Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.
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PMID:Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression. 1867 Jun 39

We report three cases of metastatic renal cell carcinoma (RCC) in which combination treatment of cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin system inhibitor (angiotensin converting enzyme inhibitor or angiotensin II type 1 receptor antagonist) (CCA therapy) was effective. Case 1: A 47-year-old man who had a 12-cm right renal tumor with multiple pulmonary and hepatic metastases refused cytokine therapy for economic reasons and received CCA therapy. All of the metastases showed partial remission, which continued for 12 months. Case 2: A 62-year-old man with multiple pulmonary and mediastinal lymph node metastases from clear cell RCC refractory to interferon-alpha and interleukin-2 started CCA therapy. Partial remission has been maintained for 16 months. Case 3: A 64-year-old man with pulmonary metastases from clear cell RCC discontinued interferon-alpha treatment due to its side effects after six months and received CCA therapy. Pulmonary metastases showed partial remission for 31 months. The CCA therapy could be an alternative treatment for metastatic RCC patients unfit for cytokine therapy.
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PMID:Favorable response to combination treatment of cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin system inhibitor in metastatic renal cell carcinoma: Report of three cases. 1878 6

Cyclooxygenase-2 (COX-2) is associated with aggressive breast cancers. The COX-2 product prostaglandin E(2) (PGE(2)) acts through four G-protein-coupled receptors designated EP1-4. Malignant and immortalized normal mammary epithelial cell lines express all four EP. The EP4 antagonist AH23848 reduced the ability of tumor cells to colonize the lungs or to spontaneously metastasize from the mammary gland. EP4 gene silencing by shRNA also reduced the ability of mammary tumor cells to metastasize. Metastasis inhibition was lost in mice lacking either functional Natural Killer (NK) cells or interferon-gamma. EP4 antagonism inhibited MHC class I expression resulting in enhanced ability of NK cells to lyse mammary tumor target cells. These studies support the hypothesis that EP4 receptor antagonists reduce metastatic potential by facilitating NK-mediated tumor cell killing and that therapeutic targeting of EP4 may be an alternative approach to the use of COX inhibitors to limit metastatic disease.
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PMID:Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. 1879 78

Unresectable hepatic colorectal cancer (CRC) metastases are a leading cause of cancer mortality. These tumors and other epithelial tumors often express both cyclooxygenase-2 (COX-2) and carcinoembryonic antigen (CEA). Because adenovirus (Ad) vectors infect the liver and lack tumor tropism, they cannot be used for systemic therapy of hepatic metastases. We used COX-2 transcriptional restriction, in combination with transductional Ad hepatic untargeting and tumor retargeting by a bispecific adapter, sCARhMFE, composed of sCAR [the coxsackie/Ad receptor (CAR) ectodomain] and MFE-23 (a single-chain anti-CEA antibody), to untarget liver after i.v. administration of Ad vectors expressing firefly luciferase and to retarget virus to hepatic colorectal tumor xenografts and non-small cell lung tumor xenografts. To improve both liver untargeting and tumor retargeting, we developed sCARfMFE, a trimerized sCARhMFE adapter. Trimerization greatly improves both untargeting of CAR-dependent Ad infection and CEA-dependent virus retargeting in culture and in vivo. Combining sCARfMFE bispecific adapter transductional liver untargeting and transductional tumor retargeting with COX-2 transcriptional tumor-restricted transgene expression increases systemically administered Ad therapeutic efficacy for hepatic CRC tumors, using herpes virus type 1 thymidine kinase (HSV1-tk) as a therapeutic gene in conjunction with the prodrug ganciclovir (GCV). Both transductional untargeting and COX-2 transcriptional restriction also reduce HSV1-tk/GCV hepatic toxicity. In addition, transductional sCARfMFE untargeting reduces the innate immune response to systemic Ad administration. Combined transductional liver Ad untargeting, transductional tumor retargeting, and transcriptional transgene restriction suggests a means to engineer practical, effective therapeutic agents for hepatic CRC metastases in particular, as well as hepatic metastases of other epithelial cancers.
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PMID:Combined transductional untargeting/retargeting and transcriptional restriction enhances adenovirus gene targeting and therapy for hepatic colorectal cancer tumors. 1914 69

Several studies illustrated considerably elevated levels of cyclooxygenase-2 (COX-2) protein in various types of human cancer including malignant melanoma. Recently, it was reported that COX-2 is strongly expressed in malignant melanoma and may be correlated with the development and progression of disease. In contrast, other groups did not detect COX-2 protein in primary melanoma cells but did in infiltrating inflammatory cells or metastases. However, there are no reports about patterns or alterations of COX-2 expression in melanoma cells during disease progression or of a correlation between COX-2 expression and overall survival. The aim of this study was to investigate whether there is a correlation between expression of COX-2 protein and disease prognosis in malignant melanoma. We therefore analyzed the expression of COX-2 protein by immunohistochemistry in 101 primary malignant melanomas and 28 metastases and correlated our data with Breslow tumor thickness, Clark levels, different melanoma subtypes, metastases, and overall survival. We detected a strong COX-2 expression in 95% of all primary melanomas, primarily restricted to melanoma cells as shown by various immunohistochemical methods. Levels of COX-2 expression in primary melanoma and corresponding metastases remained stable. A significant correlation between immunohistochemical staining intensity and tumor thickness was demonstrated. Furthermore, Kaplan-Meier curves illustrated a significant correlation between staining intensity and disease-specific survival. Our findings emphasize that the COX-2 protein might be a novel prognostic marker. Owing to its strong expression in melanoma cells it might also be a reasonable therapeutic target.
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PMID:COX-2 expression in malignant melanoma: a novel prognostic marker? 1943 Apr 2

It is well known that cyclooxygenase-2 (COX2) plays an important role in the development of many tumors including breast cancer. Our study was concerned with evaluating the effects of the selective COX2 inhibitor, celecoxib, on mammary tumorigenesis and aging in HER2/neu transgenic mice (24). Celecoxib (celebrex) 25 mg/kg was administered 5 times a week from the age of 2 months. Twenty-four intact females were in control. Monitoring kept track of tumor detection time, size, presence of lung metastases, food and water consumption, estral function, body weight and temperature. No significant differences between the two groups were reported as far as life-span, tumor growth rate, size and number of metastases to the lung is concerned. To sum up, celecoxib treatment failed to produce any significant effect on carcinogenesis in HER2/neu transgenic mice.
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PMID:[The effects of Celebrex on mammary tumorigenesis and aging in HER2/neu transgenic mice]. 1943 7

The current use of antineoplastic drugs in human therapy causes a substancial number of toxic or side effects which consequently lead to a reduction of the amount of drug to be administered, and in some cases to discontinuation of the therapy. A reduction of the amount of drug to be administered or discontinuation of the therapy causes an increase in primary tumour growth and/or the occurrence of tumour metastases. For this reason, the development of new anti-cancer drugs with lower side effects is necessary. This review gives a general idea about the origins of cancer and the importance of cyclooxygenase-2 (COX-2) in oncogenesis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumour cell invasion and metastasis. The recent anti-tumour drugs are based on tests of known selective COX-2 inhibitors and on the drawing and synthesis of new potent derivatives. Maybe, this can be the way to obtain new anti-tumour drugs with very low collateral effects. Selective COX-2 inhibitors are being mixtured with new anti-cancer drugs in order to obtain better results in the regression of cancers. Some natural products are selective COX-2 inhibitors and have anti-inflammatory and anti-cancer properties. The relevant patents are discussed.
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PMID:Selective cyclooxygenase-2 (COX-2) inhibitors used for preventing or regressing cancer. 1951 38

Breast cancer frequently metastasizes to the skeleton resulting in bone degradation due to osteoclast activation. Metastases also downregulate differentiation and the bone-rebuilding function of osteoblasts. Moreover, cancer cells trigger osteoblast inflammatory stress responses. Pro-inflammatory mediators such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), expressed by osteoblasts (MC3T3-E1) stimulated with human breast cancer cell (MDA-MB-231) conditioned medium, are pivotal to osteoclast activation and metastasis. Given that these genes are regulated by nuclear factor-kappaB (NF-kappaB), a redox-sensitive transcription factor, we hypothesized that selenium (Se) could abrogate the inflammatory response to metastatic breast cancer cells by modulating NF-kappaB. Caffeic acid phenethyl ester and parthenolide inhibited NF-kappaB activation, as seen by gel shift assays and immunoblotting for p65 in nuclear fractions, as well as decreased production of IL-6 and MCP-1. Supplementation of MC3T3-E1 with methylseleninic acid (MSA) (0.5 microM to 4 microM) reduced the activation of NF-kappaB leading to a decrease in IL-6, MCP-1, COX-2 and iNOS in response to MDA-MB-231 conditioned medium. Addition of MSA to osteoblasts for as little as 15 min suppressed activation of NF-kappaB suggesting that short-lived active metabolites might be involved. However, brief exposure to MSA also brought about an increase in selenoprotein glutathione peroxidase 1. In summary, our data indicate that the osteoblast response to metastatic breast cancer cells is regulated by NF-kappaB activation, which can be effectively suppressed by MSA either through short-lived active metabolites and/or selenoproteins. Thus, Se supplementation may prevent the osteoblast inflammatory response or dampen the vicious cycle established when breast cancer cells, osteoblasts and osteoclasts interact.
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PMID:Selenium modifies the osteoblast inflammatory stress response to bone metastatic breast cancer. 1975 93

Background. To further improve the screening, diagnosis, and therapy of patients with nonsmall cell lung cancer (NSCLC) additional diagnostic tools are urgently needed. Gene expression of Cyclooxygenase-2 (COX-2) has been linked to prognosis in patients with NSCLC. The role of the COX-2 926G>C Single Nucleotide Polymorphism (SNP) in patients with NSCLC remains unclear. The aim of this study was to investigate the potential of the COX-2 926G>C SNP as a molecular marker in this disease. Methods. COX-2 926G>C SNP was analyzed in surgically resected tumor tissue of 85 patients with NSCLC using a PCR-based RFLP technique. Results. The COX-2 926G>C SNP genotypes were detected with the following frequencies: GG n = 62 (73%), GC n = 20 (23%), CC n = 3 (4%). There were no associations between COX-2 SNP genotype and histology, grading or gender detectable. COX-2 SNP was significantly associated with tumor stage (P = .032) and lymph node status (P = .016, Chi-square test). With a median followup of 85.9 months, the median survival was 59.7 months. There were no associations seen between the COX-2 SNP genotype and patients prognosis. Conclusions. The COX-2 926G>C SNP is detectable at a high frequency in patients with NSCLC. The COX-2 926G>C SNP genotype is not a prognostic molecular marker in this disease. However, patients with the GC or CC genotype seem more susceptible to lymph node metastases and higher tumor stage than patients with the GG genotype. The results suggest COX-2 926G>C SNP as a molecular marker for lymph node involvement in this disease.
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PMID:Prognostic Significance and Clinicopathological Associations of COX-2 SNP in Patients with Nonsmall Cell Lung Cancer. 2001 51

Glioblastoma multiforme is the most common and most malignant primary brain tumour. Prognosis after diagnosis remains poor despite recent advances in adjuvant therapy. Treatment of choice is gross surgical resection and combined radio-chemotherapy with temozolomide as chemotherapeutic agent. Experimental continuous low-dose chemotherapy with temozolomide in combination with a cyclooxygenase-2 inhibitor has shown encouraging effects on progression-free survival and overall survival in patients, but leads to a high proportion of distant recurrences. Here, we describe extreme far-distant metastases along the neural axis of glioblastoma multiforme in four patients receiving metronomic antiangiogenic chemotherapy and review the literature to discuss possible mechanisms.
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PMID:Far-distant metastases along the CSF pathway of glioblastoma multiforme during continuous low-dose chemotherapy with temozolomide and celecoxib. 2030 5


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