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PubMed2002

Effects of long-term administration of sulindac on APC mRNA and apoptosis in colons of rats treated with azoxymethane.

PURPOSE: Non-steroidal anti-inflammatory drugs, including sulindac, have been shown to exhibit anti-colon cancer activity; however, the detailed mechanisms concerning continuous long-term administration are still unclear. Therefore, we examined the anti-colon carcinogenesis effects of sulindac after prolonged administration. METHODS: Administration of AOM, a colon-specific carcinogen, induced colonic preneoplastic lesions, which can progress to carcinomas about 40-50 weeks after AOM administration. We studied the effects of sulindac on the incidence of preneoplastic lesions, proliferative activity of colonic cells (AgNORs), tumor suppressor adenomatous polyposis coli (APC) gene expression, and apoptosis using AOM-treated rat colon mucosa at 4 weeks and 40 weeks (early and late stage of colon carcinogenesis, respectively). RESULTS: Sulindac suppressed the development of preneoplastic lesions induced by AOM at 4 weeks and 40 weeks by about 50% ( P<0.01); the proliferative activity of colonic cells increased by AOM was suppressed almost completely. Furthermore, APC expression was significantly increased by sulindac at both the early and late stages ( P<0.01). However, apoptosis was clearly increased at the early stage ( P<0.01), but not at the late stage. CONCLUSIONS: APC overexpression induced by sulindac can suppress colon carcinogenesis at both the early and late stages, but apoptosis might work as one of anti-cancer mechanisms at the early stage of colon carcinogenesis.

Adenomatous Polyposis Coli Protein↗

PubMed2001

Combination cancer chemoprevention with green tea extract and sulindac shown in intestinal tumor formation in Min mice.

Green tea is the most effective beverage for cancer prevention in humans. Looking at the concept of combination cancer chemoprevention, we previously reported the synergistic effects of (-)-epigallocatechin gallate (EGCG) with sulindac, and the additive effects of EGCG with tamoxifen, on cancer-preventive activity in human lung cancer cell line PC-9. This paper reports confirmation of the synergistic effects of EGCG with sulindac on the inhibition of intestinal tumors in multiple intestinal neoplasia (Min) mice. Treatment with both green tea extract and sulindac significantly reduced the number of tumors from 72.3 +/- 28.3 to 32.0 +/- 18.7 tumors per mouse, a decrease of 44.3%, whereas treatment with green tea extract alone or with sulindac alone reduced it to 56.7 +/- 3.5 and 49.0 +/- 12.7, respectively. The results also indicated that green tea extract inhibited tumor growth in Min mice almost as potently as sulindac itself did. The three treated groups did not show any adenocarcinomas, whereas 10.8% of the control group did. Since cancer-preventive agents like sulindac and tamoxifen are associated with adverse effects, we discuss the possibility of non-toxic, combination cancer chemoprevention with green tea, looking at the goal of truly effective cancer prevention.

Adenocarcinoma↗

PubMed1991

Sulindac causes regression of rectal polyps in familial adenomatous polyposis.

In familial adenomatous polyposis, sulindac-induced polyp regression has been reported by several authors. In this study, the goal was to confirm these results by a randomized, placebo-controlled, double-blind crossover study in 10 patients with rectal polyps that had been previously treated by colectomy and ileorectal anastomosis. Patients received sulindac, 300 mg/day, or placebo during two 4-month periods separated by a 1-month wash-out phase. One patient was not compliant and was excluded. With sulindac, the authors observed a complete (6 patients) or almost complete (3 patients) regression of the polyps. With placebo, the authors observed an increase (5 patients), no change (2 patients), and a relative decrease (2 patients) in the number of polyps. The difference between sulindac and placebo was statistically significant (P less than 0.01). In biopsy specimens of polyps and normal rectal mucosa of 6 patients, the authors conducted an immunohistochemical study of the cellular proliferation index using the Ki 67 monoclonal antibody (Ki 67 index), at the beginning and at the end of each treatment period. They were not able to show a sulindac-induced modification of the Ki 67 index. The authors conclude that sulindac is effective in inducing the regression of rectal polyps in familial adenomatous polyposis.

Adenomatous Polyposis Coli↗

PubMed1985

Sulindac does not preserve renal prostacyclin synthesis during endotoxemia.

Previous reports have suggested that sulindac is a unique non-steroidal anti-inflammatory (NSAID) agent, because it does not inhibit renal prostaglandin synthesis in doses that inhibit platelet thromboxane B2 synthesis when tested ex vivo. NSAIDS are of potential therapeutic benefit in the treatment of septic or endotoxic shock. Therefore, this study was designed to investigate the proposed unique action of sulindac in experimental endotoxemia. In the current study, the effect of sulindac on aortic, portal and renal venous immunoreactive (i) 6-keto-PGF1 alpha levels, the stable metabolite of prostacyclin, was investigated during endotoxemia in the rat. In doses sufficient to reduce the elevation in aortic and portal venous plasma i6-keto-PGF1 alpha levels, sulindac also significantly (p less than 0.05) attenuated the elevated renal venous plasma 6-keto-PGF1 alpha levels, compared to the vehicle group. Using lower doses, sulindac failed to reduce the endotoxin associated increase in either aortic or renal venous plasma i6-keto- PGF1 alpha levels. Thus, sulindac failed to demonstrate any selective sparing effect on renal prostacyclin generation during endotoxemia.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

Determination of sulindac and its metabolites in human serum by reversed-phase high-performance liquid chromatography using on-line post-column ultraviolet irradiation and fluorescence detection.

On irradiation with ultraviolet light, the antiinflammatory agent sulindac and its two metabolites sulindac sulfone and sulindac sulfide form highly fluorescent derivatives. This reaction was exploited for the sensitive and selective detection of these compounds in serum using reversed-phase high-performance liquid chromatography on a Ultrasphere octylsilane column (150 x 4.6 mm I.D.) at ambient temperature with a flow-rate of 0.5 ml/min. The analytes of interest were isolated from serum using a Bond-Elut C2 column with satisfactory recovery and selectivity. The detection limits were 10 ng/ml for each of the three analytes using 1 ml of serum and the limit of quantitation was 50 ng/ml. Linear calibration curves from 50 to 1000 ng/ml for all three analytes show coefficients of determination of 0.9999. The post-column ultraviolet irradiation was optimized and the effect of irradiation time on the fluorescence response was determined for all three analytes. Precision and accuracy of the method were 0.4-5.6 and 1.6-4.5% for sulindac, 2.3-5.6 and 1.4-5.3% for sulindac sulfone and 2.5-4.3 and 0.8-2.8% for sulindac sulfide, respectively.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMedDate not supplied

Human placental transfer of the prostaglandin inhibitor sulindac using an in vitro model.

OBJECTIVE: We determined whether the prostaglandin inhibitor sulindac crosses the human placenta. METHODS: The recirculating single-cotyledon placenta model was used to characterize the maternal-to-fetal and fetal-to-maternal transport of 14C-labeled sulindac in normal term placentas perfused immediately after delivery. Antipyrine was added as a standard for simple diffusion. Serial samples were taken from both reservoirs during each 3-hour perfusion. Transport was calculated using liquid scintillation spectrometry for 14C-labeled sulindac and high-performance liquid chromatography for antipyrine. RESULTS: There was significant maternal-to-fetal transfer of sulindac. The mean (+/- SD) transfer at 2 hours was 7.22 +/- 2.57%. The fetal-to-maternal transfer was similar at 10.75 +/- 3.80%. The mean maternal/fetal concentration ratio of sulindac was 0.42 at 3 hours. Placental uptake ranged from 24-45 ng/g of placenta. CONCLUSIONS: Sulindac crosses the human placenta in small but significant amounts. The transport is similar in both directions, implying simple diffusion.

Antipyrine↗

PubMed2005

Sulindac activates nuclear translocation of AIF, DFF40 and endonuclease G but not induces oligonucleosomal DNA fragmentation in HT-29 cells.

Sulindac is one of the most widely studied nonsteroidal anti-inflammatory drugs in the prevention of colon cancer. Thus, from the viewpoint of colon cancer chemotherapy it is important to reveal the mechanism of sulindac-induced cell death. This study was undertaken to dissect the molecular mechanism underlying sulindac-induced apoptosis in human colon cancer cell line HT-29 (mutant p53), focusing on nuclear translocation of AIF, DFF and endonuclease G. On induction of apoptosis by sulindac, it was associated with decreased mitochondrial membrane potential, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of mitochondrial proteins to the nucleus, and morphological evidence of nuclear condensation. However, sulindac led to only disintegration of nuclear DNA into high molecular weight DNA fragments of about 100-300 kbp as determined by a pulse-field gel electrophoresis, suggesting a predominantly AIF-mediated cell death process. In summary, our findings indicate that sulindac induces large-scale DNA fragmentation without oligonucleosomal DNA fragmentation. This result suggests that nuclear translocation of DFF and endonuclease G are not sufficient for the induction of oligonucleosomal DNA fragmentation in HT-29 cells.

Active Transport, Cell Nucleus↗

PubMed1999

Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines.

We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.

Androgens↗

PubMed1997

Differential effects of sulindac on renal hemodynamics and function in the rat.

Renal hemodynamics were studied using an electromagnetic perivascular flow sensor in anesthetized rats injected i.v. with vehicle, 5 or 10 mg/kg body weight (b.w.) sulindac. No hemodynamic changes occurred with vehicle (n = 6), but mean arterial pressure was significantly decreased (by 15 mmHg) with sulindac (n = 12). In the 5 mg/kg b.w. sulindac group (n = 7), renal blood flow progressively and significantly increased from 7.88 +/- 0.36 to 8.98 +/- 0.58 ml/min, except during concomitant intrarenal infusion of 3 mg/kg b.w. per h proadifen (n = 7). The pressure limits for efficient and no renal blood flow autoregulation remained unchanged (approx. 100 and 80 mmHg, respectively). In the 10 mg/kg b.w. sulindac group (n = 5), renal blood flow did not change but autoregulatory pressure limits were lowered by 10 mmHg 2 h after treatment (P < 0.025). Also, Na+ retention was marked. Prostanoid excretion in urine was significantly reduced with either dose but basal plasma renin activity was not (about 8 ng/ml per h; n = 15). When plasma renin activity was enhanced after a reduction in renal perfusion pressure (n = 21), it was decreased from 11.5 +/- 1.2 to 7.4 +/- 0.2 ng/ml per h only by 10 mg/kg b.w. sulindac (P < 0.05; n = 6). In conclusion, differential effects of sulindac on renal hemodynamics, Na+ excretion and plasma renin activity were demonstrated. Renal hemodynamic changes could be related in part to the cytochrome P-450 arachidonic acid pathway.

Animals↗

PubMed2002

Response of Apc(min) and A33 (delta N beta-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

There is growing interest in the potential health benefits of tea, and a recent report described the potent antimutagenic activity of white tea in comparison with green tea against several heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) [Mutat. Res. 495 (2001) 61]. We compared the inhibitory effects of white and green teas with sulindac, a nonsteroidal anti-inflammatory agent, in two different mouse models of intestinal tumorigenesis. In the Apc(min) mouse, white and green teas given at human-relevant concentrations (1.5% w/v, 2-min brew), and sulindac (80 ppm in the drinking water), each suppressed polyp formation by approximately 50%, and the combination of white tea plus sulindac was more effective than either treatment alone (P=0.05). Mice expressing an N-terminally truncated, oncogenic version of beta-catenin (A 33(delta N beta-cat) mutant mice) developed colonic aberrant crypt foci (ACF) spontaneously, but PhIP treatment increased the incidence and number of ACF per colon. In the normal-looking intestinal mucosa of Apc(min) and A 33(delta N beta-cat) mice, white tea plus sulindac treatment markedly attenuated the expression of beta-catenin protein, and this was recapitulated in vitro in cells transiently transfected with beta-catenin plus Tcf-4 and treated with tea or the major tea polyphenol epigallocatechin-3-gallate (EGCG). Expression of a beta-catenin/Tcf reporter was inhibited by EGCG in the transfected cells, and the beta-catenin/Tcf target genes cyclin D1 and c-jun were downregulated in vivo by tea plus sulindac treatment. Collectively, the data support a chemopreventive role for tea and sulindac against intermediate and late stages of colon cancer, via effects on the beta-catenin/Tcf signaling pathway.

Adenomatous Polyposis Coli Protein↗

PubMed1997

Polymorphism of sulindac: isolation and characterization of a new polymorph and three new solvates.

The polymorphism of sulindac was investigated. Two polymorphs (I and II) and a new crystalline form (form III) of sulindac were prepared by recrystallization in different solvents. In addition, three new pseudopolymorphs (solvates) from acetone, chloroform, and benzene were obtained, with each containing 1 mol of solvent to 2 mol of sulindac. Different sulindac polymorphs and pseudopolymorphs were characterized by X-ray diffractometry, infrared spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot-stage microscopy. The transition behavior of the crystalline forms of sulindac, their melting points, and their enthalpies were investigated by DSC. The melting of form II was observed at 184 degrees C, and form I subsequently recrystallized from this melt. Similarly, form III melts at 145 degrees C and then recrystallizes to form I. We also investigated the influence of the crystallization solvent on sulindac crystal shape.

Calorimetry, Differential Scanning↗

PubMed1998

Prostaglandin levels in human colorectal mucosa: effects of sulindac in patients with familial adenomatous polyposis.

Recent evidence suggests that nonsteroidal antiinflammatory drugs (NSAIDs) may prevent colorectal cancer. The mechanism of action of NSAIDs in chemoprevention is unknown but may be linked to their effect on mucosal prostaglandin levels. Levels of five major prostaglandin metabolites were measured by gas chromatography-mass spectrometry in biopsy specimens of flat rectal mucosa from four patients with familial adenomatous polyposis (FAP) before and after sulindac therapy and from five healthy individuals. The prostaglandin present at highest concentration in rectal mucosa from FAP and control subjects was prostaglandin E2. The concentration of thromboxane B2 alone was significantly elevated in FAP patients compared to controls (P = 0.016). In FAP patients treated with sulindac, all prostaglandin metabolite levels were significantly reduced compared to pretreatment levels (P < 0.05) except prostaglandin D2 (P = 0.07). Prostaglandins D2, E2, F2alpha, and 6-keto-F1alpha levels also were significantly reduced in FAP patients on sulindac compared to healthy controls (P < 0.05). However, interpatient heterogeneity of response to sulindac was evident with changes ranging from +19% to -89%, and the patient with the greatest reductions after sulindac developed colorectal cancer after 35 months of therapy. Sulindac treatment, at drug doses shown to regress colorectal adenomas in FAP patients, has heterogeneous effects on the level of major prostaglandins in their rectal mucosa and may not prevent colorectal cancer due to uncoupling of prostaglandin levels and carcinogenesis.

Adenomatous Polyposis Coli↗

PubMed1983

Ibuprofen and sulindac kinetics in alcoholic liver disease.

Ibuprofen and sulindac kinetics after oral doses were compared in 15 patients with alcoholic liver disease and 29 normal subjects. The patients with alcoholic liver disease were divided into a group with fair hepatic function (FHF) and a group with poor hepatic function (PHF) based on elimination rates of indocyanine green. The effects of alcoholic liver disease on the ibuprofen kinetics were minimal. The absorption of the drug appeared to be delayed in some of the PHF patients, and slight differences were noted in the serum AUC and the elimination rate constant for ibuprofen. The absorption of sulindac was delayed in both PHF and FHF groups of patients, as was the appearance of the active metabolite, sulindac sulfide, and the inactive metabolite, sulindac sulfone. The plasma AUC for sulindac sulfide in patients with poor hepatic function was four times that in normal subjects. The kinetics of sulindac, a pro-drug that relies on the liver for conversion to an active metabolite, were markedly affected by alcoholic liver disease.

Administration, Oral↗

PubMed1985

Effects of age and disease on the pharmacokinetics and pharmacodynamics of sulindac.

The disposition and effect on hemostasis of a single 150 mg dose of sulindac was studied in young healthy subjects and in older patients with arthritis. Older patients were restudied after 2 weeks of sulindac, 150 mg b.i.d. The only difference in disposition of the first dose was a reduced plasma sulfone metabolite concentration in the elderly patients with arthritis. Chronic sulindac dosing resulted in accumulation of the drug and its sulfone and sulfide metabolites in plasma to a greater extent than previously reported for young subjects. No differences in renal clearance of sulindac and its sulfone metabolite related to age or chronic drug dosing were observed. No renal excretion of the active sulfide metabolite was detected. Bleeding time in the elderly patients was shorter than in the young healthy subjects before sulindac dosing, but was prolonged in the elderly patients after 2 weeks of dosing to values similar to control data from the young healthy subjects. This change correlated weakly with plasma sulfide metabolite concentrations. Differences in bleeding time were not reflected in changes in platelet aggregation induced by adenosine diphosphate either with respect to age or chronic drug dosing. Our data provide no justification for lowering the recommended dose of sulindac for patients older than 65 years of age.

Adult↗

PubMed1985

Sulindac metabolism: the importance of an intact colon.

The pharmacokinetics of sulindac have been studied after a single 200 mg oral dose in six normal subjects and five patients with surgical ileostomies. The plasma concentration-time curves for sulindac were similar in both groups up to 12 hours after dosing, indicating similar absorption of the drug. Higher plasma concentrations of sulindac were found in normal subjects after 12 hours, but this late phase accounted for only 12% of the total AUC in the subjects. The sulfone metabolite showed a similar pattern, with no statistically significant difference in the total AUC, but in patients with ileostomy there was a halving of the AUC after 12 hours. Plasma concentrations of the active sulfide metabolite were similar in both groups up to 12 hours, but negligible concentrations were detected in the plasma of patients with ileostomy after 12 hours. Thus the AUC after 12 hours, which represented 55% of the total AUC in normal subjects, was reduced to only 7% in patients with ileostomy. The rate of reduction of sulindac in vitro by ileostomy effluent was only one hundredth that by normal feces. Our results suggest that the gut microflora are an important site of reduction of sulindac in man. Comparison of AUC values suggests that about half the total sulfide is formed by the gut bacteria, probably from sulindac excreted in the bile.

Absorption↗

PubMed2005

Methylation in the p21WAF1/cip1 promoter of Apc+/-, p21+/- mice and lack of response to sulindac.

P21WAF1/cip1 plays a critical role in regulating intestinal cell proliferation, maturation and tumorigenesis. Our previous work demonstrated that inactivation of a single p21 allele in Apc1638+/- mice was sufficient to accelerate Apc-initiated tumor formation, and that inactivation of only one p21 allele was also sufficient to abrogate duodenal tumor inhibition by sulindac, a nonsteroidal anti-inflammatory drug. To dissect the role of p21 in sulindac inhibition of intestinal tumor development in Apc1638+/- mice, we quantified p21 expression from Apc+/-, p21+/+, +/- or -/- mice fed sulindac. In Apc+/-, p21 wild-type mice fed the sulindac supplemental diet, both p21 mRNA and protein were significantly increased in the flat mucosa and tumors of the duodenum. However, p21 was not induced by sulindac in the duodenal flat mucosa and tumors of Apc+/- mice in which one or both p21 alleles had been inactivated. Further investigation revealed that the cytosine residues in a CpG cluster in the promoter region of the mouse p21 gene displayed hypermethylation in the Apc+/-, p21+/- mice. This suggested that although the p21+/- mice retained a wild-type allele, this allele was functionally modulated by hypermethylation, and that the inability of sulindac to inhibit tumor formation in Apc+/-, p21+/- mice is likely due to the inability to induce expression of the wild-type, but differentially methylated, p21 allele.

Animals↗

PubMed1985

Differential effects of sulindac and indomethacin on blood pressure in treated essential hypertensive subjects.

Attenuation of the effectiveness of antihypertensive therapy by non-steroidal anti-inflammatory (NSAI) drugs has been attributed to inhibition of systemic or renal vasodilator prostaglandin synthesis, or a combination of both. Indomethacin is a NSAI drug with both renal and extrarenal cyclo-oxygenase inhibition properties. Sulindac is a relatively selective cyclo-oxygenase inhibitor said not to affect urinary prostaglandin excretion. This study examines the relative effect on blood pressure of 4 weeks' treatment, with indomethacin 25 mg three times daily and sulindac 200 mg twice daily, in a randomized placebo controlled trial in 26 hypertensive subjects. In nine patients treated with indomethacin, supine blood pressure rose 11 mmHg systolic and 4 mmHg diastolic by the end of the first week, whereas nine subjects treated with sulindac showed a fall in blood pressure similar to the trend seen in placebo-treated subjects. Indomethacin treatment inhibited renal cyclo-oxygenase with a 78% reduction in urinary prostaglandin E2 excretion and 89% suppression of plasma renin activity. Neither measurement was affected by sulindac. Extrarenal cyclo-oxygenase activity was inhibited by both indomethacin and sulindac with serum thromboxane B2 decreasing by 96% and 69% respectively. The results suggest that the pressor effect of NSAI drugs is predominantly related to renal cyclo-oxygenase inhibition. the lack of effect of sulindac on blood pressure may make it a safer therapeutic option if NSAI drug therapy is necessary in the hypertensive patient.

Adult↗

PubMed1999

Chemopreventive effect of S-methylmethane thiosulfonate and sulindac administered together during the promotion/progression stages of colon carcinogenesis.

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.

Adenocarcinoma↗