sulindac and Adenomatous-Polyps

Topics: Adenocarcinoma; Adenomatous Polyps; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Male; Membrane Proteins; Mice; Prostaglandin-Endoperoxide Synthases; Randomized Controlled Trials as Topic; Sulindac

A phase III clinical trial assessed the recurrence of adenomatous polyps after treatment for 36 months with difluoromethylornithine (DFMO) plus sulindac or matched placebos. Temporary hearing loss is a known toxicity of treatment with DFMO, thus a comprehensive approach was developed to analyze serial air conduction audiograms. The generalized estimating equation method estimated the mean difference between treatment arms with regard to change in air conduction pure tone thresholds while accounting for within-subject correlation due to repeated measurements at frequencies. Based on 290 subjects, there was an average difference of 0.50 dB between subjects treated with DFMO plus sulindac compared with those treated with placebo (95% confidence interval, -0.64 to 1.63 dB; P = 0.39), adjusted for baseline values, age, and frequencies. In the normal speech range of 500 to 3,000 Hz, an estimated difference of 0.99 dB (-0.17 to 2.14 dB; P = 0.09) was detected. Dose intensity did not add information to models. There were 14 of 151 (9.3%) in the DFMO plus sulindac group and 4 of 139 (2.9%) in the placebo group who experienced at least 15 dB hearing reduction from baseline in 2 or more consecutive frequencies across the entire range tested (P = 0.02). Follow-up air conduction done at least 6 months after end of treatment showed an adjusted mean difference in hearing thresholds of 1.08 dB (-0.81 to 2.96 dB; P = 0.26) between treatment arms. There was no significant difference in the proportion of subjects in the DFMO plus sulindac group who experienced clinically significant hearing loss compared with the placebo group. The estimated attributable risk of ototoxicity from exposure to the drug is 8.4% (95% confidence interval, -2.0% to 18.8%; P = 0.12). There is a <2 dB difference in mean threshold for patients treated with DFMO plus sulindac compared with those treated with placebo.

Topics: Adenomatous Polyps; Antineoplastic Combined Chemotherapy Protocols; Audiometry, Pure-Tone; Colonic Neoplasms; Double-Blind Method; Eflornithine; Hearing; Hearing Loss; Humans; Neoplasm Recurrence, Local; Sulindac

Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance-M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.

Topics: Adenoma; Adenomatous Polyposis Coli; Adenomatous Polyps; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Genotype; Humans; Oxygenases; Polymorphism, Genetic; Sulindac

Although sulindac is known to cause regression of colorectal adenomatous polyps in familial adenomatous polyposis, less is known about the effect of sulindac on sporadic adenomas. The precise mechanisms of these effects also remain to be determined.. Sulindac was given to patients with sporadic colorectal adenomatous polyps to evaluate its effects on them, and histological analysis was performed to elucidate the mechanism of the polyp regression, as well the kind of adenomatous polys that are susceptible to the agent.. 20 adenomatous polyps in 15 patients were studied.. Sulindac (300 mg daily) was given for four months, followed by colonoscopy with removal of the residual polyps. Polyp size, degree of atypia, inflammatory cell infiltration in the polyps, and immunostaining for mutant p53 product were evaluated before and after treatment.. 13 of the 20 polyps shrank or disappeared. Patient sex, polyp location, size, degree of atypia, or p53 mutation did not affect the response, but polyps in older patients were more sensitive to sulindac. The degree of atypia or inflammatory cell infiltration was not affected by the treatment. A polyp containing a focal cancer was unresponsive.. Sulindac can cause regression of sporadic colorectal adenomatous polyps.

Topics: Adenomatous Polyps; Aged; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Male; Middle Aged; Mutation; Sulindac; Tumor Suppressor Protein p53

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in

Topics: Adenomatous Polyposis Coli; Adenomatous Polyps; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Carcinogenesis; Case-Control Studies; Cells, Cultured; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Intestinal Neoplasms; Male; Mice; Mice, Transgenic; Sulindac

Preclinical studies in animal models, human epidemiological data, and clinical trials in patients with adenomatous polyposis have consistently indicated that sulindac and other nonsteroidal antiinflammatory drugs or cyclooxygenase inhibitors have the greatest potential efficacy among current candidates for colon tumor chemopreventive agents. However, at highly effective doses they all have some risk of toxicity, and their therapeutic profile might be improved by use at lower, more tolerable doses, in combination with a second agent acting via other mechanisms.. Sulindac was tested in combination with ursodeoxycholic acid (ursodiol), a naturally occurring 7-B-epimer of the bile component chenodeoxycholic acid, for prevention of adenomas in the Min mouse model of adenomatous polyposis.. Ursodeoxycholic acid caused a dose-dependent decrease in the number of intestinal tumors. Unlike sulindac and other nonsteroidal anti-inflammatory drugs, which are quite beneficial in the distal intestine but are somewhat less effective in the proximal small intestine (especially the clinically important periampullary duodenum), ursodeoxycholate had equal efficacy throughout the entire intestine, both proximal and distal. Combined treatment with low-dose sulindac was less toxic, with normal weight gain and fewer gastrointestinal ulcerations than high-dose sulindac. Combined treatment with sulindac and ursodeoxycholate was more effective than either agent alone for the prevention of tumors throughout the entire intestine.. These experiments provide the first evidence that ursodeoxycholic acid is effective for preventing adenomas in an animal model. Cyclooxygenase inhibition, when combined with this naturally occurring bile component, may become a promising approach for colon cancer prevention.

Topics: Adenomatous Polyps; Animals; Anticarcinogenic Agents; Chemoprevention; Cholagogues and Choleretics; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Intestinal Polyposis; Mice; Mice, Inbred C57BL; Models, Animal; Sulindac; Ursodeoxycholic Acid

Topics: Adenomatous Polyposis Coli; Adenomatous Polyps; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Colonic Polyps; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Genes, APC; Germ-Line Mutation; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Sulindac

Recent experimental and epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the prevention of colorectal cancer. However, the toxicity associated with the long-term use of most classical NSAIDs has limited their usefulness for the purpose of cancer chemoprevention. Inflammatory bowel disease (IBD) patients, in particular, are sensitive to the adverse side effects of NSAIDs, and these patients also have an increased risk for the development of intestinal cancer. 5-Aminosalicylic acid (5-ASA) is an anti-inflammatory drug commonly used in the treatment of IBD and may provide protection against the development of colorectal cancer in these patients. To directly evaluate the ability of 5-ASA to suppress intestinal tumors, we studied several formulations of 5-ASA (free acid, sulfasalazine, and Pentasa) at multiple oral dosage levels [500, 2400, 4800, and 9600 parts/million (ppm)] in the adenomatous polyposis coli (Apc) mouse model of multiple intestinal neoplasia (Min). Although the ApcMin mouse is not a model of colitis-associated neoplasia, it is, nonetheless, a useful model for assessing the ability of anti-inflammatory agents to prevent tumor formation in a genetically preinitiated population of cells. We used a study design in which drug was provided ad libitum through the diet beginning at the time of weaning (28 days of age) until 100 days of age. We included 200 ppm of piroxicam and 160 ppm of sulindac as positive controls, and the negative control was AIN-93G diet alone. Treatment with either piroxicam or sulindac produced statistically significant reductions in intestinal tumor multiplicity (95% and 83% reductions in tumor number, respectively; P < 0.001 versus controls). By contrast, none of the 5-ASA drug formulations or dosage levels produced consistent dose-progressive changes in polyp number, distribution, or size, despite high luminal and serum concentrations of 5-ASA and its primary metabolite N-acetyl-5-ASA. Thus, 5-ASA does not seem to possess direct chemosuppressive activity against the development of nascent intestinal adenomas in the ApcMin mouse. However, because intestinal tumor development in the ApcMin mouse is driven by a germline mutation in the Apc gene rather than by chronic inflammation, we caution that these findings do not definitively exclude the possibility that 5-ASA may exert a chemopreventive effect in human IBD patients.

Topics: Adenomatous Polyps; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Chemoprevention; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Fluorometry; Intestinal Neoplasms; Mesalamine; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Piroxicam; Sulfasalazine; Sulindac

Like adenomatous polyps in familial adenomatous polyposis, some sporadic colorectal polyps have been reported to regress in response to sulindac administration. However, a rapidly growing invasive rectal cancer developed in one of 15 patients with sulindac-treated sporadic adenomatous colorectal polyps 16 months after sulindac treatment. In this patient, both the adenomatous polyp that responded partially to sulindac and the rectal cancer developing after sulindac therapy showed immunostaining for cyclooxygenase-2. Although short term sulindac therapy seems to be able to cause some adenomatous colorectal polyps to regress, 4 months of sulindac therapy may not reliably prevent colorectal cancer development in these patients.

Topics: Adenocarcinoma; Adenomatous Polyps; Anti-Inflammatory Agents, Non-Steroidal; Colonic Polyps; Humans; Male; Middle Aged; Neoplasms, Second Primary; Rectal Neoplasms; Sulindac

Topics: Adenomatous Polyps; Anti-Inflammatory Agents, Non-Steroidal; Colonic Neoplasms; Humans; Sulindac

Sulindac, a non-steroidal anti-inflammatory drug, causes regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP) but the response is variable. Specific clinical factors predictive of sulindac induced regression have not been studied.. 22 patients with FAP were given sulindac 150 mg orally twice a day. Polyp number and size were determined before treatment and at three months. The relation of nine clinical factors to polyp regression (per cent of baseline polyp number after treatment) was evaluated by univariate and multivariate analysis.. After three months of sulindac, polyp number had decreased to 45 per cent of baseline and polyp size to 50 per cent of baseline (p < 0.001 and p < 0.01, respectively). Univariate analysis showed greater polyp regression in older patients (p = 0.004), those with previous colectomy and ileorectal anastomosis (p = 0.001), and patients without identifiable mutation of the APC gene responsible for FAP (p = 0.05). With multivariate regression analysis, response to sulindac treatment was associated with previous subtotal colectomy.. Sulindac treatment seems effective in producing regression of colorectal adenomas of FAP patients with previous subtotal colectomy regardless of baseline polyp number and size. Changed sulindac metabolism, reduced area of the target mucosa, or changed epithelial characteristics after ileorectal anastomosis may explain these findings.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyps; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Remission Induction; Single-Blind Method; Sulindac

Topics: Adenomatous Polyps; Child; Colonic Neoplasms; Hepatoblastoma; Humans; Liver Neoplasms; Male; Remission Induction; Sulindac

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.. 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.

Topics: Adenomatous Polyps; Aged; Anti-Inflammatory Agents, Non-Steroidal; Colonic Polyps; Female; Humans; Male; Middle Aged; Pilot Projects; Piroxicam; Sulindac