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Biomedical subjects

A D Spigelman

Publications and source records attributed to A D Spigelman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac.

BACKGROUND: Recent work has demonstrated a correlation between frequency of aspirin ingestion and colorectal cancer prevention. Sulindac, another nonsteroidal anti-inflammatory drug (NSAID), has been shown to cause polyp regression and a fall in cell proliferation in patients with familial adenomatous polyposis, who are destined to develop colorectal cancer unless the colon is removed. However, the mode of action of NSAIDs in colorectal carcinogenesis prevention remains to be determined, although a prostaglandin-mediated mechanism seems likely. METHODS: Rectal or duodenal biopsies from 20 patients with familial adenomatous polyposis, who had been randomized to sulindac or placebo, were analyzed for prostaglandin (PG) E2 and F2 alpha levels before and after treatment. RESULTS: A significant fall in prostaglandin E2 and F2 alpha levels was seen in patients who were on sulindac; this correlated with a visual improvement in number and size of polyps in the same patients (P = 0.0096; PGE2, P = 0.036; PGF2 alpha, Spearman's rank correlation). CONCLUSIONS: Nonsteroidal anti-inflammatory drugs may prevent colorectal cancer by their inhibition of prostaglandin synthesis. Prostaglandins may be implicated in carcinogenesis through an increase in cell proliferation, through immunosuppression, by increasing neovascularization, or via a mutagenic effect.

Adenomatous Polyposis Coli↗
PubMed1996

Colorectal polyp counts and cancer risk in familial adenomatous polyposis.

BACKGROUND & AIMS: In familial adenomatous polyposis, colorectal cancer prevention is by prophylactic colectomy, but dietary or chemopreventative strategies have been recently proposed in low-risk individuals. The aim of this study was to define predictive risk factors for colorectal cancer in familial adenomatous polyposis. METHODS: Between 1918 and 1993, 317 patients underwent colectomy. A multivariate analysis was performed to assess the relationship between colorectal cancer risk and polyp count, sex, and age at colectomy. RESULTS: The median polyp count was 842 (range, 78-7500), and cancer was found in 22% of patients. Polyp count and age, but not sex, predicted cancer risk. Patients with >1000 polyps had 2.3 times greater risk of cancer than those with <1000 polyps (P=0.006). Synchronous cancers increased with poly count (P<0.05). Each 10-year age group had a 2.4-fold difference in cancer risk (95% confidence interval, 1.9-3.2; P<0.001). Four cases of cancer occurred in patients at low risk (younger than 30 years of age, <1000 polyps; 3.3%). CONCLUSIONS: More adenomas and older age are associated with a higher risk of colorectal cancer. However, cancer does occur in low-risk individuals and may be missed by surveillance, making alternatives to prophylactic surgery inadvisable.

Adenomatous Polyposis Coli↗
PubMed1996

Differences in the levels and pattern of DNA-adduct labelling in human cell lines MCL-5 and CCRF, proficient or deficient in carcinogen-metabolism, treated in vitro with bile from familial adenomatous polyposis patients and from unaffected controls.

In patients with familial adenomatous polyposis (FAP), duodenal adenomas cluster around the ampulla and their distribution closely resembles mucosal exposure to bile, suggesting a role for bile in their development. Previous studies using 32P-postlabeling to detect DNA adducts, have provided evidence to support this hypothesis. We have now investigated the role of metabolic activation in influencing the levels and patterns of adduct formation by incubating precolectomy gallbladder bile from FAP patients and bile from unaffected controls with human lymphoblastoid cell lines that are metabolically proficient (MCL-5), or deficient (CCRF). 32P-Postlabeling assays showed that MCL-5 cells (genetically engineered to express five human cytochromes P450 and microsomal epoxide hydrolase) formed characteristic adduct spots with benz[a]pyrene, benzo[g]chrysene, 7,12-dimethylbenz[a]anthracene, benzidine, sterigmatocystin and 3-methylcholanthrene, whereas CCRF cells did not. Accordingly, we assayed the ability of bile from FAP patients and controls to form DNA adducts in MCl-5 and in CCRF cells. Relative adduct labelling (RAL) in MCL-5 cells treated with FAP bile (12 patients, median 10, range 1-74) was significantly higher than in cells treated with control bile (12 patients, median 4, range 0-9; P = 0.0007) as was RAL for the two major adduct spots. These two major adduct spots were not observed when bile was incubated with CCRF cells. The adduct spots in CCRF DNA appeared in positions similar to some of the minor adduct spots produced by bile in MCL-5 DNA and to some of the adduct spots seen previously when bile was incubated with salmon sperm DNA in vitro. RAL for CCRF cells incubated with FAP bile (seven patients, median 23.0, range 0-49) was significantly higher than in cells treated with control bile (seven patients, median 2.0, range 0-26; P = 0.0034). These results indicate that the bile obtained from FAP and control patients contains adduct-forming substances, some of which are direct acting and some of which require metabolic activation. In both cell lines, FAP bile produced significantly higher adduct labelling than control bile, adding to the evidence that bile can induce DNA damage in vitro and plays a role in neoplastic development in the FAP foregut.

Adenomatous Polyposis Coli↗
PubMed1996

A modifying locus for familial adenomatous polyposis may be present on chromosome 1p35-p36.

Mutations of the APC gene cause familial adenomatous polyposis (FAP) in humans and multiple intestinal neoplasia (Min) in laboratory mouse strains. A dominant modifying gene (Mom1), which partially suppresses the min phenotype, has been mapped to mouse chromosome 4. This region is syntenic with human chromosome 1p35-p36. The phospholipase A2 (Pla2s) locus is an excellent candidate for Mom1 and the equivalent human locus PLA2G2A is found on chromosome 1p35. It does not necessarily follow, however, than any modifier of mouse polyposis also influences human disease. In order to test whether a locus on 1p modifies FAP, subjects from 28 FAP families have been typed at microsatellite loci on this chromosome arm. The severity of their duodenal polyposis has also been assessed by endoscopy. Pedigree (lod score) linkage analysis found no evidence of a simple, dominant modifying gene, comparable with the action of Mom1 in inbred mouse strains. Given the more complex genetic and environmental interactions likely to exist in outbred human populations, it is probably more appropriate to use tests which do not specify a mode of inheritance. Using these methods of analysis, the data suggest that a locus on chromosome 1p35-p36 may influence the severity of duodenal FAP.

Adenomatous Polyposis Coli↗
PubMed1996

Overexpression of p53 in duodenal tumours in patients with familial adenomatous polyposis.

Duodenal polyps and tumours of different histology from patients with familial adenomatous polyposis (FAP) were examined for p53 overexpression to determine the genetic events in duodenal tumorigenesis. Samples from endoscopic biopsy specimens of 152 duodenal adenomatous polyps (taken from 79 patients) and from 13 surgically resected adenomatous polyps or cancers (taken from nine patients) were studied by routine histological examination and immunohistochemistry. p53 was overexpressed in: 0 per cent of normal mucosa samples (none of 29), 25 per cent of tubular adenomas (28 of 111), 72 per cent of tubulovillous and villous adenomas (13 of 18) and 100 per cent of duodenal cancers (seven of seven); and in 28 per cent of mildly dysplastic polyps (32 of 113), 56 per cent of moderately or severely dysplastic polyps (nine of 16) and 100 per cent of cancers (seven of seven). Overexpression of p53 increased with passage down the adenoma-carcinoma pathway and might therefore be a valuable additional marker of risk for duodenal malignancy in patients with FAP.

Adenomatous Polyposis Coli↗
PubMed1995

Polyposis: the Peutz-Jeghers syndrome.

The classical pigmentation of Peutz-Jeghers syndrome distinguishes it immediately from the other polyposis syndromes. Less widely appreciated than this most obvious manifestation are the pitfalls in management presented by the risk of cancer and by the performance of multiple laparotomies that also characterize this condition. An outline of these risks and an approach that minimizes them is presented.

Diagnosis, Differential↗
PubMed1995

Appearance of artefacts when using 32P-postlabelling to investigate DNA adduct formation by bile acids in vitro: lack of evidence for covalent binding.

We reported (Scates et al. Carcinogenesis 1994, 15, 2945-2948) that incubating a range of bile acids with DNA in vitro, with or without exogenous metabolic activation, gave no evidence of DNA adduct formation as judged by the nuclease P1 method of 32P-postlabelling. In contrast Hamada et al. (Carcinogenesis 1994, 15, 1911-1915), also using postlabelling, claimed that chenodeoxycholic acid, lithocholic acid, glycolithocholic acid and taurolithocholic acid bound covalently to DNA in vitro. To investigate this discordance we incubated solutions of salmon sperm DNA for 1 h at 37 degrees C with 1 mg/ml of cholic acid, chenodeoxycholic acid, lithocholic acid, glycolithocholic acid or taurolithocholic acid. Each incubate was extracted extensively with diethyl ether after which a sample of DNA was taken and 32P-postlabelled using the nuclease P1 method. The DNA in the remaining incubate was precipitated from high salt solution with ethanol. Aliquots of this DNA were postlabelled. The remainder of the DNA was purified with proteinase-K, ribonuclease, phenol-chloroform, precipitated and postlabelled. Parallel incubates were made with the same bile acids, under the same conditions but in the absence of DNA and were then extracted, precipitated and postlabelled as described above. When DNA was present in the incubate but was not precipitated, chenodeoxycholic acid, lithocholic acid, glycolithocholic acid and taurolithocholic acid, but not cholic acid, produced spots similar to those reported by Hamada et al. No such spots were seen when DNA was postlabelled after precipitation, or after precipitation and purification. These same bile acids produced spots when postlabelled in the absence of DNA, but spots were absent when these incubates were precipitated and purified before postlabelling. We conclude that the spots obtained when bile acids are incubated with DNA which is not precipitated from high salt before it is postlabelled are technical artefacts, and cannot be regarded as evidence that bile acids bind covalently to DNA to form adducts. We also confirm reports (Vulimiri et al. Carcinogenesis 1994, 15, 2061-2064) that bile acids alone can produce spots when incubated with T4 polynucleotide kinase and [gamma-32P]ATP.

Animals↗
PubMed1995

Caffeine phenotyping of cytochrome P4501A2, N-acetyltransferase, and xanthine oxidase in patients with familial adenomatous polyposis.

Patients with familial adenomatous polyposis (FAP) and age and sex matched controls were tested for cytochrome P4501A2 (CYP1A2), N-acetyltransferase, and xanthine oxidase activities using caffeine urinary metabolites as a discriminator. FAP patients showed significant underactivity of N-acetyltransferase (which inactivates some carcinogens) and significant overactivity of CYP1A2 (which activates some carcinogens). Xanthine oxidase activity, which can generate free radicals and cause cellular damage, was significantly increased in the FAP patients. All but one of the FAP patients had undergone colectomy. A separate group of six patients was therefore assessed before and at an average time of eight weeks after colectomy. No effect on enzyme activity was seen. The differences in enzyme activities detected in this study could produce an excess of active carcinogenic metabolites in the bile of FAP patients and contribute to the high risk for intestinal cancer in FAP.

Acetyltransferases↗
PubMed1995

High pH reduces DNA damage caused by bile from patients with familial adenomatous polyposis: antacids may attenuate duodenal polyposis.

Patients with familial adenomatous polyposis (FAP) develop periampullary duodenal tumours, suggesting that bile contributes to their formation. The hypothesis that bile contains carcinogens has been tested by looking for DNA adducts (markers of carcinogen exposure) in the duodenum of patients with or without FAP and by determining whether bile can produce DNA adducts in vitro. Using 32P-postlabelling to detect adducts, there was an excess (compared with unaffected patients) of DNA adducts in the duodenum of FAP patients and an excess of DNA adducts in the small bowel of rats treated with FAP bile, while bile from FAP patients formed significantly more DNA adducts in vitro than did bile from controls. In this study it is shown that the excess of adduct labelling produced by FAP bile in vitro depends on the pH of the incubate. While adduct labelling at pH 6-8 did not differ significantly between bile from six FAP patients and six controls, at pH 4-5 FAP bile, but not control bile, produced a near threefold excess of adduct labelling over that at pH 6-8. Therapy that increases duodenal pH may therefore alleviate duodenal polyposis.

Adenomatous Polyposis Coli↗