sulindac and Intestinal-Polyps

Gastro-duodenal polyps develop in up to 90% of familial adenomatous polyposis (FAP) patients and periampullary carcinoma is one of the most common extra-colonic malignancies in this syndrome. Periampullary adenomas have been shown to be precursor lesions to periampullary carcinoma. Sulindac, a non-steroidal anti-inflammatory drug, has been reported to cause regression of rectal polyps in FAP patients, however its role in periampullary polyp regression is unclear.. In May 1993, a prospective study was begun to evaluate the role of sulindac in prevention of polyp recurrence after resection of large (> 1 cm) duodenal polyps in FAP patients. Eight patients, mean age 50 years (range 35 to 65), with documented large periampullary polyps were placed on sulindac 150 mg twice daily. Prior to enrollment, all patients had their large polyps removed from the periampullary region by interventional endoscopy or by surgery. All patients had multiple small residual duodenal polyps. Follow-up was performed by one experienced endoscopist with a side-viewing video endoscope. Endoscopy was performed 6 monthly. Median follow-up time was 17.5 months (range 10 to 24 months).. In 3 patients, sulindac was discontinued due to side effects: abdominal cramps (n = 2) and upper G-I bleeding (n = 1). None of the patients had regression of small periampullary polyps. In addition, one patient developed an invasive periampullary carcinoma while on sulindac and 3 patients developed large recurrent periampullary polyps requiring further treatment.. In our experience, sulindac is of no significant benefit for the control of periampullary polyps in FAP. Effective medical treatment of these polyps is still lacking.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Duodenal Neoplasms; Endoscopy, Gastrointestinal; Female; Humans; Intestinal Polyps; Male; Middle Aged; Prospective Studies; Sulindac; Treatment Outcome

Eighteen patients with familial adenomatous polyposis (FAP) who had previously undergone colectomy but had upper gastrointestinal polyps were studied in a double-blind randomized crossover trial comparing sulindac with calcium and calciferol. Sulindac produced a reduction in the crypt proliferation index in the gastric epithelium of patients but did not significantly affect duodenal mucosa. Calcium with calciferol did not have any effects on crypt proliferation index in patients with FAP.

Topics: Adenomatous Polyposis Coli; Calcium; Cell Division; Common Bile Duct Neoplasms; Cross-Over Studies; Duodenal Neoplasms; Ergocalciferols; Humans; Intestinal Polyps; Prospective Studies; Stomach Neoplasms; Sulindac

Topics: Adenomatous Polyposis Coli; Duodenal Neoplasms; Humans; Intestinal Polyps; Rectal Neoplasms; Sulindac

Twenty-four patients with familial adenomatous polyposis who had previously undergone prophylactic colectomy and had advanced duodenal polyposis were entered into a randomized trial to assess the effect of the non-steroidal anti-inflammatory drug sulindac on duodenal and rectal polyps. Polyp size and number were assessed by videotaped duodenoscopy (and rectoscopy in 14 patients) at entry and after 6 months of treatment; the tapes were compared by two assessors who were unaware of the randomization and the shuffled chronological order of the recordings. Mucosal cell proliferation was measured by in vitro incorporation of 5-bromo-2'-deoxyuridine. Sulindac therapy was associated with a reduction in epithelial cell proliferation in the duodenum (median labelling index (LI) 15.8 versus 14.4 per cent, P = 0.003) and a trend towards duodenal polyp regression (P = 0.12). In the rectum, cell proliferation showed a marked reduction (median LI 8.5 versus 7.4 per cent, P = 0.018), and significant (P = 0.01) polyp regression was seen. Rectal polyposis was less severe than that in the duodenum and responded more dramatically. Sulindac is a possible treatment for patients in whom rectal polyps have failed to show significant regression after ileorectal anastomosis and who are unsuitable for pouch surgery; it may be useful in early duodenal polyposis or as an adjunct after duodenal clearance.

Topics: Adenomatous Polyposis Coli; Adult; Aged; Cell Division; Double-Blind Method; Duodenal Neoplasms; Duodenum; Female; Humans; Intestinal Mucosa; Intestinal Polyps; Male; Middle Aged; Rectal Neoplasms; Rectum; Sulindac

Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported.. We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year.. A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted.. Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.

Topics: Adenomatous Polyposis Coli; Adult; Double-Blind Method; Female; Humans; Intestinal Polyps; Male; Rectal Neoplasms; Sulindac

To investigate the in vivo effects of Lactobacillus rhamnosus GG (LGG) on intestinal polyp development and the interaction between this single-organism probiotic and the gut microbiota therein.. The Apc. Our study using shotgun metagenomics highlights how single probiotic LGG may exert its beneficial effects and decrease polyp formation in mice by maintaining gut microbial functionality.. This probiotic intervention targeting microbiota may be used in conjugation with other dietary supplements or drugs as part of prevention strategies for early-stage colon cancer, after further clinical validations in human.

Topics: Adenomatous Polyposis Coli Protein; Animals; Humans; Intestinal Polyps; Lacticaseibacillus rhamnosus; Metagenomics; Mice; Microbiota; Phylogeny; Probiotics; Specific Pathogen-Free Organisms; Sulindac

The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its prodrug DM-sulindac] that do not inhibit COX-2 activity. Sulindac sulfide and DM-sulindac induced the expression of NAG-1/GDF15 in HCT116 cells as determined by quantitative real-time PCR and Western blot. We fed APC/Min mice with 320 ppm of sulindac and doses of DM-sulindac. Only sulindac significantly inhibited tumor formation inAPC/Min mice. To determine the pharmacokinetic properties of sulindac and DM-sulindac in vivo, wild-type C57/B6 mice were fed with sulindac and DM-sulindac at 80, 160, and 320 ppm. High-performance liquid chromatography analysis revealed that the conversion of DM-sulindac to DM-sulindac sulfide (active form) was less efficient than the conversion of sulindac to sulindac sulfide (active form) in the mice. Lower levels of DM-sulindac sulfide accumulated in intestinal and colon tissues in comparison with sulindac sulfide. In addition, NAG-1/GDF15 was induced in the liver of sulindac-fed mice but not in the DM-sulindac-fed mice. Collectively, our results suggest that the tumor-inhibitory effects of sulindac in APC/Min mice may be due to, in part, NAG-1/GDF15 induction in the liver. Our study also suggests that pharmacologic properties should be carefully evaluated when developing drug candidates.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blotting, Western; Disease Models, Animal; Genes, APC; Growth Differentiation Factor 15; Humans; Immunoenzyme Techniques; Intestinal Polyps; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulindac; Tissue Distribution; Tumor Cells, Cultured

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited syndrome in humans. The Apc(Min/+) mouse, which expresses a mutant homolog of the adenomatous polyposis coli gene, is a model of FAP in humans. Treatment with the nonsteroidal anti-inflammatory drugs (NSAIDS) sulindac or celecoxib can suppress polyp development in FAP patients, but responses are generally transient and incomplete. Combination chemoprevention with the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) and either celecoxib or sulindac was evaluated in the Apc(Min/+) mouse. Combinations of DFMO and either NSAID reduced intestinal tumor number by more than 80% (P < 0.0001) compared to untreated controls. In addition to the dramatic reduction in tumor number, the combination of DFMO and sulindac reduced the development of high-grade intestinal adenomas compared to sulindac alone (P = 0.003). The fraction of high-grade intestinal adenomas remaining after treatment was similar for the combination of DFMO and celecoxib and celecoxib alone. Only combinations of DFMO plus sulindac reduced total intestinal polyamine contents compared to untreated mice. These data support the rationale for treatment of FAP patients postcolectomy with DFMO combined with either celecoxib or sulindac but indicate that sulindac may be more effective than celecoxib in reducing intestinal polyamine contents and the incidence of high-grade intestinal adenomas when combined with DFMO.

Topics: Adenoma; Adenomatous Polyposis Coli; Animals; Biogenic Polyamines; Celecoxib; Chemoprevention; Eflornithine; Female; Genes, APC; Intestinal Neoplasms; Intestinal Polyps; Male; Mice; Mice, Inbred C57BL; Pyrazoles; Sulfonamides; Sulindac

Epidemiological and animal studies suggest that tea may be protective towards cancers of the GI tract. White tea, the least processed form of tea, contains high levels of polyphenols and, like green tea, is chemopreventive towards heterocyclic amine-initiated colonic aberrant crypt formation in male F344 rats. We examined for the first time the relative effectiveness of white and green tea in suppressing intestinal tumorigenesis in C57BL/6J-Apc(Min/+) (Apc(min)) mice. Each tea was also compared with sulindac, a non-steroidal anti-inflammatory drug known to be highly effective in Apc(min) mice. Male C57BL/6J (+/+) (wild-type) and Apc(min) mice were treated in the drinking water with white tea or green tea (1.5% w/v, 2 min brew-time), 80 p.p.m. sulindac, a combination of 80 p.p.m. sulindac in 1.5% white tea, or pH buffered water. After 12 weeks of treatment, Apc(min) mice given white tea, green tea, or sulindac had significantly fewer tumors than controls (P < 0.05). The protection provided by 1.5% green or white tea was comparable to that provided by 80 p.p.m. sulindac. Mice treated with a combination of white tea plus sulindac had significantly fewer tumors than either treatment alone (P < 0.05). beta-catenin and beta-catenin/Tcf-4 regulated proteins Cyclin D(1) and c-Jun were readily detected in polyps, but markedly reduced in normal-looking intestines of mice treated with both tea and sulindac. This research provides evidence that teas, particularly when administered in combination with sulindac, are highly effective at inhibiting intestinal neoplasia in male Apc(min) mice via direct or indirect effects on the beta-catenin/APC pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; beta Catenin; Cytoskeletal Proteins; Down-Regulation; Genes, APC; Intestinal Polyps; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Signal Transduction; Sulindac; Tea; Trans-Activators

Mutations in the human adenomatous polyposis (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. The APC gene is a tumor suppressor that has been termed the "gatekeeper gene" for colon cancer. In addition to the 100% mutation rate in FAP patients, the APC gene is mutated in >80% of sporadic colon and intestinal cancers. The Apc gene in mice has been mutated either by chemical carcinogenesis, resulting in the Min mouse Apcdelta850, or by heterologous recombination, resulting in the Apcdelta716 or Apedelta1368 mice (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). Although homozygote Apc-/- mice are embryonically lethal, the heterozygotes are viable but develop numerous intestinal polyps with loss of Apc heterozygosity within the polyps (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). The proinflammatory, prooncogenic protein cyclooxygenase (COX)-2 has been shown to be markedly induced in the Apcdelta716 polyps at an early stage of polyp development (M. Oshima et al., Cell, 87: 803-809, 1996). We demonstrate here that treatment with the specific COX-2 inhibitor rofecoxib results in a dose-dependent reduction in the number and size of intestinal and colonic polyps in the Apcdelta716 mouse. The plasma concentration of rofecoxib that resulted in a 55% inhibition of polyp number and an 80% inhibition of polyps > 1 mm in size is comparable with the human clinical steady-state concentration of 25 mg rofecoxib (Vioxx) taken once daily (A. Porras et al., Clin. Pharm. Ther., 67: 137, 2000). Polyps from both untreated and rofecoxib- or sulindac-treated Apcdelta716 mice expressed COX-1 and -2, whereas normal epithelium from all mice expressed COX-1 but minimal amounts of COX-2. Polyps from either rofecoxib- or sulindac-treated mice had lower rates of DNA replication, expressed less proangiogenic vascular endothelial-derived growth factor and more membrane-bound beta-catenin, but showed unchanged nuclear localization of this transcription factor. This study showing the inhibition of polyposis in the Apcdelta716 mouse suggests that the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a chemopreventive agent in human intestinal and colon cancer.

Topics: Animals; Anticarcinogenic Agents; beta Catenin; Cell Nucleus; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytoskeletal Proteins; DNA Replication; Dose-Response Relationship, Drug; Female; Genes, APC; Intestinal Neoplasms; Intestinal Polyps; Isoenzymes; Lactones; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Sulfones; Sulindac; Trans-Activators

Epidemiological studies suggest that nonsteroidal anti-inflammatory agents decrease the risk of colorectal cancer. This is believed to be mediated, at least in part, by inhibition of cyclooxygenase (COX) activity. There are two COX isoenzymes, namely the constitutively expressed COX-1 and the inducible COX-2. COX-2 is overexpressed in adenomas and colorectal cancers, and COX-2-specific inhibitors have been shown to inhibit intestinal polyps in Apc(Delta716) mice more effectively than dual COX-1/COX-2 inhibitors such as sulindac. Various Apc knockout mice, including the multiple intestinal neoplasia (Min) mouse and the Apc(Delta716) mouse, are limited by their lack of large numbers of colonic adenomas and aberrant crypt foci, the putative precursors of large-bowel polyps and cancers. Our DNA mismatch-repair-deficient Min mouse model (Apc+/-Msh2-/-) has genetic features of both familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, and most importantly, rapidly develops numerous small- and large-bowel adenomas, as well as colonic aberrant crypt foci. The purpose of this study was to determine the effects of COX inhibitors on intestinal adenomas and colonic aberrant crypt foci in this accelerated polyposis, mismatch-repair-deficient Min mouse model, in addition to a standard Min mouse model. Weanling Apc+/-Msh2-/- and Min mice were fed diets containing no drug, sulindac, or a specific COX-2 inhibitor (MF-tricyclic). Apc+/-Msh2-/- and Min mice were sacrificed after 4 weeks and 5 months on diet, respectively. Apc+/-Msh2-/- mice treated with MF-tricyclic had significantly fewer small-bowel polyps (mean +/- SD, 178 +/- 29) compared with mice on sulindac (278 +/- 80), or control diet (341 +/- 43; P < 0.001). There was no difference in numbers of large-bowel polyps or aberrant crypt foci in mice in the three groups. MF-tricyclic was also effective in reducing both small- and large-bowel polyps in Min mice. Western analysis demonstrated COX-2 expression in both large- and small-bowel polyps from mice of both genotypes. This study demonstrates that a specific COX-2 inhibitor is effective in preventing small-bowel polyps in mismatch-repair-deficient Min mice and both small- and large-bowel polyps in standard Min mice. Therefore, specific COX-2 inhibitors may be useful as chemopreventive and therapeutic agents in humans at risk for colorectal neoplasia.

Topics: Adenoma; Animals; Colorectal Neoplasms; Crosses, Genetic; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; DNA Repair; DNA-Binding Proteins; Female; Furans; Genes, APC; Intestinal Polyps; Isoenzymes; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; MutS Homolog 2 Protein; Precancerous Conditions; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Substrate Specificity; Sulindac

Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), decreases the occurrence of polyps in patients with familial adenomatous polyposis (FAP). The effects of colectomy with ileorectal anastomosis (IRA) and sulindac treatment on rectal mucosa proliferation and polyp occurrence were examined in patients with FAP.. The number and size of rectal polyps were measured with colonoscopy. The labeling index, the percentage of labeled cells per crypt compartment, was assessed in rectal biopsy specimens with [3H]thymidine incorporation and autoradiography in 6 non-IRA and 14 IRA patients before and after treatment with 200 mg of sulindac/day for 60 days.. The IRA patients had a lower labeling index and a decrease in the percentage of labeled cells in the upper compartment of the crypt (P < 0.01) relative to non-IRA subjects. Sulindac did not influence the labeling index and the distribution of labeled cells along the crypt. On the contrary, a dramatic decrease in the size and number of polyps was observed after sulindac treatment (P < 0.001).. The persistence of a abnormal mucosal proliferation after sulindac therapy, in spite of the reduction of polyp number, suggests caution in assuming a lower risk of rectal cancer in patients with FAP.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Anastomosis, Surgical; Cell Division; Child; Female; Humans; Ileum; Intestinal Polyps; Male; Middle Aged; Rectal Neoplasms; Rectum; Sulindac

Duodenal polyps with a malignant potential pose a serious threat to Gardner's patients. Several reports have shown regression or disappearance of colonic polyps with sulindac therapy. We report the first case of disappearance of duodenal polyps with sulindac.

Topics: Aged; Duodenal Neoplasms; Gardner Syndrome; Humans; Intestinal Polyps; Male; Recurrence; Remission Induction; Sulindac

Topics: Adult; Colonic Polyps; Female; Humans; Indenes; Intestinal Polyps; Male; Rectal Neoplasms; Sulindac