical features, especially age at diagnosis and number of first-degree relatives with colon cancer, already allow stratification of familial risk. Risk stratification is important for colon cancer screening, as some higher-risk persons should probably have more intensive screening. Research is needed to identify the genes or their polymorphisms that give rise to common inherited susceptibility for colon cancer, to examine how susceptibility genes interact with environmental factors and give rise to colonic neoplasms and to verify suggested screening approaches that incorporate familial risk.

Adult↗
PubMed1996

Familial risk and colorectal cancer.

Familial risk of colon cancer is common. The rare syndromes of FAP and HNPCC account for a small fraction of familial cases. A working knowledge of these syndromes is important, however, because appropriate management can prevent most cases of colon cancer in families with these conditions. Furthermore, the genes that give rise to FAP and HNPCC have been identified, and genetic testing to find gene carriers in affected families is now commercially available. In addition to the syndromes, colon cancer commonly clusters in families. The risk of colon cancer is two to threefold increased when a first-degree relative is affected with this malignancy. The risk is further increased if multiple first-degree relatives have colon cancer or if a diagnosis in a relative is made at an age of 50 years or younger. The genetic causes of this more commonly observed of familial clustering have not been clarified, but screening based on the degree of familial risk has been suggested.

Adenomatous Polyposis Coli↗
PubMed1996

Cohorts with familial disposition for colon cancers in chemoprevention trials.

Colon cancer provides an attractive setting for chemoprevention trials because of the frequency and variation of familial predisposition that is observed in this malignancy. Additionally, the adenomatous polyp, the precursor of colon cancer, is a valuable intermediate marker for judging the effectiveness of candidate chemopreventive agents. Inherited colon cancer susceptibility varies from mild to severe. Conditions with extreme susceptibility include the autosomal dominantly inherited syndromes of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). These are highly penetrant syndromes with extreme cancer risk. FAP arises from mutations of the APC gene and HNPCC from mutations of the mismatch repair genes. Specific and individual genetic diagnosis is now possible in both syndromes, thus allowing identification of genetically affected individuals for chemoprevention trials. FAP accounts for less than 1% of colon cancers, while HNPCC may be present in up to 5% of cases. Familial clustering is common in the remainder of cases, which are often referred to as sporadic, but probably arise in part from inherited susceptibility. Epidemiologic studies have shown that first-degree relatives have a two- to four-fold increased risk of acquiring colon cancer compared to the general population. Ten percent of individuals in the U.S. have a first-degree with colon cancer. This clinically identifiable higher risk group thus constitutes a large potential cohort for chemoprevention trials. The common familial cases of colon cancer can be further stratified by severity. A relative diagnosed under the age of 50 or two first-degree relatives affected with colon cancer confers an even greater risk for this malignancy, estimated to be four to six times that of the general population. Adenomatous polyps also precede the development of colon cancer in these categories, thereby providing a readily identifiable clinical endpoint to judge the effectiveness of chemoprevention. It is expected that genetic markers will soon be available for more precise identification of common colon cancer susceptibility. Candidate markers include mild mutations of the APC and mismatch repair genes, glutathione transferase isoenzymes, acetylator status, and phospholipase A2 expression. Bile acid concentrations of the bowel may be genetically and/or environmentally determined and likely have a role in colon cancer susceptibility. We recently identified a large kindred with polyp and cancer susceptibility arising from a mild mutation of the APC gene. There are over 4,000 kindred members and mutational testing has demonstrated 140 gene carriers to date. We expect to institute chemoprevention trials in this kindred using adenomatous polyp number as an endpoint of effectiveness.

Adenomatous Polyposis Coli↗
PubMed1996

The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics.

The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial examining the effect of a low-fat (20% of total energy intake), high-fiber (18 g/1000 kcal), high-vegetable and -fruit (5-8 daily servings) dietary pattern on the recurrence of adenomatous polyps of the large bowel, precursors of most colorectal malignancies. Eligibility criteria include one or more adenomas removed within 6 months of randomization; complete nonsurgical polyp removal and complete colonic examination to the cecum at the qualifying colonoscopy: age 35 years of more; no history of colorectal cancer, inflammatory bowel disease, or large bowel resection; and satisfactory completion of a food frequency questionnaire and 4-day food record. Of approximately 38,277 potential participants with one or more polyps recently resected, investigators at eight clinical centers randomized 2,079 (5.4%; 1,037 in the intervention and 1,042 in the control arm) between June 1991 and January 1994, making the PPT the largest adenoma recurrence trial ever conducted. Of PPT participants, 35% are women and 10% are minorities. At study entry, participants averaged 61.4 years of age; 14% of them smoked, and 22% used aspirin. At the baseline colonoscopy, 35% of participants had two or more adenomas, and 29% had at least one large (> of = 1 cm) adenoma. Demographic, behavioral, dietary, and clinical characteristics are comparable across the two study arms. Participants have repeat colonoscopies after 1 (T(1)) and 4 (T(4)) years of follow-up. The primary end point is adenoma recurrence; secondary end points include number, size, location, and histology of adenomas. All resected lesions are reviewed centrally by gastrointestinal pathologists. The trial provides 90% power to detect a reduction of 24% in the annual adenoma recurrence rate. The primary analytic period, on which sample size calculations were based is 3 years (T(1) to T(4)), which permits a 1-year lag time for the intervention to work and allows a more definitive clearing of lesions at T(1), given that at least 10-15% of polyps may be missed at baseline. The final (T(4)) colonoscopies are expected to be completed in early 1998.

Adenoma↗
PubMed1995

Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis.

The nonsteroidal anti-inflammatory drug sulindac is known to inhibit chemical carcinogenesis in rodent models and cause regression of adenomas in patients with adenomatous polyposis coli. Sulindac is a prodrug that is metabolized to a pharmacologically active sulfide derivative that potently inhibits prostaglandin synthesis. Recent studies, however, have shown that a sulfone derivative of sulindac, which essentially lacks prostaglandin synthesis inhibitory activity, also inhibits chemical carcinogenesis, suggesting that reduction of prostaglandin levels is not necessary for the antineoplastic activity of this class of drugs. Both sulindac sulfide and the sulfone inhibit the growth of cultured tumor cells, although the cellular mechanism(s) responsible for the antineoplastic activity of sulindac derivatives is unknown. In this study, we investigated the effects of sulindac sulfide and sulfone on the proliferation, differentiation, and apoptosis of HT-29 human colon carcinoma cells. Sulindac sulfide and sulfone significantly reduced cell number in both preconfluent and confluent cultures of HT-29 cells with the sulfide showing approximately 4-fold greater potency. In addition to HT-29 cells, both drugs inhibited the growth of a variety of tumor cell lines derived from other tissues, as well as normal epithelial cells and fibroblasts. Neither sulindac sulfide nor sulfone inhibited cell proliferation under conditions where the drugs were growth inhibitory. Only under specific conditions involving mitogenic stimulation did sulindac sulfide and sulfone cause cell cycle arrest. Neither sulindac sulfide nor the sulfone induced differentiation of HT-29 cells, but both drugs strongly induced apoptosis. The apoptotic response to sulindac sulfide and sulfone was both time- and dose-dependent and involved a mechanism independent of their inhibitory effect on cell cycle progression. These data suggest that apoptosis is responsible for the cell growth inhibitory activity of sulindac sulfide and sulfone and represents a potential mechanism for the antineoplastic activity of these drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase?

Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potential as chemopreventive agents for colorectal cancer. Recent case-control drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/or decreased death rate from this disease. Several different NSAIDs reduce formation of both colon adenomatous polyps (the precursor lesion of colon cancer) and cancers in experimental animals given known carcinogens. Perhaps most convincing are reports that the NSAID sulindac promotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized pharmacologic effect of the NSAIDs is their reduction of prostaglandin synthesis by inhibiting prostaglandin synthetase PGE2, which catalyzes the formation of prostaglandin precursors from arachidonic acid. Several lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effects. Relatively high levels of prostaglandins have been reported to inhibit tumor cell growth both in vivo and in vitro, and to inhibit differentiation in some tumor cell lines. We evaluated comparative chemopreventive effects on colon tumor formation in an azoxymethane (AOM)-induced colon carcinogenesis rat model using the NSAIDs piroxicam, sulindac, and sulindac sulfone, a metabolite of sulindac which lacks the anti-prostaglandin synthetase activity typically associated with NSAID-induced gastrointestinal toxicities. The results demonstrate that sulindac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM-induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Genetics of colon cancer: impact of inheritance on colon cancer risk.

The genes that are mutated in two of the rare syndromes of hereditary colon cancer were recently identified, and genetic diagnosis is already possible in some cases. Acquired mutations of these same genes also appear to be important in sporadic colon cancers. Familial clustering of sporadic cases is common and may likewise arise from inherited susceptibility. Screening strategies for both the rare syndromes and the common cases of colon cancer with familial risk have been suggested. Certain clinical features allow stratification of colon cancer risk among common cases. It is anticipated that continued genetic investigation will result in more precise screening and improved diagnostic and therapeutic options for colon cancer.

Adenomatous Polyposis Coli↗
PubMed1995

Prevention of colorectal cancer: guidelines based on new data. WHO Collaborating Center for the Prevention of Colorectal Cancer.

Recently published good quality data are the basis for this update. The newly reported studies include randomized trials, non-randomized cohort studies, and case-control studies; some of the data had mortality reduction as the endpoint. These guidelines, which were developed by the WHO Collaborating Center for the Prevention of Colorectal Cancer at Memorial Sloan-Kettering Cancer Center in conjunction with an International Advisory Committee, include primary prevention, screening of average-risk individuals, screening of individuals with heritable factors for colorectal cancer, surveillance of patients with colorectal polyps, and surveillance of patients with chronic ulcerative colitis. A list of papers reviewed for this update are cited, including recently published trials evaluating faecal occult-blood testing, case-control studies of sigmoidoscopy, the National Polyp study, and familial colon cancer studies. These guidelines will help inform patients and guide physicians in their approach to the prevention of colorectal cancer.

Colorectal Neoplasms↗