sulindac and Colonic-Polyps

Sulindac suppresses the growth of colon polyps in Gardner syndrome and familial adenomatous polyposis. The mechanism of action is not known. The problems are to ascertain the significance of high prostaglandin concentrations in transformed cells, colon polyps and cancers and to explain how sulindac restores normal growth patterns. A few clinical observations and an abundance of experimental data can be integrated to produce a reasonable model based on current biochemical and physiologic concepts. A fundamental defect in the formation of colon polyps is mutation of the APC (adenomatous polyposis coli) gene that leads to inadequate suppression of proliferation. There is high PGE2 content in colon polyps and cancers, presumably the result of stimulation by protein kinase C (PKC). In small quantities it stimulates cyclic AMP production but with persistent high concentrations it desensitizes and down-regulates specific PG receptors and inactivates adenylate cyclase, cAMP synthesis, and the cAMP-dependent mechanism for control of proliferation. The PKC pathway is thereby unopposed. It is hypothesized that restriction of PG synthesis by sulindac is accompanied by resensitization of PG receptors, and reactivation of the cAMP-dependent pathway for control of cell growth. It is further postulated that restoration of cAMP synthesis and protein kinase A activity converts a functionally inadequate mutant APC suppressor gene to one sufficient to inhibit colon polyp formation.

Topics: Colonic Neoplasms; Colonic Polyps; Dinoprostone; Genes, APC; Humans; Phenotype; Receptors, Prostaglandin; Sulindac

On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer.. Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted.. ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed.. ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer.

Topics: Aberrant Crypt Foci; Adenoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Polyps; Colorectal Neoplasms; Etodolac; Female; Humans; Male; Middle Aged; Sulindac

We sought to determine in a double-blinded, placebo-controlled study if the nonsteroidal anti-inflammatory drug sulindac causes regression of sporadic colonic polyps. The impetus for this study is the profound regressive effect of sulindac on polyps in familial adenomatous polyposis.. Asymptomatic patients undergoing routine screening flexible sigmoidoscopy were enrolled if they had polyps of < or = 1 cm in size. Of 162 patients screened, 22 patients were randomly enrolled to take 150 mg of sulindac twice daily, and 22 patients took a placebo. Treatment duration was 4 months and was followed by colonoscopy with removal of all polyps.. Four patients were dropped from the study (sulindac group) due to urosepsis (1 patient), heartburn (2 patients), and anemia (1 patient). Compliance (determined by monthly pill counting), mean age, and the effect of sulindac vs. placebo on polyp regression or size were not statistically different in the two treatment groups. Analysis of our data indicated that there is only a 0.8% chance that the probability of polyp regression with sulindac is as large as 50%.. Four months of treatment with sulindac does not result in a clinically significant regression of sporadic colonic polyps, although a small effect may not have been detected by the size of our study. Our data suggest that the biological response of sporadic and familial polyposis polyps to sulindac is different.

Topics: Aged; Anemia; Colonic Polyps; Double-Blind Method; Female; Heartburn; Humans; Male; Middle Aged; Patient Compliance; Remission Induction; Sulindac

Topics: Adenomatous Polyposis Coli; Animals; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colonic Polyps; Disease Models, Animal; Dose-Response Relationship, Drug; Erlotinib Hydrochloride; Genes, APC; Intestinal Neoplasms; Male; Mutation; Rats; Sulindac

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid.. As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apc. Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone.. Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.

Topics: Adenomatous Polyposis Coli Protein; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Colonic Polyps; Colorectal Neoplasms; Disease Models, Animal; Humans; Mice; Phospholipids; Sulindac

Sulindac has been used for treating colorectal polyps widely. However, the efficacy and safety of sulindac for colorectal polyps are unclear. This study aims to evaluate the efficacy and safety of sulindac for colorectal polyps.. Randomized controlled trials of sulindac in the treatment of colorectal polyps will be searched in PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, the Chongqing VIP Chinese Science, and Technology Periodical Database, and China biomedical literature database (CBM) from inception to August, 2020. And Baidu Scholar, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain more relevant studies comprehensively. Two researchers will perform data extraction and risk of bias assessment independently. Statistical analysis will be conducted in RevMan 5.3.. This study will summarize the present evidence by exploring the efficacy and safety of sulindac in the treatment of colorectal polyps.. The findings of the study will provide helpful evidence for the efficacy and safety of sulindac in the treatment of colorectal polyps, facilitating clinical practice and further scientific studies.. The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.. DOI 10.17605/OSF.IO/N5GDH.

Topics: Antineoplastic Agents; Colonic Polyps; Humans; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Rectum; Research Design; Sulindac; Systematic Reviews as Topic

PIRC rats (F344/NTac-Apc (am1137) ) mutated in the Apc gene spontaneously develop colon tumors thus mimicking familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC) more closely than Apc-based rodent models developing tumors mostly in the small intestine. To understand whether microscopic dysplastic lesions precede the development of macroscopic tumors, PIRC rat colon was examined for the presence of mucin depleted foci (MDF), microadenomas of the rodent and human colon. Few MDF (about 4/animal) were already present in 1-month-old rats and their number rapidly increases to about 250 in 8-month-old rats. These lesions showed Wnt signaling activation (nuclear β-catenin accumulation) and were dramatically decreased by sulindac (320 ppm), a drug with chemopreventive activity (MDF/rat at 4 months: 156 ± 8 and 38 ± 6 in controls and sulindac-treated rats, respectively, means ± SE, p < 0.001). Since altered proliferation and apoptosis could underlie the early phases of carcinogenesis, we studied these processes in the apparently normal colon mucosa (NM) of 1-month-old PIRC and wt rats. Colon proliferation (PCNA expression) was significantly higher in PIRC rats. Notably, PIRC rat NM showed resistance to apoptosis since it sustained proliferation and had lower apoptosis after a cytotoxic insult with 1,2 dimethylhydrazine. Gene expression of Myc, p21, Birc5, Ogg1, Apex1 and Sod2 were significantly up-regulated in the NM of PIRC rat. The overall results put forward PIRC rat as useful model of colon carcinogenesis, either to study the process itself or to test in vivo chemopreventive agents in both short- and long-term studies.

Topics: Animals; Apoptosis; Cell Proliferation; Colon; Colonic Neoplasms; Colonic Polyps; Cyclin-Dependent Kinase Inhibitor p21; Female; Genes, APC; Genes, myc; Male; Microtubule-Associated Proteins; Mucins; Mutation; Rats; Rats, Inbred F344; Sulindac; Survivin

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac effectively prevent colon cancer in humans and rodent models. However, their cellular targets and underlying mechanisms have remained elusive. We found that dietary sulindac induced apoptosis to remove the intestinal stem cells with nuclear or phosphorylated β-catenin in APC(Min/+) mice. NSAIDs also induced apoptosis in human colonic polyps and effectively removed cells with aberrant Wnt signaling. Furthermore, deficiency in SMAC, a mitochondrial apoptogenic protein, attenuated the tumor-suppressive effect of sulindac in APC(Min/+) mice by blocking apoptosis and removal of stem cells with nuclear or phosphorylated β-catenin. These results suggest that effective chemoprevention of colon cancer by NSAIDs lies in the elimination of stem cells that are inappropriately activated by oncogenic events through induction of apoptosis.

Topics: Adenomatous Polyposis Coli; Aged; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Apoptosis Regulatory Proteins; beta Catenin; Carrier Proteins; Cell Nucleus; Chemoprevention; Colonic Polyps; Female; Humans; Intestines; Intracellular Signaling Peptides and Proteins; Male; Mice; Middle Aged; Mitochondrial Proteins; Neoplastic Stem Cells; Phosphorylation; Signal Transduction; Sulindac; Time Factors; Wnt Proteins

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Clinical Trials as Topic; Colonic Polyps; Colonoscopy; Dietary Fiber; Drug Therapy, Combination; Eflornithine; Humans; Middle Aged; Secondary Prevention; Sulindac

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

Mutation of the adenomatous polyposis coli (APC) gene and the subsequent dysregulation of beta-catenin are well-documented abnormalities in familial adenomatous polyposis (FAP), as well as sporadic polyposis. Intriguingly, overexpression of the integrin-linked kinase (ILK) has been shown to modulate beta-catenin subcellular localization and function. However, the significance of this finding for human carcinogenesis remains unclear. Here, we report the increased biochemical activity and expression of ILK protein in polyps from FAP patients. Furthermore, dramatic increases in ILK immunoreactivity were observed in all abnormal crypts from sporadic polyps, when compared with the normal appearing crypts within the same resected specimens. As sulindac and aspirin are the two most important therapeutic/chemopreventative agents demonstrated in colorectal carcinogenesis, in both humans and animals, further investigation revealed that these non-steroidal anti-inflammatory drugs (NSAIDs) target ILK and ILK-mediated events in vivo. These include inhibition of, both the biochemical activation of ILK, inhibition of serine 9 GSK3beta phosphorylation and the enhancement of TCF-4 transcriptional activity. In conclusion, ILK protein hyperexpression appears to be an early event in colonic polyposis. Additionally, ILK signaling is shown to undergo modulation by sulindac (and aspirin) for the first time, indicating that it is likely to be one of the targets affected by these agents in vivo.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colonic Polyps; Disease Progression; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Enzymologic; Humans; Mutation; Phosphorylation; Protein Serine-Threonine Kinases; Serine; Signal Transduction; Sulindac; Time Factors; Tumor Cells, Cultured

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

A boy with generalised infantile polyposis syndrome is reported to highlight the difficulties in management. Despite attempts to reduce polyp mass by regular endoscopic polypectomy, daily transfusions of blood products, and a trial of the non-steroidal anti-inflammatory agent sulindac, his condition gradually deteriorated and he died of septicaemia.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Component Transfusion; Colonic Polyps; Endoscopy; Fatal Outcome; Humans; Infant; Male; Sepsis; Sulindac

First, and most importantly, the standard of care for treating adenomatous polyps is polypectomy and not therapy with NSAIDs. The initial clinical observation by Waddell and Loughry in 1983 that sulindac treatment influenced rectal polyps in patients with FAP has led to a considerable amount of research, commentary, and discussion during the past decade. These original observations have been validated by controlled clinical trials. Work presented in this issue by Ladenheim et al. indicates that sulindac may not be effective therapy for sporadic polyps that are present before initiation of treatment (secondary prevention). Even though their study may have failed to show a small effect of NSAIDs on polyps, further investigation of the ability of NSAIDs to cause regression of established polyps is probably not warranted. A more clinically relevant question, whether or not these agents can be used in a primary prevention strategy to prevent the development of adenomas in a colon devoid of these lesions, is currently being addressed in a large trial with sufficient statistical power to render firm conclusions (personal communication, January 1995). The multiple reports that sulindac treatment causes regression of adenomas in patients with FAP has stimulated research directed at understanding the molecular basis for these effects. If we are able to understand the molecular mechanism by which NSAIDs decrease the risk of colorectal cancer, we might be able to design more effective drugs or other approaches that would be clinically useful in humans for colorectal cancer chemoprevention.

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Colonic Polyps; Colorectal Neoplasms; Humans; Isoenzymes; Prostaglandin-Endoperoxide Synthases; 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

Topics: Adenomatous Polyposis Coli; Adult; Colonic Polyps; Female; Gardner Syndrome; Humans; Intestinal Mucosa; Male; Middle Aged; Prostaglandins; Sulindac

The effect of sulindac, a nonsteroid antiinflammatory drug, on colon polyposis has been evaluated in seven patients after subtotal colectomy and ileoproctostomy and in four patients with intact colons. The patients all had Gardner's syndrome or familial polyposis coli. All polyps were eliminated, except for a few that arose in the rectal mucosa and the anal canal. No cancers developed in these patients on follow-up.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Child; Colectomy; Colonic Polyps; Combined Modality Therapy; Drug Evaluation; Female; Gardner Syndrome; Humans; Indenes; Male; Neoplasm Recurrence, Local; Sulindac

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

Topics: Adult; Colonic Polyps; Humans; Indenes; Male; Sulindac