Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of polyps in familial polyposis coli and may prevent new lesions. However, it is not clear whether the effect of sulindac in preventing polyps also applies to carcinoma. This case report describes a patient with familial polyposis coli who developed a carcinoma in a rectal segment after subtotal colectomy and ileorectal anastomosis. She had been treated with 450 mg sulindac daily for 28 months and was free of polyps during the latter 12 months of this period. However, despite intensive endoscopic follow-up, she developed an adenocarcinoma of the rectum. This finding may have important implications for our understanding of the development of colon cancer in familial polyposis coli and the use of sulindac to prevent it. Development of de novo carcinoma in microadenomatous tissue of the rectal mucosa, which bypasses the polyp-cancer sequence, must be considered as a possibility in these patients.
 ...
PMID:Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy. 807 72

Nonsteroidal anti-inflammatory drugs lower the incidence of and mortality from colon cancer. Sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. We have shown that sulindac and sulindac sulfide reversibly reduce the proliferation rate of HT-29 colon cancer cells, alter their morphology, induce them to accumulate in the G0/G1 phase of the cell cycle, and sulindac sulfide induces cell death by apoptosis. In this study we confirmed that sulindac and sulindac sulfide prevent HT-29 cells from progressing from the G0/G1 into the S phase. This block in cell cycle progression is associated with an initial rise, then an abrupt decrease in the levels of p34cdc2 protein. Sulindac and sulindac sulfide decrease the levels of mitotic cyclins, induce the levels of p21WAF-1/cip1, and reduce the total levels of pRB, with a relative increase in the amount of the underphosphorylated form of pRB in a time- and concentration-dependent manner. In addition, these compounds reduce the levels of mutant p53. These responses are not associated with intestinal cell differentiation and occur independent of the ability of these compounds to induce apoptosis. We conclude that sulindac and sulindac sulfide reduce the levels of major components of the molecular cell cycle machinery and alter the levels of several tumor suppressor proteins in a manner consistent with cell cycle quiescence. These mechanisms may be operative in vivo to account, in part, for the anti-neoplastic effects of these compounds.
 ...
PMID:The anti-proliferative effect of sulindac and sulindac sulfide on HT-29 colon cancer cells: alterations in tumor suppressor and cell cycle-regulatory proteins. 863 12

The justification of colectomy and ileorectal anastomosis as the primary treatment for familial adenomatous polyposis (FAP) remains questionable because of the rectal cancer risk. We estimated both the cancer risk and the need of rectal excision for benign polyposis in 100 FAP patients. We also evaluated the effects of sulindac therapy and the complications of polyp fulgurations during the follow-up time of the median of 10.6 years (2 to 29 years) after ileorectal anastomosis. There were 46 women and 54 men with a mean age of 32 years (17-67 years) at the operation. Forty-two patients were propositi and 15 had colon cancer primarily. Cumulative risk of rectal cancer and combined risk of cancer and rectal excision for other causes were estimated (Kaplan-Meier analysis) both from the date of surgery and from birth. Nine patients developed rectal cancer, while 12 others has the rectum excised for benign conditions. The cumulative rectal cancer risk was 4%, 5.6%, 7.9% and 25% at 5, 10, 15 and 20 years after the operation, respectively. Rectal excision rates were 7.3%, 13.7%, 23.6%, and 36.6%, correspondingly and finally 73.8%. Age-dependent rectal cancer risks were 3.9%, 12.8% and 25.7% at 40, 50 and 60 years, and the rectal excision rates 9.5%, 26.3% and 44%, respectively. Sulindac caused at least partial regression of rectal adenomas in 71% of patients without major adverse effects, but the long term effects of sulindac and impact on malignant transformation of rectal adenomas are not known. Our results favour proctocolectomy and ileonal anastomosis as the primary operation for FAP instead of colectomy and ileorectal anastomosis.
 ...
PMID:Fate of the rectal stump after colectomy and ileorectal anastomosis for familial adenomatous polyposis. 911 43

Sulindac sulfide (SS), the active metabolite of the colon cancer chemopreventive compound sulindac, inhibits the proliferation of HT-29 colon cancer cells mainly by inducing cell quiescence. We determined by bivariate flow-cytometric analysis both the DNA and cyclin protein content of individual cells. Thus, we assessed in detail the expression of several cyclins during the cell-cycle phases and demonstrated that SS (i) decreases the expression of cyclins B1 and E and (ii) increases the expression of cyclins D1, D2 and D3, particularly in the G1 phase of the cell cycle. SS-induced apoptotic cells expressed both E- and D-type cyclins but not cyclin B1. The changes in cyclin expression combined with reduced catalytic activity of cyclin-dependent kinases could explain in molecular terms the anti-proliferative effect of SS on HT-29 colon cancer cells. These changes may contribute to the chemopreventive effect of sulindac.
 ...
PMID:Sulindac sulfide alters the expression of cyclin proteins in HT-29 colon adenocarcinoma cells. 953 68

Barrett's oesophagus is associated with an increased risk of oesophageal adenocarcinoma. In 1985, Sontag et al reported an association between Barrett's oesophagus and colorectal cancer. This association has become controversial owing to conflicting evidence. Two recent papers indicate that although the prevalence of colon adenomas is the same in persons with Barrett's oesophagus as in the rest of the population, patients have an increased risk of developing colon cancer. A biologically plausible hypothesis is presented which explains the predisposition to both oesophageal and colon cancers. This hypothesis discusses the contribution of environmental factors such as alcohol, smoking and diet. In addition, it is proposed that the increased expression of the cyclo-oxygenase 2 enzyme is central to the predisposition to both oesophageal and colon cancers. Since this enzyme is inhibited by non-steroidal anti-inflammatory drugs such as aspirin and sulindac, these drugs hold promise as cancer chemopreventive agents in Barrett's oesophagus patients. Sulindac is the most promising of these agents owing to its efficacy in regressing colon polyps in patients with familial adenomatous polyposis.
 ...
PMID:Barrett's oesophagus, oesophageal cancer and colon cancer: an explanation of the association and cancer chemopreventive potential of non-steroidal anti-inflammatory drugs. 969 27

We investigated whether the therapeutic action of sulindac, used for the treatment of familial adenomatous polyposis, desmoid tumors, and against colon cancer, could be mediated by its active metabolite, sulindac sulfide, in cell growth and apoptosis on cell lines derived from abdominal neoplasms. Sulindac sulfide actions on cell growth and apoptosis were evaluated in epithelial human colon tumor 8 (HCT8) cell line and mesenchymal cell lines (bovine bone endothelial (BBE) cell line, desmoid tumor-derived cells, human colorectal cancer-derived fibroblasts). Sulindac sulfide (0.1-60 microg/ml) induced a dose-dependent inhibition of cell proliferation of all cell lines tested. Apoptosis was induced at doses of 20 and 40 microg/ml, respectively, in BBE and HCT8 cells with no effect on desmoid tumor cells and colorectal cancer-derived fibroblasts. Since mesenchymal cells respond to clinically effective concentrations of the compound, its preferential action on the stromal compartment of intestinal polyps, desmoid tumors and colon cancer can be proposed, with consequent regression of the tumor.
 ...
PMID:Apoptosis induced by sulindac sulfide in epithelial and mesenchymal cells from human abdominal neoplasms. 984 79

Colorectal cancer is second to lung cancer as the most common cause of cancer death in the United States; both environmental (diet, physical activity) and genetic (family history, mutations, polymorphisms) factors are related to colon cancer risk. Epidemiologic, animal model, and clinical studies all suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are potent preventive agents for colon cancer. Most epidemiologic studies (case control, and cohort) are consistent with a protective effect of regular, long-term use of aspirin use, although the prospective Physicians Health Study failed to find a significant protective effect. The entire class of NSAIDs appear to be effective in preventing carcinogen induced colon cancer in animal models. Clinical trials using the NSAID sulindac have shown dramatic regression of colonic adenomas in patients with Familial Polyposis. The biologic and biochemical mechanisms of the putative chemopreventive activity of the NSAIDs is under intense investigation. These drugs can induce cell cycle arrest and apoptosis in colon cancer cell lines through a mechanism that is fundamentally different from the apoptosis caused by cancer chemotherapeutic agents. Sulindac and its metabolites also appear to induce apoptosis in colonic adenomas in vivo. The clinically used NSAIDs are anti-inflammatory due to their ability to decrease prostaglandin synthesis by inhibiting the cyclooxygenase (COX) enzymes. Cyclooxygenase inhibition, particularly COX 2 inhibition, is one putative biochemical target of the chemopreventive activity of NSAIDs. However, recent reports of chemopreventive activity of NSAID derivatives that no longer have COX inhibitory activity suggest that there are other biochemical targets as well.
 ...
PMID:Colon cancer prevention by NSAIDs: what is the mechanism of action? 1002 75

Epidemiological and model studies with laboratory animals have provided evidence that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer. Sulindac, a nonsteroidal anti-inflammatory drug, has been shown to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats when administered continuously before, during, and after carcinogen treatment (initiation and postinitiation periods) or when given continuously beginning 14 weeks after carcinogen administration (promotion/ progression stage). The present study was designed to investigate the chemopreventive efficacy of sulindac sulfone (exisulind), the sulfone metabolite of sulindac, when administered during the promotion/progression stage of colon carcinogenesis in comparison to the effect during the initiation and postinitiation periods. We have also studied the modulating effect of exisulind on colonic tumor apoptosis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0%, 0.06%, and 0.12% exisulind. At 7 weeks of age, groups of animals were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 weeks). Animals intended for the promotion/progression study and receiving 0% exisulind were switched to an experimental diet containing 0.12% exisulind at 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, 50 weeks after the second AOM injection. Colon tumors were evaluated histopathologically for tumor type. Administration of 0.06% and 0.12% exisulind during the initiation and postinitiation periods significantly inhibited the incidence and multiplicity of invasive and/or noninvasive adenocarcinomas of the colon. The inhibition of colon tumorigenesis by exisulind was associated with a significant retardation of body weight gain shortly after sulfone administration and increased apoptosis in the colon tumors. In contrast, administration of the higher dose (0.12%) of exisulind during the promotion/progression stage had only minimal effects on colon tumorigenesis and apoptosis in the colon tumors, suggesting that early administration, but not late administration, may be required for chemopreventive efficacy of this drug.
 ...
PMID:Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process. 1041 99

Sulindac is a non-steroidal anti-inflammatory agent that is related both structurally and pharmacologically to indomethacin. In addition to its anti-inflammatory properties, sulindac has been demonstrated to have a role in the prevention of colon cancer. Both its growth inhibitory and anti-inflammatory properties are due at least in part to its ability to decrease prostaglandin synthesis by inhibiting the activity of cyclooxygenases. Recently, we demonstrated that both aspirin and sodium salicylate, but not indomethacin, inhibited the activity of an IkappaB kinase beta (IKKbeta) that is required to activate the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we show that sulindac and its metabolites sulindac sulfide and sulindac sulfone can also inhibit the NF-kappaB pathway in both colon cancer and other cell lines. Similar to our previous results with aspirin, this inhibition is due to sulindac-mediated decreases in IKKbeta kinase activity. Concentrations of sulindac that inhibit IKKbeta activity also reduce the proliferation of colon cancer cells. These results suggest that the growth inhibitory and anti-inflammatory properties of sulindac may be regulated in part by inhibition of kinases that regulate the NF-kappaB pathway.
 ...
PMID:Sulindac inhibits activation of the NF-kappaB pathway. 1048 Sep 51

Non-steroidal anti-inflammatory drugs (NSAIDs) have been found to reduce cancer rates in various segments of the gastro-intestinal tract in both animals and humans. In this study we examined the effect of sulindac, sulindac sulfide, sulindac sulfone and aspirin on QR and GST activity. We found that sulindac itself increased QR activity as much as 2-fold over controls but had no effect on GST activity. Sulindac sulfone, a metabolite of sulindac which lacks the ability to inhibit prostaglandin (PG) synthesis, increased QR and GST to 1.5-fold over controls in both cases. Aspirin increased QR and GST to 1.5-fold and 3.5-fold over controls respectively. These data indicate that NSAIDs increase phase II enzyme detoxification enzyme activity. Consequently, this effect may contribute to the protective effect of NSAIDs against colon cancer and may be an anticarcinogenic effect of these drugs that is distinct from their ability to inhibit PG synthesis.
 ...
PMID:Effects of sulindac, sulindac metabolites, and aspirin on the activity of detoxification enzymes in HT-29 human colon adenocarcinoma cells. 1066 94


1 2 3 4 5 Next >>