sulindac and Adenoma

The onset of colorectal adenomas (CRAs) is significantly associated with colorectal cancer. The preventive effects of chemical drugs on the recurrence of CRAs have been evaluated in a large number of randomized controlled trials (RCTs). However, there are still uncertainties about the relative effectiveness of such chemical drugs.. We searched relevant RCTs published in six databases up to February 2023. The quality of the included studies was assessed by using the Cochrane risk of bias assessment tool and Review Manager 5.4. Pairwise comparison and network meta-analysis (NMA) were conducted using RStudio to compare the effects of chemical drugs on the recurrence of CRAs.. Forty-five high-quality RCTs were included. A total of 35 590 (test group: 20 822; control group: 14 768) subjects with a history of CRAs have been enrolled and randomized to receive placebo treatment or one of 24 interventions. Based on surface under the cumulative ranking values and NMA results, difluoromethylornithine (DFMO) + Sulindac significantly reduced the recurrence of CRAs, followed by berberine and nonsteroidal antiinflammatory drugs.. DFMO + Sulindac is more effective in reducing the recurrence of CRAs but has a high risk of adverse events. Considering drug safety, tolerance, and compliance, berberine has a brighter prospect of clinical development. However, further studies are needed to verify our findings.

Topics: Adenoma; Berberine; Colorectal Neoplasms; Humans; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sulindac

Colorectal cancer (CRC) is presently one of the most common causes of cancer-related death in our setting and affects a great number of people each year. Screening strategies are commonly used but they do not seem enough to avoid CRC development or prevent completely its mortality. Because of this fact other prevention strategies have gained interest in recent years. Chemoprevention seems to be an attractive option in this setting and several drugs have been studied in this field. This review is focused on salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs) and cycloxygenase-2 inhibitors (COXIBs), whose mechanism of action could be directly related to colon cancer chemoprevention.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Celecoxib; Chemoprevention; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Humans; Pyrazoles; Randomized Controlled Trials as Topic; Sulfonamides; Sulindac

Topics: Adenoma; Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Carcinoma; Celecoxib; Colorectal Neoplasms; Evidence-Based Medicine; Humans; Meta-Analysis as Topic; Pyrazoles; Sulfonamides; Sulindac

Chemoprevention with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) + sulindac markedly reduces risk of recurrent adenoma in colorectal adenoma patients. Obesity is associated with risk of colorectal adenoma and colorectal cancer. This study investigates how obesity influences risk of recurrent adenoma after prolonged treatment with DFMO + sulindac versus placebo.. Our analysis included subjects enrolled in the phase III colorectal adenoma prevention clinical trial investigating DFMO + sulindac versus placebo. Patients were classified by obesity (body mass index, BMI ≥ 30 kg/m(2)) status at baseline. Pearson χ(2) statistic and Mann-Whitney U test were used to compare baseline characteristics, including rectal tissue polyamine levels. Log-binomial regression analysis was used to determine the risk ratio (RR) of recurrent adenomas, adjusted for covariates and an interaction term for obesity and treatment.. The final analytic cohort was comprised of 267 patients. In separate regression models, the risk of adenoma recurrence after treatment compared to placebo was similar for obese (RR = 0.32, 95 % CI 15-71) and non-obese patients (RR = 0.27, 95 % CI 15-49). No significant interaction was detected between obesity, treatment, and risk of colorectal adenoma in the full regression model (p (interaction) = 0.91).. Obesity does not substantially modify the colorectal adenoma risk reduction ascribed to DFMO + sulindac versus placebo.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Double-Blind Method; Eflornithine; Female; Humans; Male; Middle Aged; Obesity; Placebo Effect; Polyamines; Regression Analysis; Sulindac; Treatment Outcome

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

Combination of polyamine and prostaglandin E2 (PGE2)-synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy.. We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III chemoprevention trial of DFMO/sulindac.. In the group that received DFMO/sulindac, spermidine-to-spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < .001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 vs 0.15 nmol/mg protein; P < .001) but rebounded between 12 and 36 months (0.15 vs 0.36 nmol/mg protein; P = .001). PGE2 levels did not change, although aspirin use was significantly associated with lower baseline levels of PGE2. No significant associations were observed between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high PGE2 at baseline; none of these subjects, versus 39% of those given placebo, developed CRA (P < .001). Efficacy was lowest in subjects with high Spd:Spm and low PGE2 at baseline; 28% developed CRA, compared with 36% of patients given placebo (P = .563).. A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. No relationship was found between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.

Topics: Adenoma; Aged; Anticarcinogenic Agents; Biomarkers, Pharmacological; Biopsy; Colonoscopy; Colorectal Neoplasms; Dinoprostone; Double-Blind Method; Drug Therapy, Combination; Eflornithine; Enzyme Inhibitors; Female; Humans; Intestinal Mucosa; Likelihood Functions; Logistic Models; Male; Middle Aged; Neoplasms, Second Primary; Polyamines; Putrescine; Rectum; Spermidine; Spermine; Sulindac; Time Factors; Treatment Outcome

The ornithine decarboxylase-1 (ODC1) polymorphism at position +316 affects binding by transcriptional activators and repressors and modulates the risk of metachronous colorectal adenomas, particularly in association with aspirin use. We investigated the effects of ODC1 after treatment with difluoromethylornithine (eflornithine)/sulindac or placebo. Two hundred twenty-eight colorectal adenoma patients in a randomized phase III trial were genotyped for ODC1. We used Wilcoxon rank sums tests on non-normally distributed continuous variables across two genotype groups, χ(2) or Fisher exact test to assess the association between baseline categorical variables and genotype group, and log binomial regression for the primary (adenoma recurrence) and secondary outcomes (tissue polyamine response, cardiovascular toxicity, gastrointestinal toxicity, and ototoxicity). All statistical tests were two-sided. In binomial regression models with variables age, sex, race, aspirin use, treatment, and ODC1 genotype, treatment was the only statistically significant factor associated with differences in adenoma recurrence or tissue polyamine response. A statistically significant interaction was detected between ODC1 genotype and treatment with respect to adenoma recurrence (placebo group: GG, 50%, AA/GA: 34%; treatment group: GG, 11%, AA/GA, 21%; P(interaction) = .038). Excess ototoxicity was observed among ODC1 AA patients receiving treatment, but the interaction of genotype and treatment on ototoxicity was not statistically significant (P = .45).

Topics: Adenoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Confounding Factors, Epidemiologic; Eflornithine; Enzyme Inhibitors; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Proteins; Sulindac; Treatment Outcome

Nonsteroidal anti-inflammatory drugs (NSAID) have been associated with adverse cardiovascular (CV) outcomes in cancer prevention and other clinical trials. A recent meta-analysis suggested that baseline CV risk is associated with NSAID-associated adverse CV events. We evaluated the effect of baseline CV risk on adverse CV events in a phase III trial of difluoromethylornithine (DFMO) plus the NSAID sulindac versus placebo in preventing colorectal adenomas. Trial data were analyzed to determine baseline CV risk. CV toxicity outcomes were then assessed overall and excluding high CV-risk patients. Baseline CV risk scores were evenly distributed within our overall trial population of 184 placebo (low risk, 27%; moderate risk, 34%; high risk, 39%) and 191 DFMO/sulindac (low risk, 30%; moderate risk, 29%; high risk, 41%) patients. In patients with a high baseline CV risk, the number of adverse CV events was greater among DFMO/sulindac (n = 9) than among placebo (n = 3) patients. Excluding patients with a high baseline CV risk, the numbers of adverse CV events were similar in the DFMO/sulindac (n = 7) and placebo (n = 6) arms. A high CV risk score at baseline may confer an increased risk of CV events associated with treatment with DFMO/sulindac, and a low baseline score may not increase this risk. These results have implications for future NSAID-based cancer prevention clinical trials.

Topics: Adenoma; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Agents; Colorectal Neoplasms; Double-Blind Method; Drug Therapy, Combination; Eflornithine; Humans; Middle Aged; Placebos; Risk; Sulindac

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.

Topics: Adenoma; Adult; Aged; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Colonoscopy; Colorectal Neoplasms; Double-Blind Method; Eflornithine; Female; Humans; Male; Middle Aged; Placebos; Sulindac; Treatment Outcome

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

Topics: Adenoma; Adenomatous Polyposis Coli; Adolescent; Adult; Apoptosis; Biopsy, Needle; Colonic Neoplasms; Epithelium; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Precancerous Conditions; Predictive Value of Tests; Rectum; Reference Values; Sulindac; Treatment Outcome

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

Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine whether a combination of Wnt inhibition with anti-inflammatory (sulindac) and/or proapototic (ABT263) drugs can reduce colon adenomas.. Colorectal cancer is one of the most common cancers worldwide with limited therapeutic options. APC and other Wnt signaling mutations occur in the majority of colorectal cancers but there are currently no Wnt inhibitors in the clinic. The combination of Wnt pathway inhibition with sulindac provides an opportunity for killing

Topics: Adenoma; Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colonic Neoplasms; Colorectal Neoplasms; Mice; Protein Serine-Threonine Kinases; Sulindac

The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc. Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both.. The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.

Topics: Adenoma; Animals; Antineoplastic Agents; Atorvastatin; Colorectal Neoplasms; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Sulindac

Expansion of a stem-like subpopulation with increased growth and survival potential is thought to drive colorectal tumor growth and progression. We investigated a CD44-positive (CD44((+))) subpopulation with extended growth and survival capacity in the human colon adenoma cell line LT97. This subpopulation expressed elevated levels of fibroblast growth factor 18 (FGF18) and fibroblast growth factor receptor FGFR3-IIIc. Expression levels of the FGFR3-IIIb, which does not bind FGF18, were similar in CD44((+)) and CD44((-)). Addition of FGF18 to the medium or its overexpression from an adenoviral vector increased the colony formation capacity of CD44((+)) threefold, and stimulated phosphorylation of ERK and GSK3β in both total LT97 populations and CD44((+)) cells. FGFR3 signaling blockade by expression of a dominant-negative FGFR3-IIIc mutant led to inhibition of both colony formation and down-stream signaling in the CD44((+)) cells. CD44((-)) cells did not respond. Blockade of the wnt-pathway by a dominant-negative Tcf4-mutant inhibited FGFR3 activation in LT97 cells as well as in HT29 colorectal cancer cells. The chemical wnt-inhibitor sulindac sulfide amide inhibited expression of FGF18 and FGFR3-IIIc and led to inhibition of receptor activation to less than 30% of control treated cells, both in LT97 and HT29 cultures. Our results demonstrate that an FGF18/FGFR3-IIIc autocrine growth and survival loop is up-regulated in a wnt-dependent manner and drives tumor cell growth in a subpopulation of colon adenoma cells. This subpopulation can be regarded as a precursor of colon cancer development and can be targeted for CRC-prevention by blocking either wnt- or FGFR3-signaling.

Topics: Adenoma; Antineoplastic Agents; Colon; Colorectal Neoplasms; Fibroblast Growth Factors; Humans; Hyaluronan Receptors; Receptor, Fibroblast Growth Factor, Type 3; Rectum; Signal Transduction; Sulindac; Wnt Proteins; Wnt Signaling Pathway

Topics: Adenoma; Antineoplastic Agents; Clinical Trials as Topic; Colon; Colonic Neoplasms; Eflornithine; Humans; Sulindac; Treatment Outcome

Although Apc mutation is widely considered an initiating event in colorectal cancer, little is known about the earliest stages of tumorigenesis following sporadic Apc loss. Therefore, we have utilized a novel mouse model that facilitates the sporadic inactivation of Apc via frameshift reversion of Cre in single, isolated cells and subsequently tracks the fates of Apc-deficient intestinal cells. Our results suggest that consistent with Apc being a 'gatekeeper', loss of Apc early in life during intestinal growth leads to adenomas or increased crypt fission, manifested by fields of mutant but otherwise normal-appearing crypts. In contrast, Apc loss occurring later in life has minimal consequences, with mutant crypts being less prone to either increased crypt fission or adenoma formation. Using the stem cell-specific Lgr5-CreER mouse, we generated different sized fields of Apc-deficient crypts via independent recombination events and found that field size correlates with progression to adenoma. To evaluate this early stage prior to adenoma formation as a therapeutic target, we examined the chemopreventive effects of sulindac on Apc-deficient occult crypt fission. We found that sulindac treatment started early in life inhibits the morphologically occult spread of Apc-deficient crypts and thus reduces adenoma numbers. Taken together these results suggest that: (i) earlier Apc loss promotes increased crypt fission, (ii) a field of Apc-deficient crypts, which can form via occult crypt fission or independent neighboring events, is an important intermediate between loss of Apc and adenoma formation and (iii) normal-appearing Apc-deficient crypts are potential unappreciated targets for cancer screening and chemoprevention.

Topics: Aberrant Crypt Foci; Adenoma; Age Factors; Animals; beta-Galactosidase; Chemoprevention; DNA Repair; Genes, APC; Intestinal Neoplasms; Intestines; Mice; Mice, Transgenic; Mutation; Stem Cells; Sulindac

The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial.. Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation.. A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates.. These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Diet; Eflornithine; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Polyamines; Prognosis; Sulindac; Survival Rate

TNF-related apoptosis-inducing ligand (TRAIL) receptor agonistic agents and non-steroidal anti-inflammatory drugs (NSAIDs) are interesting agents for the chemoprevention and treatment of colorectal cancer. We investigated whether NSAIDs sensitize colon cancer and adenoma cell lines and ex vivo cultured human adenomas to recombinant human (rh)TRAIL. Involvement of the crucial Wnt signalling pathway in the sensitization of colon cancer cells was examined. Five colon cancer and two adenoma cell lines, human ex vivo adenomas and normal colonic epithelium were treated with aspirin or sulindac combined with rhTRAIL. Apoptosis levels, expression of intracellular proteins and TRAIL receptor membrane expression were assessed. Ls174T cells stably transfected with an inducible dominant negative TCF-4 (dnTCF-4) construct served to analyse the role of Wnt pathway activation. Both rhTRAIL-sensitive and -resistant colon cancer cell lines were strongly sensitized to rhTRAIL by aspirin (maximum enhancement ratio, 7.1). Remarkably, in adenoma cell lines sulindac enhanced rhTRAIL-induced apoptosis most effectively (maximum enhancement ratio, 2.5). Although membrane TRAIL receptor expression was not affected by NSAIDs, caspase-8 activation was enhanced by combinational treatment. Several proteins from different biological pathways were affected by NSAIDs, indicating complex mechanisms of sensitization. Elimination of TCF-4 completely blocked the sensitizing effect in colon cancer cells. In ex vivo adenomas the combination of sulindac and rhTRAIL increased apoptosis from 18.4% (sulindac) and 17.8% (rhTRAIL) to 28.0% (p = 0.003 and p = 0.005, respectively). It was concluded that NSAID-induced sensitization to rhTRAIL requires TCF-4 activity. Thus, the combination of TRAIL-receptor agonistic agents and NSAIDs is a potentially attractive treatment option for (pre)malignant tumours with constitutively active Wnt signalling, such as colorectal tumours.

Topics: Adenoma; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Aspirin; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Caco-2 Cells; Colon; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Neoplasm Proteins; Receptors, TNF-Related Apoptosis-Inducing Ligand; Recombinant Proteins; Signal Transduction; Sulindac; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor 4; Transcription Factors; Tumor Cells, Cultured; Wnt Proteins

Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc(Min/+) mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc(Min/+) mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, beta-catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-gamma. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear beta-catenin accumulation. Importantly, p21(WAF1/cip1) and peroxisome proliferator-activated receptor-gamma expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance.

Topics: Adenoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colon; Colonic Neoplasms; Disease Models, Animal; Drug Resistance; Gene Expression Regulation, Neoplastic; Genes, APC; HCT116 Cells; Humans; Intestine, Small; Mice; Mice, Transgenic; Neoplasms, Multiple Primary; Sulindac; Tumor Burden

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

Topics: Adenoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Eflornithine; Humans; Neoplasm Recurrence, Local; Sulindac

Topics: Adenoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular System; Celecoxib; Colonic Neoplasms; Drug Administration Schedule; Eflornithine; Humans; National Cancer Institute (U.S.); Neoplasm Recurrence, Local; Pyrazoles; Randomized Controlled Trials as Topic; Sulfonamides; Sulindac; United States; United States Food and Drug Administration

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Female; Humans; Intestinal Polyposis; Middle Aged; Sulindac

Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal anti-inflammatory drugs appear to inhibit the initial stages of the adenoma-carcinoma sequence, suggesting a link to the APC/beta-catenin/TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) beta-catenin and beta-catenin/TCF-mediated transcription was investigated. Nuclear beta-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on beta-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear beta-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated beta-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated beta-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear beta-catenin localisation and beta-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Anti-Inflammatory Agents, Non-Steroidal; beta Catenin; Cell Nucleus; Cell Transformation, Neoplastic; Chemoprevention; Colorectal Neoplasms; Cytoskeletal Proteins; Female; Humans; Mitogens; Proto-Oncogene Proteins; Signal Transduction; Sulindac; Trans-Activators; Transcription, Genetic; Tumor Cells, Cultured; Wnt Proteins; Zebrafish Proteins

Aberrant crypt foci, precursors of colonic adenoma, are frequently positive for glutathione-S-transferase P1-1. Because deoxycholic acid is an apoptosis-inducing xenobiotic in the colon, we examined the possibility that aberrant crypt foci, through the cytoprotecting function of glutathione-S-transferase P1-1, resist deoxycholic acid-induced apoptosis, thereby surviving to become adenomas and subsequently cancer.. Glutathione-S-transferase P1-1 or cyclooxygenase-2 expression and the percentage of apoptotic cells in aberrant crypt foci were examined by immunohistochemistry and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, respectively. Glutathione-S-transferase P1-1 was transfected into colon cancer cells (M7609) and human lung fibroblasts, and deoxycholic acid-induced apoptosis was evaluated by a dye-uptake assay and flow cytometry. Binding of deoxycholic acid to glutathione-S-transferase P1-1 was analyzed by circular dichroism and immunoprecipitation. Caspase activities were determined by colorimetric protease assay, and sulindac binding to glutathione-S-transferase P1-1 was determined by inhibition assay of glutathione-S-transferase P1-1 activity.. Aberrant crypt foci showed positive immunostaining for glutathione-S-transferase P1-1 but negative staining for cyclooxygenase-2. The percentage of apoptotic cells in aberrant crypt foci was significantly lower than in healthy epithelium, and the difference became more apparent with deoxycholic acid treatment. The impaired sensitivity of aberrant crypt foci to deoxycholic acid was restored by the glutathione-S-transferase P1-1-specific inhibitor gamma-glutamyl-S-(benzyl)cysteinyl-R-phenylglycine diethylester. By transfection of glutathione-S-transferase P1-1, M7609 cells became more resistant to deoxycholic acid-induced apoptosis than mock transfectants. Direct binding of glutathione-S-transferase P1-1 to deoxycholic acid was proven by circular dichroism and by immunoprecipitation. The aberrant crypt foci in adenoma patients treated with sulindac, which was shown to bind to glutathione-S-transferase P1-1, underwent apoptosis in 4 days and mostly regressed in 2-3 months.. Glutathione-S-transferase P1-1 protects aberrant crypt foci from deoxycholic acid-induced apoptosis and may play a pivotal role in early colon carcinogenesis.

Topics: Adenoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Cyclooxygenase 2; Deoxycholic Acid; Detergents; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutathione; Glutathione Transferase; Humans; Intestinal Mucosa; Isoenzymes; Lung; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Sulindac; Transfection

Topics: Adenoma; Adenomatous Polyposis Coli; Age of Onset; Anti-Inflammatory Agents, Non-Steroidal; Colonic Neoplasms; Genes, APC; Germ-Line Mutation; Humans; Sulindac

This study was conducted to assess the growth inhibition of colorectal adenoma cells by sulindac and identify the possible mechanisms.. The colorectal adenoma cells from human sporadic adenomatous polyps were cultured, and then treated with sulindac. The cell viability was examined by MTT colorimetric assay; the S-phase fraction and the percentage of apoptosis were measured by flow cytometry.. Following sulindac treatment at different concentrations for 24, 48 and 72 hours, reduction of the cell viability was time- and dose-dependent. After 48-hour-treatment, S-phase fraction was decreased and the percentage of apoptosis was increased; both indexes of all groups except 0.3 mmol/L group were different from those of controls (P < 0.05).. These data suggested that sulindac could inhibit the growth of the colorectal adenoma cells, and its mechanisms might be related to suppressing proliferation and inducing apoptosis.

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Division; Colonic Neoplasms; Female; Humans; Middle Aged; Prostaglandin-Endoperoxide Synthases; Sulindac; Tumor Cells, Cultured

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumor cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulindac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC58560 on tumor cell growth in relation to COX-2 expression and prostaglandin production. To establish the role of COX-2 in NSAID action, we constructed clones expressing different levels of COX-2 from SW480 cells. All five compounds inhibited DNA synthesis and/or induced apoptosis, each with a characteristic pattern. ID(50)s were very similar in all the cell lines and were independent of COX expression, except for the COX-1 inhibitor SC58560, which was least effective in HT29/HI1, the cell line expressing the highest level of COX-1 (ID(50) 70 microM; in other cells lines the ID(50) was 15 microM). For all other compounds ID(50) concentrations varied less than two-fold: 25-40, 40-90 and 150 microM for SC236, sulindac sulfide and sulindac sulfone, respectively. SC58125 was the weakest inhibitor, never causing >50% cell loss. All compounds modulated expression of Bcl-2 and Bak and activated caspase 3. Overexpression of COX-2 in SW480 cells protected them against induction of apoptosis by sulindac sulfide. The effect was restricted to clones producing high levels of prostaglandin E(2). In summary, our data indicate that both COX-dependent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicating that the therapeutic effect of NSAIDs cannot be explained by a direct effect of NSAIDs on the epithelial cells alone. For therapeutic purposes, compounds using different targets could be used to minimize side effects while optimizing therapeutic effect.

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Cell Division; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Growth Inhibitors; HT29 Cells; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Substrate Specificity; Sulindac; Tumor Cells, Cultured

We tried to elucidate the effects of sulindac on human colorectal carcinoma.. Sulindac (300 mg/day) was administered for two weeks before operation to 33 patients with sporadic colorectal carcinoma (Sulindac Group). Resected specimens were used to detect apoptosis by terminal dUTP nick end labeling and transforming growth factor (TGF)-beta1 expression by immunohistochemistry. The results were compared with those from the historical Control Group. Twenty-nine available preoperative biopsies taken from carcinomas before sulindac prescription and 22 concurrent colorectal adenomas (9 and 13 in Sulindac and Control Groups, respectively) in the resected specimen were also examined regarding TGF-beta1 expression.. In the resected carcinomas and adenomas, more frequent apoptosis and higher TGF-beta1 scores were observed in the Sulindac Group than in the Control Group. Overexpression of TGF-beta1 and apoptosis occurred in the same region in adenomas but not in carcinomas. A positive correlation between TGF-beta1 scores and apoptotic frequency was found in adenomas (P = 0.01, rho = 0.91) but not in carcinomas (P = 0.89, rho = 0.03).. We conclude that sulindac induces apoptosis in human colorectal carcinomas as well as in adenomas. Also, one of the antineoplastic effects of sulindac might be mediated by upregulating TGF-beta1 expression, particularly in colorectal adenomas.

Topics: Adenoma; Aged; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Preoperative Care; Sulindac; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

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 causes the reduction of adenomas in familial adenomatous polyposis (FAP) patients, but complete regression is unusual, and breakthrough of colorectal carcinoma during sulindac treatment has been described. The molecular features related to sulindac resistance are unknown. Therefore, we investigated molecular alterations in adenomas from FAP patients with complete adenoma regression on sulindac (responsive patients) and from FAP patients with sulindac-resistant adenomas (resistant patients).. Fourteen baseline adenomas (removed before sulindac treatment) from six responsive patients were studied. Also, 9 baseline adenomas and 34 resistant adenomas (removed during sulindac treatment) from three resistant patients were analyzed. Using immunohistochemistry, we evaluated the expression of beta-catenin, cyclooxygenase-2 (Cox-2), p53, Bcl-2, and Bax. K-ras codon 12 mutations, loss of heterozygosity at 5q (APC locus), and microsatellite instability were studied with PCR-based techniques.. There were no significant differences between baseline adenomas from sulindac-responsive and -resistant patients (P > 0.05). There was less loss of membranous beta-catenin staining and less nuclear beta-catenin accumulation in resistant adenomas compared with baseline adenomas from the same (sulindac-resistant) patients (P < 0.01) or baseline adenomas from responsive patients (P < 0.01). Epithelial Cox-2 expression was less, though not significant, in resistant adenomas compared with baseline adenomas from resistant patients, but was significantly less in baseline adenomas from responsive patients (P < 0.01). K-ras mutations were found in 8 of 34 resistant adenomas (24%) and in none of the baseline adenomas (P < 0.05). Stromal Cox-2 expression, staining of p53 and Bcl-2, and loss of heterozygosity at 5q were comparable in both groups. Loss of Bax staining and microsatellite instability were not found in any adenoma.. Sulindac-resistant adenomas display less alteration in beta-catenin staining and less epithelial Cox-2 expression when compared with adenomas removed before sulindac treatment. K-ras mutations may contribute to sulindac-resistance. Continued research is needed to investigate molecular alterations related to sulindac resistance.

Topics: Adenoma; Adenomatous Polyposis Coli; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; beta Catenin; Biomarkers, Tumor; Codon; Cyclooxygenase 2; Cytoskeletal Proteins; Drug Resistance, Neoplasm; Genes, ras; Humans; Immunohistochemistry; Isoenzymes; Loss of Heterozygosity; Membrane Proteins; Mutation; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rectal Neoplasms; Sulindac; Trans-Activators; Tumor Suppressor Protein p53

A 22-year-old woman with Gardner's syndrome in whom long-term sulindac therapy, without surgical treatment, was effective in inducing complete regression of colonic adenomas is reported. One hundred milligrams of sulindac was administered twice daily after endoscopic polypectomy. Follow-up colonoscopy 6 months later revealed an encouraging regression of colonic adenomas. The tumors had disappeared after 40 months of sulindac treatment. A sustained effect was identified even after 51 months. Ten milligrams of famotidine was coadministered to prevent side effects of sulindac. Although the effect of sulindac on colorectal adenomas may be transient, this therapy may be useful for postponing prophylactic colectomy, especially for the sparse type of familial adenomatous polyposis.

Topics: Adenoma; Adult; Antineoplastic Agents; Colonic Neoplasms; Female; Follow-Up Studies; Gardner Syndrome; Humans; Radiography; Remission Induction; Skull; Sulindac; Time Factors

Non-steroidal anti-inflammatory drugs (NSAIDs) can cause regression of early intestinal tumors and although this is believed to involve cyclooxygenase-2 and apoptosis, the molecular mechanisms remain unclear. Cytoplasmic and nuclear beta-catenin are overexpressed in many of these lesions and Bcl-2, which inhibits apoptosis, may also be elevated during the course of intestinal tumorigenesis. We recently showed that sulindac causes regression of 70-80% of small intestinal tumors in Min/+ mice within 4 days, but does not have the same impact on colonic lesions; after 20 days of treatment the tumor load stabilizes at 10-20% of that in untreated animals. The aim of this study was to determine if NSAID-induced regression of intestinal adenomas might be associated with changes in beta-catenin or Bcl-2 expression. Intestinal tumors from Min/+ mice were harvested after treatment with sulindac for 2, 4 or 20 days and evaluated for expression of beta-catenin and Bcl-2 using immunohistochemistry. There was a > or = 50% decrease in beta-catenin (P = 0.001) and diminishing Bcl-2 (P = 0.019) in small intestinal tumors harvested between 2 and 4 days of treatment when compared with untreated controls. In contrast, small intestinal tumors from animals treated for 20 days were not significantly different from untreated controls. Colonic tumors expressed higher levels of Bcl-2 than those from the small intestine and did not show any significant changes in either Bcl-2 or beta-catenin expression after treatment. Results suggest that modulation of aberrant beta-catenin expression occurs during NSAID-induced regression of intestinal adenomas and that Bcl-2 may confer resistance to these effects.

Topics: Adenoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; beta Catenin; Colonic Neoplasms; Cyclooxygenase 2; Cytoskeletal Proteins; Enzyme Induction; Gene Expression Regulation, Neoplastic; Genes, APC; Genetic Predisposition to Disease; Heterozygote; Immunoenzyme Techniques; Intestinal Neoplasms; Intestine, Small; Isoenzymes; Lymphocytes; Mice; Mice, Mutant Strains; Neoplasm Proteins; Organ Specificity; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-bcl-2; Sulindac; Trans-Activators

S-methylmethane thiosulfonate (S-MMTS), isolated from cauliflower and having antiproliferative activity, and the non-steroidal anti-inflammatory drug sulindac have been shown to inhibit chemically induced colon carcinogenesis when they are administered during the initiation and/ or post-initiation stages. The present study was designed to investigate the chemopreventive efficacy of 80 p.p.m. S-MMTS administered during the initiation and post-initiation stages and of S-MMTS and sulindac administered together at low doses (40 and 160 p.p.m., respectively) during the promotion/progression phases (late in the premalignant stage) of colon carcinogenesis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0 (control diet) or 80 p.p.m. S-MMTS. At 7 and 8 weeks of age all rats except those in the vehicle-treated groups were given s.c. injections of 15 mg/kg body wt azoxymethane (AOM). Rats receiving the control diet and intended for the study of inhibition of colon carcinogenesis during the promotion/progression phases were continued on the control diet for 14 weeks after the second AOM treatment; they were then switched to experimental diets containing 80 p.p.m. S-MMTS, 160 p.p.m. sulindac or 40 p.p.m. S-MMTS plus 160 p. p.m. sulindac. The rats were maintained on their respective dietary regimens until 52 weeks after carcinogen treatment and were then killed. Colon tumors were evaluated histopathologically. Administration of 80 p.p.m. S-MMTS alone during the initiation and post-initiation stages and promotion/progression stages had no significant effect on colon tumor inhibition. In contrast, the administration of 160 p.p.m. sulindac during the promotion/progression stages did significantly inhibit total colon tumor multiplicity (P < 0.05). Moreover, co-administration of 40 p.p. m. S-MMTS with 160 p.p.m. sulindac during the promotion/progression stages suppressed the incidence and multiplicity of non-invasive adenocarcinomas (P < 0.05-0.01) and multiplicity of invasive and total adenocarcinomas of the colon to a significant degree (P < 0. 05-0.01). These findings have potential clinical implications.

Topics: Adenocarcinoma; Adenoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Alkylating; Azoxymethane; Carcinogens; Colonic Neoplasms; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Male; Methyl Methanesulfonate; Rats; Rats, Inbred F344; Sulindac

Aberrant crypt foci of the colon are possible precursors of adenoma and cancer, but these lesions have been studied mainly in surgical specimens from patients who already had colon cancer.. Using magnifying endoscopy, we studied the prevalence, number, size, and dysplastic features of aberrant crypt foci and their distribution according to age in 171 normal subjects, 131 patients with adenoma, and 48 patients with colorectal cancer. We also prospectively examined the prevalence of aberrant crypt foci in 11 subjects (4 normal subjects, 6 with adenoma, and 1 with cancer) before and after the administration of 100 mg of sulindac three times a day for 8 to 12 months and compared the results with those in 9 untreated subjects (4 normal subjects and 5 with adenoma). All 20 subjects had aberrant crypt foci at base line.. We identified 3155 aberrant crypt foci, 161 of which were dysplastic; the prevalence and number increased with age. There were significant (P<0.001) correlations between the number of aberrant crypt foci, the presence of dysplastic foci, the size of the foci, and the number of adenomas. After sulindac therapy, the number of foci decreased, disappearing in 7 of 11 subjects. In the untreated control group, the number of foci was unchanged in eight subjects and slightly increased in one (P<0.001 for the difference between the groups).. Aberrant crypt foci, particularly those that are large and have dysplastic features, may be precursors of adenoma and cancer.

Topics: Adenoma; Aged; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Colon; Colonic Neoplasms; Colonoscopy; Female; Genes, ras; Heart Diseases; Humans; Male; Methylene Blue; Middle Aged; Osteoarthritis; Point Mutation; Precancerous Conditions; Prevalence; Prospective Studies; Sulindac

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs. In this study, we demonstrated the efficacy of aspirin to inhibit lung tumorigenesis in A/J mice. Lung tumors (9.9 tumors/mouse) were induced by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), administered in drinking water between week 0 and week +7. Groups of mice were fed sulindac (123 mg/kg diet), acetylsalicylic acid (ASA; 294 mg/kg), non-buffered Aspirin (294 mg/kg) or buffered Aspirin (294 mg/kg) in AIN-76A diet from week -2 to the end of the bioassay (week +23). These doses are comparable to the maximal doses recommended for humans. ASA and non-buffered Aspirin were the most effective inhibitors and reduced lung multiplicities by 60 and 62%, respectively. Sulindac inhibited lung tumor multiplicity by 52%. Inhibition by buffered Aspirin was not statistically significant. We evaluated the efficacies of NSAIDs to inhibit NNK activation by h1A2 v2 cells expressing human P-450 1A2. Salicylates, at doses of 500 microM and 1 mM, had no effect on NNK activation. Sulindac and its sulfide and sulfone metabolites (1 mM) inhibited NNK metabolism by 90, 92 and 65%, respectively. We observed a 76% inhibition with SKF 525A, a P-450 inhibitor. Taken together, these results indicate that salicylates and sulindac could be equally effective as chemopreventive agents, but they could differ in their mode of action.

Topics: Adenoma; Animals; Aspirin; Cells, Cultured; Cytochrome P-450 CYP1A2; Enzyme Activation; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred A; Nitrosamines; Prodrugs; Sulindac

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

A case of a patient with familial adenomatous polyposis (FAP) is reported, in whom adenomas developed in an ileal pelvic pouch six years after it was made. This case is reported to serve as a warning that restorative proctocolectomy, a relatively recent addition to surgical options for FAP, does not remove the risk of metachronous intestinal neoplasia; it merely defers it.. Case of a patient with pouch polyposis was reviewed, and patient was prospectively studied after three months of sulindac therapy.. Polyps not removed at first examination became much less prominent. Literature review reveals only one study of adenomas in pelvic pouches, with 7 cases of 38.. Proctocolectomy and ileal pouch-anal anastomosis does not cure FAP, and multiple polyps can occur in the ileal pouch.

Topics: Adenoma; Adenomatous Polyposis Coli; Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Colonoscopy; Combined Modality Therapy; Humans; Ileal Neoplasms; Male; Neoplasms, Second Primary; Proctocolectomy, Restorative; 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

The efficacies of the non-steroidal, anti-inflammatory drug sulindac and the schistosomicidal agent oltipraz in inhibiting lung tumorigenesis was measured in A/J mice. Lung tumors (15.7 tumors/mouse) were induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; 9.1 mg/mouse) administered in drinking water for 7 weeks. Feeding mice with sulindac (123 mg/kg diet), 2 weeks before carcinogen treatment until they were killed reduced tumor multiplicity by 53%. Oltipraz (250 mg/kg diet), however, has no effect on tumorigenesis. The absorption and metabolism of NNK were compared in the stomachs and intestines isolated from mice fed AIN-76A diet or sulindac + diet. Sulindac had no effect on alpha-carbon hydroxylation, pyridine N-oxidation or carbonyl reduction of NNK. Mouse lung explants were cultured with 4.7 microM [5-3H]NNK for 4 or 8 h. The addition of 1 mM sulindac to the culture medium reduces the alpha-carbon hydroxylation and pyridine N-oxidation of NNK. However, the administration of sulindac in the diet prior to the excision of the lung explants had no effect on these two metabolic pathways. We compared the levels of sulindac and its sulfide and sulfone metabolites in the lungs, livers and plasma of mice fed an AIN-76A diet containing 130 mg sulindac/kg for 2 weeks. The sulfide metabolite was the most abundant of the three compounds in plasma (17.6 pmol/microliters) and liver tissues (17.7 pmol/mg) but it could not be detected in lung tissues. These results show that non-steroidal anti-inflammatory drugs constitute a new class of chemopreventive agents in lung tumorigenesis. The tumor chemopreventive activity of sulindac is not mediated by the sulfide metabolite responsible for its anti-inflammatory activity.

Topics: Adenoma; Animals; Carcinogens; Drug Screening Assays, Antitumor; Female; Intestinal Absorption; Lung; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Nitrosamines; Oxidation-Reduction; Pyrazines; Schistosomicides; Sulindac; Thiones; Thiophenes

Sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene] indene-3-acetic acid), an inhibitor of prostaglandin synthesis, has been reported to cause regression of colon polyps in patients with familial polyposis coli and Gardner's syndrome. We examined the effect of sulindac on the growth of primary colon carcinomas in rats. Colon tumors were induced in 18 rats by repeated subcutaneous administration of dimethylhydrazine. The site and diameter of each tumor were measured via laparotomy and colonoscopy. Rats were randomized to receive either sulindac (10 mg/kg) twice daily or vehicle (0.5% methylcellulose). After 4 weeks of treatment, the site and size of tumors in the colon were again recorded. In eight rats receiving sulindac, no new tumors were identified, while in 10 control rats, 13 additional tumors were found after treatment. There was a significantly greater increase in size of the tumors in the control group (56.4 mm for 26 tumors) compared with the rats receiving sulindac (9.3 mm for 14 tumors). We report that sulindac inhibits the rate of development and the rate of growth of colon tumors in the rat.

Topics: Adenocarcinoma; Adenoma; Animals; Carcinoma; Colonic Neoplasms; Dimethylhydrazines; Male; Random Allocation; Rats; Rats, Inbred Strains; Remission Induction; Sulindac

Dimethylhydrazine has been used to produce colonic tumours in mice. If sulindac, a non-steroidal anti-inflammatory drug, is administered simultaneously fewer microadenomata and fewer macroscopic tumours are produced. Those which do appear are comparable in size to the ones in the mice which do not receive sulindac. Sulindac therefore appears to exert an anti-tumour influence at the stage between dysplasia and the formation of microadenomata.

Topics: Adenoma; Animals; Colon; Colonic Neoplasms; Dimethylhydrazines; Female; Mice; Mice, Inbred BALB C; Reference Values; Sulindac

Sulindac, a non-steroidal anti-inflammatory drug, has been reported to lead to tumour regression in cases of human polyposis coli. We have investigated the effects of this drug on the growth of 1,2-dimethylhydrazine (DMH)-induced mouse colonic tumours. In one experiment, DMH and oral sulindac were administered concurrently to a group of mice for a period of up to 24 weeks, while a control group of animals received DMH only for the same period. Sulindac caused a significant reduction in both the number of mice with colonic tumours and the number of tumours per mouse. In a second experiment, two groups of mice which had already been treated with DMH for 17 weeks received either sulindac or not for 78 days. In this experiment sulindac had no effect. These results demonstrate that sulindac has a protective effect against the chemical induction of colonic tumours in mice, but does not cause the regression of established tumours.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Adenoma; Animals; Carcinogens; Colonic Neoplasms; Dimethylhydrazines; Female; Indenes; Mice; Mice, Inbred BALB C; Sulindac