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.

Assessment of mutations in Ki-ras and p53 in colon cancers from azoxymethane- and dimethylhydrazine-treated rats.

Mutations in the Ki-ras oncogene and the p53 tumor suppressor gene are known to occur at high frequencies in human colon cancers. We measured the frequency of mutations in these two genes in colon adenocarcinomas obtained from a widely used experimental model of human colon carcinogenesis: F344 rats treated with the carcinogens azoxymethane (AOM) or dimethylhydrazine (DMH). We detected codon 12 mutations in Ki-ras in approximately 60% of colon adenocarcinomas induced by either carcinogen. We characterized the rat p53 intron-exon junctions to construct primers for polymerase chain reaction amplification of this gene. We discovered that the rat p53 gene was structurally different from the human p53 gene, as the rat gene was missing one intron between exons 6 and 7. Both single-stranded DNA conformational polymorphism analysis and direct DNA sequencing of the highly conserved regions of rat exons 5-7 were conducted because the corresponding human regions (exons 5-8) have been reported as being mutated most frequently in human colon cancers. Using these methods, we were unable to identify any p53 mutations in the highly conserved regions of exons 5-7 in either AOM- or DMH-induced colon adenocarcinomas. These data confirm that Ki-ras was mutated in most colon cancers in AOM- or DMH-treated rats but indicate that molecular alterations in the p53 gene, if they occur in this animal model, are different from most p53 mutations in human colon cancers.

Contemporary medical therapy for gastroesophageal reflux disease.

Gastroesophageal reflux disease is a chronic disorder that requires long-term therapy in most patients. The appropriate medical therapy should be individualized to the severity of symptoms, the degree of esophagitis and the presence of other acid-reflux complications. Lifestyle changes should form the basis of any therapeutic approach. In patients with mild to moderate disease, initial therapy with histamine H2-receptor antagonists in conventional dosages is suggested. Prokinetic agents are potentially useful in patients with impaired esophageal or gastric motor function, but their efficacy as single agents does not appear to surpass that of standard doses of H2 blockers. Sucralfate, a cytoprotective agent, is an additional therapeutic option. For patients with more severe disease, omeprazole and lansoprazole provide unequaled healing rates and accelerated symptom relief. In most patients, maintenance therapy is vital. Surgery is indicated in patients whose disease is refractory to medical therapy and in those who develop complications not amenable to medical therapy.

Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells.

Several lines of evidence suggest that nonsteroidal antiinflammatory drugs may be effective in preventing colorectal cancer. These include animal experiments, case-control studies, and clinical experience with sulindac in promoting the regression of adenomatous colon polyps in adenomatous polyposis coli. We determined the antiproliferative activity of various nonsteroidal antiinflammatory drugs, including two sulindac derivatives, against human colon cancer cells in vitro. Ht-29, SW480, and DLD-1 cells were continuously incubated with serial drug dilutions for 6 days prior to fixation. Cell number was determined using the sulforhodamine B assay, and drug concentrations which inhibited cell growth by 50% were estimated for each agent by interpolation. All drugs exhibited antiproliferative activity against Ht-29 and DLD-1 cells, and most inhibited SW480 cells. For Ht-29 cells, the 50% inhibitory concentration varied from 55 microM for diclofenac to 2100 microM for 5-aminosalicylic acid, with three drug groups of high, intermediate, and low potency evident. Inhibition of cell growth by sulindac sulfide was reversible following drug removal. Nonsteroidal antiinflammatory drugs exert an antiproliferative effect against human colon cancer cells with a wide range of potencies. A cytostatic response was demonstrated with sulindac sulfide. These data further support the potential role of these agents for chemoprevention of colorectal neoplasia.

Sources of variability in estimating ornithine decarboxylase activity and polyamine contents in human colorectal mucosa.

The activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is elevated during epithelial carcinogenesis. Since this enzyme is a target for colon and other cancer chemoprevention strategies, we sought to identify sources of variability affecting the measurement of tissue ODC activities and polyamine contents. Multiple colorectal biopsies were obtained from 39 patients undergoing colonoscopy. Biopsy size affected polyamine but not ODC values. Spermidine (spd):spermine (spm) ratios varied less than the contents of the individual amines. Bowel preparation methods did not affect any of the measurements. ODC activities and spd:spm ratios did not vary with bowel location. Lab assay methods contributed to sources of error. Variability was greatest for polyamine content measurements but was reduced when polyamine contents were analyzed as spd:spm ratios. Intrapatient variability of these parameters was as great or greater than interpatient variability. When measured in apparently unaffected colorectal mucosa, none of these parameters were significantly correlated with prior polyp history, number of prevalent polyps found at current colonoscopy, or polyp size. Thus, neither ODC activity nor polyamine contents of normal mucosa appear to be discriminatory markers of colorectal carcinogenesis. However, spd:spm ratios, which show the least variability among measures of polyamine contents, should be a good marker of the consequence of polyamine synthesis inhibition in chemoprevention trials.

Two-year incidence of colon adenomas developing after tandem colonoscopy.

OBJECTIVES: We attempted to determine an accurate frequency of new polyp growth in a cohort of veteran male patients who were initially cleared of polyps by tandem colonoscopy. METHODS: Followup colonoscopy was performed 2 yr after tandem colonoscopy. A polyp was categorized as "new" if it was not located in a segment of the colon or rectum that had harbored a neoplastic polyp of the same histology at tandem colonoscopy, in contradistinction to lesions designated as "same-segment" polyps. RESULTS: Fifty-eight of 90 patients who had tandem colonoscopy as a part of a previous study were available for follow-up colonoscopy for 2 yr. Ninety-one percent had a history of benign neoplastic polyps or cancer. Neoplastic polyps were documented in 52% (95% CI, 45-74%) of patients at followup, and 38% (95% CI, 26-52%) were found to have a total of 31 "new" lesions. All new lesions were tubular adenomas. The largest number of new polyps in an individual patient was four, and the largest new lesion was 20 mm in size with a flat, linear configuration. Most (25/31) new polyps were < or = 5 mm, and the number of neoplastic polyps per patient at follow-up was less than at tandem colonoscopy. CONCLUSIONS: Approximately one-half of older, male patients with a history of neoplastic polyps will demonstrate neoplastic polyps at 2 yr. In at least one-third of patients, these appear to be new lesions. In some patients, de novo neoplastic polyps can grow to > or = 1 cm within 2 yr.

Prevalence of distal colonic neoplasia associated with proximal colon cancers.

BACKGROUND: The number, size, and histologic features of distal colorectal adenomatous polyps have been reported to correlate with the risk of developing proximal colon cancer. To investigate this putative relationship further, we evaluated the frequency of distal colorectal neoplastic polyps in patients with colon cancer located proximal to the splenic flexure. METHODS: All cases of colorectal adenocarcinomas treated at a tertiary referral center and Veterans Affairs hospital between 1979 and 1992 were identified by International Classification of Diseases coding and review of pathology and colonoscopy reports. The medical records of patients with documented cancers proximal to the splenic flexure were examined for the presence, location, size, and histopathologic features of synchronous neoplastic lesions found at colonoscopy. RESULTS: Among 634 patients with colorectal cancer identifiable by location, 172 had proximally located tumors. Of these, 60 patients were excluded because of lack of complete colonoscopy or because surgical resection was performed elsewhere. Forty percent of the remaining 112 patients for whom data could be evaluated demonstrated neoplastic lesions in addition to the proximal cancer. The colon was devoid of "sentinel" neoplasia distal to the splenic flexure and descending colon-sigmoid colon junction in 69% and 72% of patients, respectively. CONCLUSIONS: The majority of proximal colon cancers are not associated with distal sentinel lesions. We surmise that flexible sigmoidoscopy will fail to find evidence of neoplasia in at least 25% of patients with prevalent colon cancers.

Biliary obstruction. Nonsurgical treatment with endoscopic and radiologic techniques.

Several methods and combinations of techniques are available to treat biliary obstruction. The approach to treatment should be determined by the patient's situation and the expertise available in the various treatment options rather than by adherence to a standard plan. Clinical outcomes reported in the literature reflect results achieved by experts, and traditional surgical approaches may be most appropriate if experience with endoscopic and radiologic techniques is lacking in the patient's community. Various methods can often be used in a complementary or sequential fashion to provide optimal patient care.

NSAID effect on sporadic colon polyps.

UNLABELLED: In this study, our objective was to determine whether 6 months of open-label therapy with sulindac 400 mg/daily or piroxicam 20 mg/daily promote regression of adenomatous colonic polyps left in situ. Left-sided colonic polyps (size 3-12 mm) detected at colonoscopy were measured and left without being biopsied. The bowel wall opposite to the polyps was marked with India ink submucosally. Patients were assigned to drug therapy, and compliance was determined by pill count. Polyps were measured during sigmoidoscopy after 3 and 6 months of treatment; polyps were removed at the 6-month examination. Examiners were not blinded to drug therapy or previous polyp measurements. Seven patients completed 6 months of therapy (five sulindac and two piroxicam). Two additional patients treated with piroxicam were withdrawn secondary to adverse events (bleeding gastric ulcer and rash). In one patient treated with sulindac, a 6-mm polyp disappeared, and two other polyps seemed to regress partially. One polyp regressed partially in a piroxicam-treated patient. All other polyps remained unchanged. CONCLUSIONS: We did not observe dramatic regression of sporadic colon adenomatous polyps to either sulindac or piroxicam after 6 months of therapy in this small uncontrolled pilot study.

Ornithine decarboxylase and polyamines in colorectal neoplasia and mucosa.

Ornithine decarboxylase (ODC) and polyamines are intimately involved in normal cellular proliferation and are likely to play a role in carcinogenesis. ODC activity and polyamine content were measured in tissue samples obtained during colonoscopy from 48 benign neoplastic polyps (20 tubular adenomas; 28 villous adenomas), 18 cancers (including 5 malignant polyps), and adjacent mucosa. ODC activity in polyp and cancer tissue specimens was higher than in adjacent mucosa in 75 and 83% of pairs, respectively. Similarly, putrescine, spermidine, and spermine contents were higher in the majority of polyps and cancers compared to adjacent mucosa. ODC activity and polyamine content in colonic mucosa from 10 patients without a history of colorectal neoplasia were not different from adjacent mucosal values in the patients with neoplasia. In conclusion, ODC and polyamines are elevated in the majority of colorectal neoplasms, but amounts in normal mucosa do not differentiate between patients with cancer, benign neoplastic polyps, and normal subjects.

Fatal hyperphosphatemia following Fleet Phospo-Soda in a patient with colonic ileus.

A fatal case of hyperphosphatemia secondary to enteral administration of Fleet Phospo-Soda is presented. A 64-yr-old male admitted for theophylline toxicity was treated with activated charcoal and sorbitol, but subsequently developed colonic ileus. Two sequential doses of Phospo-Soda were administered to facilitate clearance of the charcoal; however, this resulted in marked hyperphosphatemia, hypocalcemia, acidemia, and other electrolyte abnormalities, followed by the patient's demise. This case is added to several other reports about the risks of injudicious use of sodium phosphate cathartics.

Are endoscopic measurements of colonic polyps reliable?

Many clinical studies of colorectal adenomatous polyps rely on endoscopic estimation of polyp size. To examine the reliability of such measurements, we conducted a study using artificial polyps in an endoscopy teaching model. Eight experienced endoscopists estimated the size of 13 polyps in two separate sessions 2 wk apart. Endoscopic estimates of polyp size tended to be significantly lower than the true polyp size for all polyps and all endoscopists at both sessions. We also found a statistically significant difference in the magnitude of the underestimation between the first and second session (p < 0.0001). At the first session, polyps tended to be estimated at 64% of their true size, and at the second session, the estimates tended to be at 77% of the actual polyp size. We estimate the magnitude of the variation in polyp measurements due to individual polyps, endoscopist, and examination session, and discuss the impact these sources of variation have in planning of clinical trials.

Regression of Barrett's esophagus by laser ablation in an anacid environment.

Consistent regression of intestinal metaplasia in Barrett's esophagus has not been achieved with medical or surgical interventions. In this case report, a patient with Barrett's esophagus of stable length had half the circumference of the Barrett's epithelium ablated with laser therapy while on a high-dose proton-pump inhibitor. In the absence of esophageal acid exposure and after laser ablation, the intestinal metaplasia was documented to reepithelialize with normal squamous mucosa, which has persisted.

Plasma selenium concentration predicts the prevalence of colorectal adenomatous polyps.

The objective of this cross-sectional study was to determine whether plasma selenium concentration predicts the prevalence of adenomatous polyps of the colon and rectum. The source population for the study was 101 patients undergoing sequential colonoscopies at the Veterans Affairs Medical Center, Tucson, AZ. The study population was then limited to the 48 patients (all male) undergoing their initial colonoscopy who did not have a diagnosis of colorectal cancer. For each of these patients, a prediagnostic fasting plasma selenium concentration was determined. The data from this study suggest that fasting plasma selenium concentrations may be an important risk factor for colorectal adenomas. Patients with fasting plasma selenium concentrations below the median (< 128 mcg/liter) were significantly more likely to have one or more adenomatous polyps (prevalence odds ratio 4.2) and more adenomatous polyps (3.5 times) per patient. There was also a suggestion of a more proximal distribution of adenomatous polyps in the patients with a lower level of selenium. These associations were not confounded by age or smoking. The results of this study are consistent with the experimental animal studies, geographic mortality studies, and prospective cohort studies of selenium and colorectal cancer.

Gastric intestinal metaplasia in ethnic groups in the southwestern United States.

The incidence of gastric cancer has declined dramatically in the United States during this century. However, the incidence of gastric cancer among Hispanics, Blacks, and Native Americans remains 2-3-fold higher than among Whites in this country. Populations with an increased risk of gastric cancer have predominantly the "intestinal" type of gastric cancer, and intestinal metaplasia is regarded as a histological precursor lesion of this type of gastric cancer. We sought to establish the prevalence of intestinal metaplasia, identify associated epidemiological factors, and improve detection of this lesion in a patient population undergoing clinically indicated endoscopy in the Southwestern United States. Among the 440 patients studied, we observed an overall crude prevalence of intestinal metaplasia of 19%. However, the crude prevalence among Hispanics and Blacks was found to be markedly higher than among non-Hispanic Whites (50% versus 13%). Two biopsy protocols (two biopsies versus four biopsies) were used during this study, with a significantly higher rate of intestinal metaplasia detection under the four-biopsy protocol. Adjusting for protocol, we found that age and ethnicity were significantly and independently associated with the prevalence of intestinal metaplasia. The odds of intestinal metaplasia diagnosis was significantly higher in Hispanics compared to non-Hispanic Whites (P < 0.001), and the prevalence of intestinal metaplasia increased with advancing age (P = 0.01). The presence of Helicobacter pylori was also significantly associated with the presence of intestinal metaplasia (P = 0.02), although the direction of the association differed between Hispanics and non-Hispanic Whites.

Current trends in the pharmacotherapy for gastroesophageal reflux disease.

Medical therapy for gastroesophageal reflux disease should entail a multistep approach. After life-style changes, many patients will require histamine2 receptor antagonists in conventional doses with repeated therapeutic courses, if not continuous maintenance. Prokinetic agents are potentially useful in those patients with impaired motor function of the esophageal or gastric smooth muscle. Combination therapy with histamine2 receptor antagonists and prokinetic agents or sucralfate provides modest healing benefit, if any, over that by histamine2 receptor antagonists alone. For patients with more severe refractory disease, omeprazole has provided unequaled healing rates and accelerated symptomatic relief. High-dose (twofold or more standard dose) histamine2 receptor antagonist therapy may also heal high-grade esophagitis, but the reported experience is small. After healing is achieved, an attempt should generally be made to "step down" therapy to standard-dose histamine2 receptor antagonist as maintenance. Finding the least amount of drug to control symptoms and maintain the integrity of the esophageal mucosa would minimize cost and potential long-term risk.

Current trends in the pharmacotherapy for peptic ulcer disease.

A variety of options are available for the medical treatment of peptic ulcer disease, including antacids, histamine2 receptor antagonists, omeprazole, prostaglandin analogues, and sucralfate and bismuth formulations. Seventy percent to 90% of peptic duodenal and gastric ulcers will heal after 4 to 8 weeks of therapy. Combination regimens using these agents have not been demonstrated to be superior to single-agent therapy. Aggressive acid suppression with "high-dose" histamine2 receptor antagonists or omeprazole accelerates healing of ordinary ulcers and promotes healing of previously refractory ulcers. Although ulcer recurrence is diminished by continuous "maintenance" therapy with the aforementioned agents, recurrence seems to be dramatically suppressed after eradication of Helicobacter pylori from the gastroduodenal mucosa.