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

5'-Deoxy-5-fluorouridine (5'-DFUR) is converted to 5-FU by the enzyme of Pyrimidine nucleoside phosphorylase (PyNPase). Its efficacy for lung metastases from colorectal cancer is known. So we investigated PyNPase activity in primary and metastatic lesions of colorectal cancer patients. The results revealed that PyNPase activity (microgram 5-FU/mg protein/hour) (mean +/- SD) was 122.1 +/- 61.1 (n = 48) in primary lesions, 91.6 +/- 48.3 (n = 4) in lymph node metastases, 135.2 +/- 56.4 (n = 10) in liver metastases and 168.2 +/- 79.8 (n = 11) in lung metastases. In non-cancerous tissues adjacent to the cancer lesions, PyNPase activity was 51.5 +/- 18.8 in normal colorectal mucosa, 61.8 +/- 24.7 in normal liver and 43.0 +/- 21.2 in normal lung. These results demonstrated that PyNPase activity in the cancer lesions reached significantly higher levels than in the non-cancerous tissues (p < 0.01); and the T/N ratio of PyNPase activity in lung was also significantly higher than in primary or other metastatic lesions (p < 0.05). It was surmised that the clinical response of colorectal cancer to 5'-DFUR had been influenced by PyNPase activity.
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PMID:[PyNPase activity in primary and metastatic colorectal cancer]. 908 88

Thymidine phosphorylase (TdRPase) is an enzyme involved in the pyrimidine metabolism. It was reported that many cancers contained higher levels of TdRPase than normal tissues. And TdRPase has been reported to be identical with the platelet-derived endothelial cell growth factor. To clarify the distribution of TdRPase in primary and metastatic colorectal cancer, we carried out immunohistochemical staining of formalin-fixed specimens. We investigated 35 primary colorectal cancers resected surgically, 27 hepatic metastases and 8 lung metastases from colorectal carcinoma. TdRPase was highly expressed in primary colorectal cancer with lung metastases (100.0%) and surgically resected lung metastases cancer (87.5%). The staining correspondence between primary colorectal cancer and metastases was 19 cases (70.4%) in the liver metastases and 7 cases (87.5%) in the surgically resected lung metastases. The above results suggested that immunohistochemical staining for primary colorectal cancer may provide information about the sensitivity of metastases to the chemotherapy.
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PMID:[Immunohistochemical staining of thymidine phosphorylase in primary colorectal carcinoma and metastases]. 949 28

The 92-kDa type IV collagenase (MMP-9) is a metalloproteinase frequently localized in both tumor stroma and in tumor cells, particularly at the tumor invasion front. To explore the factors regulating transcriptional activation of MMP-9 in stromal cells, we used a model system in which fibroblast MMP-9 expression can be upregulated by cell-cell contact with metastatic transformed rat embryo cells. Using transient transfection of reporter gene constructs containing 5'-deleted or mutated MMP-9 promoter fragments, as well as electrophoretic mobility shift assays, the upstream NFkappaB, SP-1, and Ets sites and the downstream AP-1 site and retinoblastoma binding element were shown to be necessary for basal transcriptional activity of fibroblast MMP-9. In contrast only Ets or SP-1 appeared to be involved in contact-mediated induction of MMP-9. Mutation of the upstream AP-1 site increased both basal and contact-stimulated promoter activation. Deletion of the alternating purine-pyrimidine repeat in the downstream promoter decreased transcriptional activity. Together these findings suggest that Ets and SP-1 are the central transcriptional activators of MMP-9 gene expression in fibroblasts specifically responding to tumor cell contact, and that promoter conformation may regulate MMP-9 expression.
Clin Exp Metastasis 1998 Feb
PMID:Tumor cell contact mediated transcriptional activation of the fibroblast matrix metalloproteinase-9 gene: involvement of multiple transcription factors including Ets and an alternating purine-pyrimidine repeat. 951 98

1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxyuridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihydrofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.
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PMID:5-fluorouracil: a pharmacological paradigm in the use of cytotoxics. 980 59

Fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) are commercially available fluorinated pyrimidine analogues. 5-FU has antitumor activity against adenocarcinomas arising in the breast, gastrointestinal tract, and ovary, and against squamous cell carcinomas arising in the head, neck, and esophagus, with single-agent response rates of 10% to 30%. FdUrd has mainly been used for hepatic arterial infusions for patients with isolated hepatic metastases, with response rates of 42% to 62% as first-line therapy for colorectal cancer patients and 30% in those failing prior systemic 5-FU-based therapy. An appreciation for the factors influencing the cellular pharmacology of 5-FU has generated interest in combining it with both modulatory agents that enhance its metabolism or cytotoxic effects and other antineoplastic agents or modalities, such as cisplatin, methotrexate, and ionizing radiation, with which it can produce synergistic cytotoxicity. The preclinical and clinical pharmacology of 5-FU is reviewed, and novel approaches to permit oral adminstration as a means of mimicking protracted infusional schedules are discussed.
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PMID:Mechanisms of Action and Modulation of Fluorouracil. 1071 22

The frail population is increasing: currently, approximately 400,000 frail persons have cancer in the USA. Although the frail person is not a candidate for aggressive life-prolonging antineoplastic treatment, he/she is a candidate for aggressive symptom palliation. Most common symptoms include pain, especially bone pain, anemia, and fatigue. Destruction of cancer with antineoplastic treatment is pivotal to symptom palliation. A number of cytotoxic agents including gemcitabine, taxanes in low doses, vinorelbine, oral fluorinated pyrimidine, appear suitable for the management of metastatic cancer in the frail patient and should be tested in clinical trials.
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PMID:Management of the frail person with advanced cancer. 1073 76

A novel class of dianionic Ru(III) dimers of formula Na2[[trans-RuCl4(Me2SO)]2(mu-L)], with L = pyrazine (pyz, 1), pyrimidine (pym, 2), 4,4'-bipyridine (bipy, 3), and 1,2-bis(4-pyridine) ethane (etbipy, 4), was developed by us with the specific aim of assessing their antitumor properties. The dimers are in fact structurally related to the antimetastatic mononuclear compound (ImH) [trans-RuCl4(Me2SO)(Im)] (NAMI-A, Im = imidazole). Preliminary results concerning the antineoplastic activity of 1-4 against the murine MCa carcinoma model, a tumor which spontaneously metastasizes in the lungs, are reported. Similarly to what is normally observed with NAMI-A, the treatment with the dimeric complexes was scarcely effective against the growth of the primary tumor. However, dimers 1, 2, and 4 reduced very effectively the number and, in particular, the weight of lung metastases (to about 5% with respect to controls); in particular, Na2[[trans-RuCl4(Me2SO)]2(mu-etbipy)] (4) was as effective as NAMI-A in reducing the spontaneous metastases at a dosage which, in terms of moles of ruthenium, is about 3.5 times lower compared to that normally used for NAMI-A. Furthermore, in vitro tests showed that dimers 1-4 are capable of forming interstrand cross-links with linearized plasmidic DNA in a time-dependent manner. All the dimeric species are more active in inducing cross-links compared to NAMI-A, and the dimer bridged by the etbipy ligand (4) is the most effective among those tested.
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PMID:Antimetastatic properties and DNA interactions of the novel class of dimeric Ru(III) compounds Na2[[trans-RuCl4(Me2SO)]2(mu-L)] (L = ditopic, non-chelating aromatic N-ligand). A preliminary investigation. 1083 Aug 63

S-phase fraction (SPF) is a reference for cell-kinetic analysis. In this study, the links between SPF and the essential enzymes participating in the pyrimidine synthesis were investigated in breast cancer and their relationships with the natural history of the disease were compared. We measured thymidine kinase (TK) for salvage synthesis, thymidylate synthase (TS) for de novo synthesis and thymidylate kinase (TMK), which is required for both pathways. Our study population consisted of 211 premenopausal women with node-negative tumors. SPF was assessed prospectively by flow cytometry, whereas enzyme activities were measured retrospectively in cytosols using radioenzymatic methods. Among the enzymes analyzed, only TK demonstrated a strong correlation with SPF (r(s) = 0.59). In univariate analysis, high SPF and high levels of TK were associated with increased risk of developing distant recurrences (p < 0.001). Correlations with other prognostic factors (histological grade, steroid receptors, DNA ploidy status, urokinase plasminogen activator and plasminogen activator inhibitor type 1) confirmed a parallel association of SPF and TK with the most aggressive tumors. In contrast, TS and TMK were not associated with prognosis. After adjustment for SPF, the risk of relapse increased significantly with TK values. Subgroup analysis showed that additional information was provided by TK in the tumors with low SPF. When urokinase plasminogen activator (uPA) was a candidate variable in multivariate analysis, TK remained significant. Combined with SPF and uPA, TK could be useful to define premenopausal node-negative patients with rapidly proliferating tumors at a high risk of metastatic disease.
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PMID:DNA-synthesizing enzymes in breast cancer (thymidine kinase, thymidylate synthase and thymidylate kinase): association with flow cytometric S-phase fraction and relative prognostic importance in node-negative premenopausal patients. 1124 12

It is essential for actively proliferating cells to increase their rate of DNA synthesis to progress through the cell cycle. This is reflected in the increased uracil usage that is a common feature in solid tumours. Thymidine phosphorylase (TP) anabolises formation of pyrimidine nucleosides available for DNA synthesis, whereas dihydropyrimidine dehydrogenase (DPD) catabolises the degradation of pyrimidine bases, thereby reducing levels of uracil and thymine available for DNA synthesis. In addition, tissue levels of TP or DPD have been associated with the clinical efficacy of pyrimidine anti-metabolites commonly used in the treatment of colorectal cancer. There is little information, however, on the relative expression or degree of co-ordinated regulation of either protein in primary or metastatic colorectal cancer. DPD and TP protein levels were measured in 15 primary colorectal carcinomas, 10 colorectal liver metastases and 25 adjacent uninvolved tissues. DPD was reduced in 67% (10/15) of colorectal tumours (mean tumour/normal = 0.52) and in all liver metastases (mean tumour/normal = 0.41) compared with the corresponding normal tissue. In contrast, TP was increased in 80% (12/15) of colorectal tumours (mean tumour/normal = 18.91) and in all metastases (mean tumour/normal = 3.70). TP and DPD protein expression were highly variable in uninvolved and tumour tissues. The ratio of TP:DPD was higher in 87% of colorectal tumours and in all liver metastases compared with the adjacent uninvolved tissues. This suggests the presence of co-ordinated regulation of these pyrimidine metabolic enzymes and offers a strategy for optimising the use of pyrimidine-based chemotherapy.
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PMID:Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer. 1166 12

The poor response of colorectal liver metastases to fluorinated pyrimidine chemotherapy may be due to poor drug penetration into the tumour. Chemotherapy delivered by the blood to well perfused areas of tumour must reach less well perfused areas by diffusion. This study examined the relationship between intratumoural blood flow and drug uptake in a hypovascular liver metastasis animal model. We used a double isotope technique to examine the microdistribution of the blood flow tracer [125I]-iodoantipyrine (IAP) and fluorinated pyrimidine 5-[6-3H]-fluorouracil (5-FU) within intrahepatic, hypovascular HSN tumours. There was a significant fall (P < 10(-6)) in both IAP and 5-FU uptake between the liver/tumour edge and tumour centre which resulted in a significant covariation (P < 10(-5)) in tracer uptake with distance. The finding of a close covariation between blood flow and drug uptake in liver metastases suggested that 5-FU diffusion did not compensate for low 5-FU delivery in areas of poor tumour blood flow. The lower 5-FU levels in low compared with high areas of tumour blood flow could reduce the cytotoxic effect and increase the potential for development of drug resistance.
Clin Exp Metastasis 2000
PMID:Correlation between tumour blood flow and fluorouracil distribution in a hypovascular liver metastasis model. 1168 68


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