Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutation of adenomatous polyposis coli (APC) gene results in incidence or development of polyps and colorectal cancer. It has been reported that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cell growth, cause cell cycle arrest, and induce apoptosis. The aims of this study are to investigate chemopreventive effects of piroxicam and elucidate its mechanism. All APC(delta474) mice have intestinal polyps. Thirty-five APC(delta474) mice were divided into three groups: 0.005% solution of piroxicam in tap water was given for P group (n = 15) and 0.001% solution for P' group (n = 5), and water without piroxicam for C group (n = 15) from 4 weeks of age to 12 weeks, respectively. All mice were sacrificed at the 12th week after birth. Hematoxylin-eosin staining for number and size of polyps, immunohistochemical staining for cyclooxygenase (COX)-1 and -2, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), TUNEL method, and Western blot analysis of COX-2 and VEGF were performed. Polyps were divided into two types of large polyps of >or=300 microm in diameter and small polyps of <300 microm. The number of large polyps in P group decreased significantly compared with C group (p <.0001), but without significant difference in small polyps. There were no significant differences in PCNA index in both of large and small polyps among the three groups. Apoptotic index of polyps in P group increased more than those in C group (p <.05). There was immunohistochemically no significant difference in COX-1 positivity of normal intestinal epithelia and adenomas among three groups. Both numbers of VEGF-positive cells and COX-2 positive cells in the stroma of the small intestine were significantly downregulated in P group (p <.05). COX-2 expression was inhibited in dose-dependent manner without significant difference. There were no significant differences in VEGF expression between P' and C groups. In conclusion, piroxicam suppressed the development of large polyps in APC(delta474) mice by inducing apoptosis and inhibiting VEGF expression in interstitial cells of polyps.
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PMID:Piroxicam-induced regression of intestinal adenomatous polyps in APC(delta474) mice. 1274 90

The regular intake of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with decreased incidence of certain types of cancer particularly those with an inflammatory component. The protective effects of these drugs in colorectal cancer are particularly marked, with a 40-50% reduction in risk. Research in this area has focussed on understanding and optimising these cytoprotective effects. NSAIDs are believed to operate by inhibiting COX-2, an enzyme that appears to be involved in a number of cancer promoting processes. This hypothesis is consistent with the observation that the COX-2 selective inhibitors dramatically decrease tumour formation in human and animal studies. Surprisingly aspirin, which is selective for COX-1 over COX-2, and sulindac, which is an equipotent inhibitor of the COX isoenzymes, appear to have a similar anticancer profile to the COX-2 selective NSAIDs. A number of mechanisms have been proposed to explain the anomalous effects of aspirin. The first of these relates to the unique mode of action of aspirin, which acetylates the COX-2 enzyme and generates the cancer-suppressing 15R-hydroxyeicosatetraenoic acid at the site of a potential tumour. The alternative rationale relates to the metabolism of aspirin to salicylic acid, which has a cyclooxygenase independent anti-inflammatory mechanism, preventing the inflammatory response at the gene transcription level. A new generation of drugs could evolve from approaches to improving the therapeutic index of aspirin or by modifications to known therapies such as sulindac and celecoxib.
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PMID:The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs. 1276 97

Aspirin consumption has been reported to be able to reduce colorectal cancer risk in humans and in animal models of colon carcinogenesis. Although the mechanism involved in such an effect is not yet clear, both prostaglandin-dependent and -independent effects have been proposed. Using HT-29 Glc(-/+)cells, which originate from a human colon adenocarcinoma, we demonstrated in this study a dose-dependent effect of millimolar concentration of aspirin on cell growth that was concomitant with a rapid accumulation of the cells in the G0/G1 phase, followed by an accumulation in the G2/M phase and by a minor increase in the proportion of cells undergoing nuclear condensation. Cell membrane integrity and cell release into the culture medium were not affected by this treatment. The aspirin effects were apparently unrelated to prostaglandin biosynthesis inhibition, since although these cells were found to express high levels of cyclooxygenase 1 (COX-1) and low levels of COX-2 proteins, they did not produce any measurable net amounts of prostaglandins, based on both utilization of radiolabelled arachidonic acid and the radioimmunoassay of prostaglandins E2 and F2 alpha. In contrast, we identified polyamine biosynthesis as a cellular target of aspirin, since the treatment of HT-29 Glc(-/+) cells with aspirin reduced the flux of L-ornithine through ornithine decarboxylase, an effect that could not be explained by an acute action of the drug on the ornithine decarboxylase catalytic activity. Since polyamine biosynthesis is strictly necessary for HT-29 cell growth, our data suggest that reduced flux through ornithine decarboxylase may participate in the antiproliferative activity of aspirin towards colonic tumoral cells. It is concluded that in HT-29 Glc(-/+) cells that are not functional for prostaglandin production, aspirin can affect cell growth, cell cycle, and polyamine biosynthesis without affecting cell membrane integrity.
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PMID:Prostaglandin-independent effects of aspirin on cell cycle and putrescine synthesis in human colon carcinoma cells. 1277 50

Current evidence suggests that two forms of prostaglandin (PG) E synthase (PGES), cytosolic PGES and membrane-bound PGES (mPGES) -1, preferentially lie downstream of cyclooxygenase (COX) -1 and -2, respectively, in the PGE2 biosynthetic pathway. In this study, we examined the expression and functional aspects of the third PGES enzyme, mPGES-2, in mammalian cells and tissues. mPGES-2 was synthesized as a Golgi membrane-associated protein, and spontaneous cleavage of the N-terminal hydrophobic domain led to the formation of a truncated mature protein that was distributed in the cytosol with a trend to be enriched in the perinuclear region. In several cell lines, mPGES-2 promoted PGE2 production via both COX-1 and COX-2 in the immediate and delayed responses with modest COX-2 preference. In contrast to the marked inducibility of mPGES-1, mPGES-2 was constitutively expressed in various cells and tissues and was not increased appreciably during tissue inflammation or damage. Interestingly, a considerable elevation of mPGES-2 expression was observed in human colorectal cancer. Collectively, mPGES-2 is a unique PGES that can be coupled with both COXs and may play a role in the production of the PGE2 involved in both tissue homeostasis and disease.
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PMID:Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. 1283 22

For a number of solid tumors, including pancreatic cancer, efforts aimed at disease prevention may be more successful than currently available anticancer treatments. While specific interventions are emerging to prevent breast, prostate, lung, and colorectal cancer, no trials of chemoprevention are being conducted in pancreatic cancer. Importantly, there are significant obstacles to the conduct of such research. However, preclinical and epidemiologic studies suggest that several drugs may have chemopreventive potential in pancreatic cancer. These include aspirin and other non-steroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase inhibitors, somatostatin analogs, selective estrogen receptor modulators (SERMs), and anti-androgenic agents. As the oncology community evaluates some of these agents in large chemoprevention trials for breast, colon, and prostate cancer, it may be found that pancreatic cancer prevention occurs as an unintended, but desirable consequence. Moreover, other general societal trends, such as smoking cessation and the widespread use of cholesterol-lowering agents and aspirin, could have a role in reducing the risk of pancreatic cancer, and in the future, may lead to a decrease in its incidence.
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PMID:Chemoprevention for pancreatic cancer. 1290 36

A substantial body of evidence from rodent colon carcinogenesis models, in vitro experiments with human colorectal cancer cells and limited clinical observations in humans suggest that the non-steroidal anti-inflammatory drug indomethacin has anti-colorectal cancer activity. However, although many mechanisms of the anti-neoplastic activity of indomethacin have been suggested, e.g., cyclooxygenase inhibition and peroxisome proliferator-activated receptor gamma activation, the precise relevance of the majority of in vitro pharmacological observations to the in vivo anti-neoplastic activity of indomethacin remains unclear. Herein, we review the existing literature describing the chemopreventative and chemotherapeutic efficacy of indomethacin against colorectal cancer, and draw together the disparate literature describing potential mechanisms of action of indomethacin in human colorectal cancer cells in vitro. Although indomethacin itself has significant adverse effects, including serious upper gastrointestinal toxicity, the development of novel derivatives that may have an improved safety profile means that further investigation of the anti-colorectal cancer activity of indomethacin is warranted.
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PMID:Activity of the non-steroidal anti-inflammatory drug indomethacin against colorectal cancer. 1292 71

Increasing evidence indicates that Non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), can reduce the number and size of adenomas in patients with familial adenomatous polyposis as well as the incidence of colorectal cancer. The COX enzyme family consists of the classic COX-1 and a second enzyme, COX-2, which is induced by various stimuli, such as mitogens and cytokines. While it is well proven that COX-2 overexpression is a central event in colorectal carcinogenesis, that prostaglandins (PGs) can contribute to tumorigenesis, and that COX-2 selective inhibitors are active chemopreventive agents, the molecular mechanisms by which NSAIDs exert their chemopreventive effect is not fully understood. However, significant advances have been made in understanding the interference of NSAIDs with the pathways that control cell growth and survival even independently from their COX-inhibiting properties, making their use attractive both alone and in combination with standard therapies in the treatment of advanced colorectal cancer. In addition, the recently recognized anti-angiogenic and radiosensitizer properties of COX-2 inhibitors support, further suggest their use in the adjuvant setting.
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PMID:Cyclo-oxygenase inhibition in colorectal adenomas and cancer. 1450 83

Colorectal carcinoma is a leading cause of cancer related death worldwide. This deadly disease advances through a series of clinical and histopathological stages, initiated by single crypt lesions to small benign tumors and finally to malignancy. Although some progress has been made in elucidating the formation of colorectal tumors at molecular/genetic levels, the possible mechanisms of dietary lipids in inducing and promoting colorectal tumorigenesis are poorly understood. Recent epidemiological studies, however, indicate that lipid-rich diet containing omega-6 fatty acids (i.e. linoleic acid, arachidonic acid, etc.) may somehow be related with the disease process. Rapid metabolism of arachidonic acid, increased activities of phospholipases (i.e. phospholipase-A2s), and the elevated levels of cyclooxygenase (COX) and lipoxygenase (LOX) in colonic cells were reported in various stages of the malignancy, suggesting a possible link between dietary lipids and the incidence of colorectal cancer. The major focus of this review is to delineate the recent findings on enhanced arachidonic acid metabolism and its conversion into eicosanoids during the initiation and progression of colorectal carcinogenesis. In addition, the identification and participation of various phospholipases are also discussed. It is speculated that many of these phospholipases can be used as targets for developing new drugs against colorectal as well as other adenocarcinomas.
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PMID:Arachidonic acid and colorectal carcinogenesis. 1461 64

Epidemiological, clinical and animal studies indicate non-steroidal anti-inflammatory drugs (NSAIDs) to be chemopreventive for colorectal cancer. The best established target for NSAIDs are the two isoforms of cyclooxygenase (COX), a key enzyme in the biosynthesis of prostaglandins. Recent investigations using human colorectal tumor cell lines have focused on the cellular and molecular mechanisms potentially underlying the chemopreventive effect of NSAIDs. These studies have used 'traditional' NSAIDs and their metabolites which either do not inhibit COX, are non-selective for the COX isoforms or selectively inhibit COX-1 over COX-2, and recently developed NSAIDs that are highly selective for COX-2. In vitro, apoptosis is the dominant anti-proliferative effect of each of these classes of NSAID and sensitivity to NSAID-induced apoptosis increases with the malignant potential of the tumor cells. Limited in vivo evidence backs up these findings. Cell cycle arrest also contributes to the in vitro growth inhibitory effect of traditional NSAIDs. The induction of apoptosis by NSAIDs may result from the inhibition of the COX isoforms but other as yet undefined paths to NSAID-induced apoptosis clearly exist. A member of each class of NSAID is under trial as a chemopreventive agent for colorectal cancer.
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PMID:Induced apoptosis in the prevention of colorectal cancer by non-steroidal anti-inflammatory drugs. 1463 39

Liver metastasis is a major contributor to mortality in patients with colorectal cancer. Hence, it is essential to establish preventive therapy to control liver metastasis. Recently, it has become widely accepted that cyclooxygenase (COX)-2 inhibitors possess anti-cancer activity for various types of tumor, especially colorectal. The clinical application of COX-2 inhibitors may therefore be beneficial. In this study, we have developed a combined treatment with a selective COX-2 inhibitor and fluorinated pyrimidines for liver metastasis of colorectal cancer, and examined the effect of these agents on proliferation and invasion of a highly metastatic human colon cancer cell line, LM-H3. The COX-2 inhibitor etodolac was found to inhibit cell invasion of LM-H3. 5-Fluorouracil (5-FU) inhibited proliferation of this line in vitro. Etodolac did not increase the inhibitory effect of 5-FU on cell proliferation. We also examined the inhibitory effect of etodolac and UFT, belonging to the fluorinated pyrimidines, on liver metastasis by using a liver metastatic model in the nude mouse. Combined treatment with etodolac and UFT markedly reduced liver metastasis. Serious side effects were not observed. In conclusion, combined treatment with etodolac and UFT might be a promising preventive therapy for liver metastasis of colon cancer.
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PMID:Combined treatment with selective cyclooxygenase-2 inhibitor and fluorinated pyrimidines for liver metastasis of colon cancer. 1465 21


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