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

Chronic intake of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing gastrointestinal tumors, in particular colon cancer. Increasing evidence indicates that NSAID exert tumor-suppressive activity on pre-malignant lesions (polyps) in humans and on established experimental tumors in mice. Some of the tumor-suppressive effects of NSAIDs depend on the inhibition of cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxane, which is highly expressed in inflammation and cancer. Recent findings indicate that NSAIDs exert their anti-tumor effects by suppressing tumor angiogenesis. The availability of COX-2-specific NSAIDs opens the possibility of using this drug class as anti-angiogenic agents in combination with chemotheapy or radiotherapy for the treatment of human cancer. Here we will briefly review recent advances in the understanding of the mechanism by which NSAIDs suppress tumor angiogenesis and discuss their potential clinical application as anti-cancer agents.
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PMID:Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives. 1199 85

Hepatocellular carcinoma (HCC) is a growing health problem worldwide. The limited treatment and poor prognosis of this disease emphasizes the importance of developing effective prevention, including chemoprevention. Improvement in early diagnosis of HCC and regular screen of individuals with increased risk for HCC provide the possibility of effective chemoprevention for HCC in the future. Hepatocarcinogenesis is best described as a continuity of regeneration, proliferation, unregulated hyperplasia, dysplasia, and malignant transformation. Uncontrolled proliferation of hepatocytes clearly plays a key role in hepatocarcinogenesis. Overexpression of cyclooxygenase-2 (COX-2) has been associated with tumorigenesis of colon cancer. Selective COX-2 inhibitors possess potent suppression on the growth of colon cancer. Overexpression of COX-2 has also recently been demonstrated in patients with HCC, especially in nontumorous tissue with cirrhosis and well-differentiated tumorous tissue. In vitro studies have revealed that both NS-398, a selective COX-2 inhibitor, and sulindac, an analog of nonsteroidal anti-inflammatory drugs, effectively inhibit growth of human hepatoma cell lines, which is mediated by a decreased rate of cell proliferation. Although further in vivo studies are required in animal models to confirm these findings and define optimal doses for future clinical trials in human subjects, these findings provide a rationale for the use of COX-2 inhibitors as HCC chemoprevention.
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PMID:Rationale and feasibility of chemoprovention of hepatocellular carcinoma by cyclooxygenase-2 inhibitors. 1202 11

Cyclooxygenase-2 (COX-2) is an inducible enzyme that plays an important role in several pathophysiological processes, including inflammation, angiogenesis, and tumorigenesis. We have recently observed that COX-2 induction is restrained in proliferating fibroblasts. The mechanism by which this occurs is unclear. Here, we report the detection and isolation from the conditioned medium of proliferating fibroblasts a factor that suppressed COX-2 expression. This factor, which was named cytoguardin, suppressed COX-2 protein levels induced by phorbol 12-myristate 13-acetate, interleukin-1beta, tumor necrosis factor alpha, and lipopolysaccharide (LPS) in fibroblasts and LPS-induced COX-2 protein levels and promoter activities in human endothelial cells and murine RAW 264.7 cells in a comparable concentration-dependent manner. It inhibited COX-2 expression induced by angiogenic factors and endothelial tube formation induced by angiogenic factors and colon cancer cell medium. These findings provide evidence for the control of COX-2 transcription by an endogenous cellular factor.
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PMID:Purification and characterization of a cyclooxygenase-2 and angiogenesis suppressing factor produced by human fibroblasts. 1206 Jun 68

The nonsteroidal anti-inflammatory drugs (NSAIDs) are found to be potential chemopreventive agents of colorectal cancer. Celecoxib, an NSAID with selective cyclooxygenase-2 inhibition, was proved to be effective for the prevention of colon cancer in patients with familial adenomatous polyposis (FAP) and sporadic polyps. In the light of this information, the present study was carried out to develop oral colon-targeting drug delivery systems for celecoxib using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for hardness, drug content and were subjected to in vitro drug release studies. The amount of celecoxib released from the matrix tablets at different time intervals was estimated by a HPLC method. Guar gum matrix tablets released only 2-4% of celecoxib in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets containing 20% of guar gum released another 37% of celecoxib after degradation by the colonic bacterial action. The matrix tablets containing 30% of guar gum released about 24% of celecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that the matrix tablets containing either 20 or 30% of guar gum are most likely to target celecoxib for local action in the colon. The guar gum matrix tablets of celecoxib showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. Differential scanning calorimetry (DSC) studies indicated no possibility of interaction between celecoxib and guar gum/other formulation excipients.
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PMID:Studies on the development of colon-targeted delivery systems for celecoxib in the prevention of colorectal cancer. 1207 26

During recent years, multidisciplinary studies in epidemiology and molecular biology, as well as preclinical studies, have contributed much to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. Clinical trials with NSAIDs have demonstrated that NSAID treatment caused regression of preexisting colon adenomas in patients with familial adenomatous polyposis. Preclinical efficacy studies have provided compelling evidence that several phytochemicals with antiinflammatory properties and NSAIDs act to retard, block, or reverse colon carcinogenesis. Equally exciting are opportunities for effective chemoprevention with selective cyclooxygenase-2 (COX-2) inhibitors including celecoxib and rofecoxib in a variety of preclinical models of colon cancer. Naturally occurring COX-2 inhibitors such as curcumin and certain phytosterols have been proven to be effective as chemopreventive agents against colon carcinogenesis with minimal gastrointestinal toxicity. Multistep process of carcinogenesis has provided substantial insights into the mechanisms by which naturally occurring and synthetic antiinflammatory agents modulate these events leading to suppression of tumorigenesis. Growing knowledge in this area has brought about innovative approaches using a combination of agents with different modes of action as a means of increasing efficacy and minimizing toxicity. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance would be to identify molecular targets that are critical in the growth and survival of the malignant colorectal cell and are modulated by NSAIDs and COX-2 inhibitors.
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PMID:Novel approaches for colon cancer prevention by cyclooxygenase-2 inhibitors. 1208 2

Tumorigenesis is a complex process, and understanding the mechanisms behind tumorigenesis is key to identifying effective targeted therapies. Prostaglandins are signaling lipophilic molecules derived from phospholipids that are involved in normal physiologic functions. However, overexpression of prostaglandins has been associated with tumorigenesis. Several epidemiologic studies have shown an inverse correlation between the incidence of colon cancer and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin synthesis. The NSAIDs target cyclooxygenases (COX), essential enzymes inprostaglandin production. Cyclooxygenase-2 (COX-2) is an inducible form of the enzyme that is usually not expressed in normal tissue. Because COX-2 is frequently overexpressed in premalignant lesions and neoplasms, specific COX-2 inhibitors have been investigatedas chemoprevention andpotential chemotherapeutic agents. There is now preclinical and early clinical data that suggest inhibitors of COX-2 may protect against colon, breast, lung, esophageal, and oral tumors. This paper will discuss evidence addressing the possible mechanistic contribution of COX-2 in tumorigenesis and will explore the link between COX-2 activity and carcinogenesis. The potential role of COX-2 inhibitors in the chemoprevention and treatment of various tumors will also be discussed. Clinical trials using targeted inhibitors of COX-2 will be critical in determining if COX-2 is a viable molecular target in cancer management.
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PMID:Potential role of selective COX-2 inhibitors in cancer management. 1210 78

Colorectal cancer is one of the leading causes of cancer deaths in the Western world. More than 56,000 newly diagnosed colorectal cancer patients die each year in the United States. Available therapies are either not effective or have unwanted side effects. Epidemiological data suggest that dietary manipulations play an important role in the prevention of many human cancers. Curcumin the yellow pigment in turmeric has been widely used for centuries in the Asian countries without any toxic effects. Epidemiological data also suggest that curcumin may be responsible for the lower rate of colorectal cancer in these countries. Curcumin is a naturally occurring powerful anti-inflammatory medicine. The anticancer properties of curcumin have been shown in cultured cells and animal studies. Curcumin inhibits lipooxygenase activity and is a specific inhibitor of cyclooxygenase-2 expression. Curcumin inhibits the initiation of carcinogenesis by inhibiting the cytochrome P-450 enzyme activity and increasing the levels of glutathione-S-transferase. Curcumin inhibits the promotion/progression stages of carcinogenesis. The anti-tumor effect of curcumin has been attributed in part to the arrest of cancer cells in S, G2/M cell cycle phase and induction of apoptosis. Curcumin inhibits the growth of DNA mismatch repair defective colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic agent for the treatment of tumors exhibiting DNA mismatch repair deficient and microsatellite instable phenotype. Curcumin should be considered as a safe, non-toxic and easy to use chemotherapeutic agent for colorectal cancers arise in the setting of chromosomal instability as well as microsatellite instability.
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PMID:Chemotherapeutic potential of curcumin for colorectal cancer. 1217 41

The inducible cyclooxygenase-2 (COX-2) gene regulates prostaglandin biosynthesis,is up-regulated in colorectal cancers, and can influence apoptotic susceptibility. We determined whether forced COX-2 expression modulates apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of tumor necrosis factor ligand family, and examined determinants of the apoptotic pathway, including membrane death receptors (DR-4 and DR-5). HCT-15 colon cancer cells lacking endogenous COX-2 proteins were stably transfected with the COX-2 cDNA and incubated with TRAIL. Forced COX-2 expression significantly attenuated TRAIL-induced apoptosis and was associated with transcriptional repression of DR-5 and up-regulation of Bcl-2. COX-2 transfectants showed reduced DR-5 mRNA and protein expression as well as reduced caspase-8, caspase-3, and caspase-9 activation relative to parental cells. Sulindac sulfide treatment restored DR-5 expression and, when combined with TRAIL, reduced cell viability to a greater extent than did either drug alone. In summary, modulation of DR-5 and Bcl-2 levels by COX-2 attenuates TRAIL-induced apoptosis and represents a novel mechanism of intrinsic drug resistance in human colon cancer cells.
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PMID:Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells. 1220 39

Colorectal cancer is the second leading cause of cancer death in Western countries. If surgery remains the only cure, recurrence rates for colon cancer range from 30% to 60% for stage III tumors. Adjuvant chemotherapy is the standard treatment for stage III colon tumors and consists of monthly administration of bolus 5-fluorouracil and leucovorin for 5 consecutive days a month over a 6-month period (Mayo regimen). Adjuvant chemotherapy for stage II colon cancer remains controversial, and its administration is not routinely recommended except in certain high-risk and selected patients. Immunotherapy, new drug-based therapies or combinations, and cyclooxygenase-2 inhibitors are being tested in the adjuvant setting. Total mesorectum excision is now the gold standard surgical technique for rectal cancer resection, and this procedure has dramatically decreased local recurrence. Nevertheless, adjuvant chemoradiotherapy is commonly indicated in the United States. In Europe, neoadjuvant radiotherapy is recommended for stage II and III resectable rectal cancers; the role of chemotherapy remains mostly investigational.
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PMID:Adjuvant chemotherapy for colorectal cancer. 1222 45

There is considerable interest in the involvement of cyclooxygenase-2 (COX-2) in colon carcinogenesis and its progression, because nonsteroidal anti-inflammatory drugs (NSAIDs) reduce mortality from colon cancer and COX-2 is one of the known targets of NSAIDs. COX-2 mRNA and protein levels are increased in colon cancer tissues from patients and in some colon cancer cell lines. The relationship between COX-2 and colon cancer is further confirmed by studies using the murine models of adenomatous polyposis coli, in which NSAIDs and gene knockouts reduce the number of spontaneously developing intestinal polyps. COX-2 expression in intestinal epithelial cells increases resistance to apoptosis, promotes tumor angiogenesis, and enhances invasion and metastasis. COX-2 expression in stromal cells appears to have a role in tumor angiogenesis because tumor growth is attenuated when colon cancer cells are implanted in COX-2 knockout mice due to a decreased vascular supply to the tumors. Although NSAIDs act via COX-2 to inhibit colon cancer growth, there also appear to be COX-2 independent actions for NSAIDs. COX-2 selective inhibitors can be the core drugs for the prevention and the treatment of colon cancer.
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PMID:Cyclooxygenases and colon cancer. 1243 18


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