sulindac-sulfone and Adenomatous-Polyposis-Coli

In population-based observational studies, people had lower rates of colorectal cancer if they were taking various agents, including nonsteroidal anti-inflammatory drugs, calcium, and folate. In placebo-controlled trials in patients with familial adenomatous polyposis and in patients with sporadic colon adenomas, nonsteroidal anti-inflammatory drugs reduced the rates of adenomas, and there is a biologic rationale that they would be effective in reducing colorectal cancer as well. Randomized trials of chemopreventive agents are underway in the general population.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Celecoxib; Colorectal Neoplasms; Folic Acid; Humans; Pyrazoles; Sulfonamides; Sulindac

A 12 month, multicentre, randomised, double blind, placebo controlled, phase 3, dose-response study was carried out. Exisulind inhibits tumour growth by induction of apoptosis. The aim of our study was to investigate if exisulind induces regression of sporadic colonic adenomas.. A 12 month multicentre randomised double blind placebo controlled phase 3 dose response study was carried out. At baseline colonoscopy, left sided polyps (3-10 mm) were tattooed, measured, and left in place. Subjects received exisulind 200 or 400 mg, or placebo daily. Follow up sigmoidoscopy was performed after six months, and removal of any remaining polyps at the 12 month colonoscopy. The primary efficacy variable was change in polyp size from baseline.. A total of 281 patients were enrolled and randomised; 155 (55%) fulfilled the criteria for the intention to treat (ITT) analysis and 114 (41%) fulfilled the criteria for the efficacy evaluation analysis (patients who underwent the 12 month colonoscopy). The decrease in median polyp size was significantly greater (p=0.03) in patients who received exisulind 400 mg (-10 mm2) compared with those who received placebo (-4 mm2). Complete or partial response was significantly higher in the exisulind 400 mg group (54.6%) compared with the placebo group (30.2%), and disease progression was significantly lower (6.1% v 27.9%) (p=0.04 and 0.02, respectively). Increased liver enzymes (8.4%) and abdominal pain (14.7%) were also reported at a greater frequency in the exisulind 400 mg group.. Exisulind caused significant regression of sporadic adenomatous polyps but was associated with more toxicity. This model of polyp regression, short in its term and involving a comparatively small patient sample size, may be the best available tool to assess a therapeutic regimen before launching into large preventive clinical studies.

Topics: Adenomatous Polyposis Coli; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Colonoscopy; Combined Modality Therapy; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Sulindac; Treatment Outcome

Exisulind (sulindac sulfone; FGN-1), a metabolite of sulindac without known effects on prostaglandin synthesis, can promote apoptosis and inhibit tumorigenesis in preclinical systems. We performed a Phase I trial of this compound in patients with familial adenomatous polyposis (FAP) to examine the tolerability and safety of this drug in the cancer chemoprevention setting. Six patients each were treated with exisulind at doses of 200, 300, and 400 mg p.o. twice a day. Reversible hepatic dysfunction was noted in four of six patients treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six patients treated at each of the lower dose levels. The serum half-life of exisulind was 6-9 h; little drug accumulation was noted over time. A nonsignificant trend toward increased apoptosis in polyps was noted at the maximum tolerated dose, but no decrease in polyp numbers or significant effects on cellular proliferation was noted. After treatment, polyps tended to display a "halo" appearance grossly and mucinous differentiation histologically. The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies. Reversible hepatic dysfunction limits further dose escalation. A decrease in polyp numbers could not be demonstrated, but the trend toward increased apoptosis at the MTD and the observation of mucinous change histologically suggest that further investigation of drugs of this class might be warranted.

Topics: Adenomatous Polyposis Coli; Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Apoptosis; Female; Half-Life; Humans; In Situ Nick-End Labeling; Ki-67 Antigen; Male; Middle Aged; Sulindac

Topics: Adenomatous Polyposis Coli; Adult; Antineoplastic Agents; Health Education; Humans; Male; Sulindac; United States

Sulindac sulfone (Exisulind), a metabolite of the non-steroidal anti-inflammatory drug, sulindac, was evalauted for its effects on the development of rectal polyps in patients with familial adenomatous polyposis. Three cohorts of 6 patients each were given doses of 200, 300, or 400 mg Exisulind twice daily. Hepatotoxicity, shown by elevation in blood transaminase levels, was the dose-limiting toxicity and occurred at the 400 mg bid dose. Due to this toxicity, all patients treated with the 400 mg dose were subsequently reduced to the 200 mg dose level. Subsequently, 2 of the 6 patients were dose-escalated to 400 mg bid dose. The patients were treated with Exisulind for a period of six months. Sixteen of 18 patients had regression of small polyps (> or = 6 mm in diameter) characterized by a flattening of the polyps and a macular "halo" appearance. Histopathologic examination of the polyp biopsy specimens showed a marked increase in the proportion of mucin producing cells in the glands after treatment with Exisulind at all dose levels. Ki-67 staining, a measure of cell proliferation, was higher in the polyps than in normal mucosa. There was no significant change in the proliferation index between baseline and six month values in any of the groups treated with Exisulind or in normal tissues. The median apoptotic labeling index, as determined by the TUNEL technique, was higher in the polyps than in normal-appearing mucosa. Overall, there was no significant change in the apoptotic labeling index between base-line and 6 months in normal-appearing mucosa however, the index in polyps was increased. These results suggest that treatment of FAP patients with Exisulind for a period of six months may lead to regression of small polyps, and that the mechanisms of Exisulind--induced regression appear to be through stimulation of mucus differentiation and apoptosis in glandular epithelium.

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Division; Dose-Response Relationship, Drug; Humans; Ki-67 Antigen; Sulindac

Colorectal cancer (CRC) is the second leading cause of cancer death in the USA. Accumulation of beta-catenin protein is nearly ubiquitous in colon adenomas and cancers, presumably due to mutations in the APC or beta-catenin genes that inhibit proteasome-dependent degradation of beta-catenin protein. Substantial clinical, epidemiological, and animal evidence indicate that sulindac and other non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of CRC. The mechanisms by which sulindac exerts its potent growth inhibitory effects against colon tumor cells are incompletely understood, but down-regulation of beta-catenin has been suggested as one potential mechanism. The goal of this study was to determine the mechanism of beta-catenin protein down-regulation by sulindac metabolites. Treatment of human colon cancer cell lines with apoptotic concentrations of sulindac metabolites (sulindac sulfide, sulindac sulfone) induced a dose- and time-dependent inhibition of beta-catenin protein expression. Inhibition of proteasome activity with MG-132 partially blocked the ability of sulindac sulfide and sulindac sulfone to inhibit beta-catenin protein expression. Pretreatment with the caspase inhibitor z-VAD-fmk blocked morphological signs of apoptosis as well as caspase cleavage, and also partially prevented beta-catenin degradation by sulindac metabolites. These effects occurred in cells with bi-allelic APC mutation (SW480), with wild-type APC but mono-allelic beta-catenin mutation (HCT116) and in cells that lack expression of either COX-1 or -2 (HCT15). These results indicate that loss of beta-catenin protein induced by sulindac metabolites is COX independent and at least partially due to reactivation of beta-catenin proteasome degradation and partially a result of caspase activation during the process of apoptosis.

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Apoptosis; beta Catenin; Caspase 3; Caspase Inhibitors; Caspases; Cell Nucleus; Colonic Neoplasms; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Cytoskeletal Proteins; Down-Regulation; Enzyme Inhibitors; Humans; Leupeptins; Multienzyme Complexes; Proteasome Endopeptidase Complex; Signal Transduction; Sulindac; Trans-Activators; Tumor Cells, Cultured

Exisulind and its analogues are inhibitors of cyclic GMP phosphodiesterases (PDEs) that have been shown to activate and induce protein kinase G, resulting in the induction of apoptosis in colon cancer cells. These drugs also reduce beta-catenin protein levels and decrease cyclin D1 mRNA levels in SW480 cells. Herein we report on studies pertaining to exisulind regulation of beta-catenin levels and activity in colon tumor cells. Exisulind and its higher-affinity PDE analogues, (Z)-5-fluoro-2-methyl-(4-pyridylidene)-3-(N-benzyl)-indenylacetamide hydrochloride (CP461) and (Z)-1H-indene-3-acetamide, 5-fluoro-2-methyl-N-(phenylmethyl)-1-[(3,4,5-trimethoxyphenyl)methylene] (CP248), reduced beta-catenin, including the nuclear beta-catenin in SW480 cells (EC(50) approximately 200 microM, 1 microM, and <1 microM, respectively). The 50% reduction of beta-catenin was seen in 8-14 hr. There was no change in beta-catenin mRNA. Exisulind-induced beta-catenin reduction was blocked by the proteasomal inhibitor MG132 (Z-leu-Leu-Leu-CHO), indicating that the effect of exisulind involved ubiquitin-proteasomal degradation. A consequence of reduced beta-catenin in SW480 cells was that exisulind, CP461, and CP248 caused a concentration- and time-dependent decrease in cyclin D1 levels (EC(50) approximately 300 microM, 1 microM, and <1 microM, respectively) in 4 hr. The effect was via decreased cyclin D1 mRNA levels. Exisulind-induced degradation of beta-catenin was not blocked by the inhibition of caspase-3 activity and/or apoptosis, and some SW480 cells showed a reduction in beta-catenin levels before the appearance of early apoptosis indicators. Expression of the N-terminal 170 amino acid fragment of beta-catenin reduced the effects of beta-catenin degradation, cyclin D1 reduction, and the apoptosis response to exisulind. These results indicate that exisulind-induced beta-catenin degradation precedes the induction of apoptosis and that the down-regulation of inappropriate beta-catenin-activated genes accounts in part for the pro-apoptotic effects of exisulind and CP461 in colon tumor cells.

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Apoptosis; beta Catenin; Caspase 3; Caspases; Colonic Neoplasms; Cyclin D1; Cysteine Endopeptidases; Cytoskeletal Proteins; Down-Regulation; Humans; Multienzyme Complexes; Proteasome Endopeptidase Complex; Protein Biosynthesis; Signal Transduction; Sulindac; Trans-Activators; Tumor Cells, Cultured; Ubiquitin

Topics: Adenomatous Polyposis Coli; Anticarcinogenic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Precancerous Conditions; Sulindac; Treatment Outcome

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Apoptosis; Biotechnology; Clinical Trials as Topic; Drug Industry; Humans; Investments; Phosphodiesterase Inhibitors; Sulindac

Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in treating intestinal adenomas in humans with Familial Adenomatous Polyposis (FAP) and in preventing intestinal tumors in the C57Bl/6J-Min+ (Min) mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the liver and intestinal flora to a sulfone, which has no anti-inflammatory activity, and a sulfide, which is the active anti-inflammatory metabolite. In this study, we determined which of these metabolites is responsible for the anti-tumor effect of sulindac in Min mice. Min mice were treated with either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation (+/+) were used as controls. At 110 days of age, all mice were euthanized and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6 tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte apoptosis was observed in Min control mice and Min mice treated with sulindac sulfone. Sulindac sulfide restored to normal the level of apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the small intestine of treated Min animals by 59% (P < 0.001). These data suggest that the anti-tumor effect of sulindac in Apc-deficient animals is mediated by the sulfide metabolite and correlates with suppression of tissue prostaglandin synthesis.

Topics: Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Apoptosis; Female; Genes, APC; Heterozygote; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Prodrugs; Sulindac

Sulindac is a non-steroidal anti-inflammatory drug which induces regression of colonic polyps in patients with familial adenomatous polyposis. Animal and in vitro studies have shown that both the sulphide metabolite of sulindac, which is able to inhibit cyclo-oxygenase, and the sulphone metabolite, which lacks this ability, are able to inhibit the growth of colonic carcinoma cells. The exact mechanism by which these effects occurs is not known.. To examine the effect of sulindac sulphide and sulindac sulphone on the expression of APC messenger RNA (mRNA), and on the proliferation of colonic carcinoma cells in vitro.. The colonic carcinoma cell line LIM 1215 was treated with sulindac sulphide and sulindac sulphone (10 microM or 100 microM) for 24 hours. Total RNA was extracted and APC mRNA was quantitated using competitive reverse transcription polymerase chain reaction. Measurements of cell number, cell proliferation, and prostaglandin E2 concentrations were also made.. A significant increase in APC mRNA was observed after treatment with 10 microM of both sulindac sulphide and sulindac sulphone (control: 37.2 (19.7); 10 microM sulindac sulphide: 129 (112.8); 10 microM sulindac sulphone: 207.7 (102.9) pg/(g total RNA) (p < 0.05). Prostaglandin E2 concentrations were significantly reduced after treatment with sulindac sulphide, but not after sulindac sulphone. Both agents produced a dose dependent reduction in cell numbers and cell proliferation, which was more noticeable after treatment with sulindac sulphide.. Both sulindac sulphide and sulindac sulphone inhibit the growth of carcinoma cells in vitro and cause an increase in APC mRNA. The effect of these agents on colonic carcinogenesis is not mediated entirely by means of an inhibition of prostaglandin biosynthesis.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Base Sequence; Cell Division; Cytoskeletal Proteins; Dinoprostone; Gene Expression Regulation, Neoplastic; Humans; Intestinal Mucosa; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Messenger; Sulindac; Tumor Cells, Cultured

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Colonic Neoplasms; Humans; Sulindac