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)

Intravenous (i.v.) administration of a lipopolyplex consisting of a ternary complex of DOTAP:cholesterol cationic liposomes, protamine sulfate, and noncoding plasmid DNA (LPD-pDNA) is capable of stimulating a potent Th-1 cytokine response and inhibiting the growth of established tumors in mice. Both activities are mainly elicited by unmethylated CpG motifs in the plasmid DNA (pDNA) component, which are bacterial in origin. Since oligodeoxynucleotides (ODN) that possess a consensus immunostimulatory CpG motif of RRCpGYY (R is purine and Y is pyrimidine) can mimic the immunostimulatory actions of bacterial DNA, we hypothesized that i.v. administration of LPD prepared with GpG-ODN would mimic the ability of LPD-pDNA to stimulate Th-1 cytokines and antitumor activity and provide an improved vector for probing the immune mechanisms underlying the observed antitumor effects. These hypotheses were tested for the treatment of established 24JK experimental pulmonary metastases that are syngeneic in C57BL/6 mice. Mice treated with LPD containing 25 microg of the prototypical phosphodiester (PO) CpG-ODN 1668 (tccatGACGTTcctgatgct, motif capitalized) demonstrated a dramatic reduction in lung tumor burden (>80% inhibition, P<0.01) compared to dextrose-treated controls. The antitumor effect was dependent on the CpG dinulceotide and correlated with the ability to stimulate serum Th-1 cytokines (TNF-alpha, IL-12, and IFN-gamma). Both activities required assembly of CpG-ODN in a cationic liposome/DNA complex (lipoplex) or the LPD lipopolyplex. LPD delivery of both PO-1668 and phosphorothioated (PS)-1668 stimulated a greater cytokine response compared to delivery of free ODN. Furthermore, within the LPD complex, both PO- and PS-1668 had similar ability to stimulate Th-1 cytokines with respect to potency and duration of response, thus eliminating the need for the PS modification. In tumor cell lysis assays, LPD-CpG DNA stimulated development of an acquired, tumor-specific CD8+ cytotoxic T-lymphocyte (CTL) activity that was dependent on CpG DNA. LPD was also capable of stimulating NK activity; however, this was not dependent on CpG DNA. Only formulations that concomitantly stimulated NK activity and CpG-specific, Th-1 cytokine were capable of stimulating the development of tumor-specific CTL activity and significant inhibition of tumor growth. Thus, we propose a model where CpG DNA in complex with cationic liposome-based lipoplexes or lipopolyplexes stimulates antitumor NK activity and CpG-stimulated Th-1 cytokine production. The combination of these two activities of the innate immune system subsequently direct the development of an acquired, tumor-specific CTL response that in total are effective for inhibiting the growth of established tumors in mice.
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PMID:Systemic administration of LPD prepared with CpG oligonucleotides inhibits the growth of established pulmonary metastases by stimulating innate and acquired antitumor immune responses. 1177 72

As many breast cancer patients receive adjuvant chemotherapy using anthracyclines or anthracenediones and taxanes, more therapeutic options are needed for subsequent lines of therapy. Pemetrexed (ALIMTA, multitargeted antifolate, LY231514) is a novel antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis. This paper reports on a subset analysis of a phase II clinical trial of pemetrexed in heavily pretreated metastatic breast cancer (MBC) patients. Patients were required to have received prior first-line anthracycline therapy for metastatic disease. Prior adjuvant chemotherapy and prior taxanes were allowed. A substantial subset of the study population (31 of 72 patients, 43%) had also received a taxane in the metastatic setting. All patients were treated with pemetrexed, 600 mg/m2 by intravenous infusion, once every 21 days. In the study subset, 23 of 31 (74%) patients were anthracyclines failures (progression > 30 days following treatment), and eight (26%) patients were anthracyclines refractory (progression during or < or = 30 days of treatment). The median age was 55 years (range, 30-75 years) and the median World Health Organization performance status was 0. Metastases were present in the liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall response rate for this subset was 26%, with one complete response, seven partial responses, and 13 (42%) patients with stable disease. The median duration of response was 5.4 months and median survival was 12.8 months. Pemetrexed was well tolerated by patients in the study. This post hoc analysis suggests promising activity in MBC patients previously treated with both anthracyclines and taxanes. An ongoing trial is prospectively evaluating activity in this same population.
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PMID:Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis. 1189 82

Thymidine synthase (TS) is a key enzyme in the synthesis of pyrimidine in the de novo pathway of DNA synthesis and a major target of 5-fluorouracil (5-FU), but the implications of TS regarding human pancreatic cancer have not been reported. We assessed the expression of TS in invasive ductal carcinoma (IDC) of the pancreas by immunostaining and evaluated its clinicopathological significance, especially its implications regarding the efficacy of chemotherapy with 5-FU or its derivatives. The expression of TS in the nuclei of pancreatic cancer cells in 72 primary lesions of resectable IDC and 30 distant metastases of unresectable IDC was examined by immunostaining using anti-TS polyclonal antibody and immunoreactivity was classified into three categories: negative (-), low (+) and high (2+). High TS immunoreactivity was detected in 43% (31 of 72) of the primary lesions of the resectable IDCs and in 47% (18 of 38) of the metastatic lesions of the unresectable IDCs. The high TS in primary lesions showed a significantly inverse correlation with the level of nodal involvement. High TS immunoreactivity had a significant influence on the outcome of patients with resectable IDC and the rate of survival of the high TS immunoreactivity group was significantly higher than that of the negative or low reactivity groups, although high TS immunoreactivity did not have a significant influence on survival of the patients with unresectable IDC. The implications of TS immunoreactivity regarding the efficacy of 5-FU-based adjuvant chemotherapy (ACT) was also assessed. The high TS immunoreactivity group showed significantly better survival in both the patients who received ACT and those who were treated by surgery alone, in the resectable IDC among patients with resectable IDC. In cases of unresectable IDC, there were no differences in survival between the high and low TS groups among the patients who received ACT and those who were treated by surgery. In conclusion, high TS immunoreactivity was found to be cogent in predicting the prognosis of patients with pancreatic IDC, but its implications regarding the efficacy of 5-FU-based ACT are still unclear.
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PMID:Implication of thymidylate synthase in the outcome of patients with invasive ductal carcinoma of the pancreas and efficacy of adjuvant chemotherapy using 5-fluorouracil or its derivatives. 1191 44

Metastatic breast cancer is a chemotherapy-responsive disease, and significant palliation of cancer-related symptoms can be achieved with effective treatment. New treatments are needed because patients with metastatic breast cancer commonly out-live the effectiveness of currently available cytotoxic and hormonal treatments. Pemetrexed is a novel antimetabolite that inhibits three enzymes critical in purine and pyrimidine biosynthetic pathways: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Several phase II studies of pemetrexed have showed objective response rates of more than 30% in minimally pretreated metastatic breast cancer patients and approximately 20% in more heavily pretreated patients. Pemetrexed is associated with limited toxicity when administered with folic acid and vitamin B(12) supplementation and is therefore a promising agent both for palliative treatment of metastatic disease and for incorporation into combination regimens for treating newly diagnosed metastatic and early-stage breast cancer.
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PMID:Pemetrexed: a promising new treatment for breast cancer. 1202 91

Neoadjuvant chemotherapy has become a standard treatment in the management of locally advanced breast cancer. Patients with earlier-stage disease may also benefit from neoadjuvant treatment in terms of improved rates of breast-conserving surgery and thus better quality of life. Gemcitabine is a pyrimidine analogue that has shown activity in a variety of solid tumors, a good toxicity profile, and nonoverlapping toxicity with other chemotherapeutic agents. Several phase II/III studies are assessing gemcitabine combined with anthracyclines, taxanes, and/or vinorelbine both in the neoadjuvant and metastatic disease settings. This article reviews developments in neoadjuvant use of gemcitabine in combination with anthracyclines and taxanes. Several phase II trials of gemcitabine combined with doxorubicin/epirubicin or with doxorubicin/paclitaxel have been carried out. Preliminary findings demonstrate increased complete response rates and good tolerability of these regimens in patients with breast cancer.
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PMID:Neoadjuvant gemcitabine therapy for breast cancer. 1205 45

Xeroderma pigmentosum is a rare disorder transmitted in an autosomal recessive manner. Xeroderma pigmentosum is based on a genetic defect in the DNA repair system. This disease manifests in early childhood. Patients with xeroderma pigmentosum have a marked sensitivity to sunlight and develop serious sunburns with onset of poikilodermia in the light-exposed skin. Squamous cell carcinomas, basal cell carcinomas and malignant melanomas already appear in childhood. The majority of patients die before reaching adulthood because of metastases. Genetically, xeroderma pigmentosum is divided into 7 complementation groups (XP-A to XP-G) and the xeroderma pigmentosum variants (XP-V). Diagnostically, assignment to the specific complementation group is made according to the fusioning of xeroderma pigmentosum fibroblasts. Differential diagnosis must distinguish xeroderma pigmentosum from other so-called DNA-repair-deficiency syndromes like the Cockayne Syndrome and trichothiodystrophy. Currently, there are reports of successful application of a topical DNA Repair Enzyme. This is a recombinant liposomal encapsulated T4 endonuclease V, which repairs UV-induced cyclobutan-pyrimidine dimers. In future, causal therapy could be based on gene therapy. The introduction of an intact repair gene which specifically codes the repair protein, could open new possibilities in the treatment of xeroderma pigmentosum.
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PMID:Xeroderma pigmentosum. 1260 73

The nucleoside 5-fluoro-2-deoxyuridine is a pyrimidine analogue accumulating in proliferative cells. We prospectively evaluated biodistribution of the PET tracer [(18)F]5-fluoro-2-deoxyuridine (FdUrd), its value for imaging malignant tumors, and its correlation to both [(18)F]2-fluoro-2-deoxyglucose (FDG)-PET findings and histological proliferation indices. In 11 previously untreated patients (5 lung carcinoma; 3 soft tissue sarcoma; 2 gastrointestinal carcinoma; 1 non-Hodgkin lymphoma [NHL]), mean doses of 290 MBq FdUrd and 390 MBq FDG were administered intravenously on subsequent days. Static PET scans were initiated 50-70 min after administration and the mean standardized uptake values (SUV) were calculated. Dynamic emission FdUrd scans were performed in 8/11 patients. Time-activity curves of blood and tumors as well as SUV of tumor lesions and organs were calculated. Proliferative activity was evaluated by Ki-67 immunohistostaining of biopsies. Tracer accumulated physiologically in liver, kidney, and bladder. SUVs were: kidney, 4.8 +/- 0.66; liver, 4.1 +/- 0.36; vertebrae, 0.70 +/- 0.17; spleen, 0.37 +/- 0.06; lungs, 0.19 +/- 0.05; femora/humeri, 0.14 +/- 0.03. Five patients exhibited significant intratumoral FdUrd-uptake (2 sarcomas; 1 NHL; 2 lung carcinomas) with mean SUVs ranging from 0.7 to 10.5. Metastases were not detected. Time-activity curves showed a rapid initial increase of intratumoral activity followed by activity retention. FDG-PET was positive in 10/11 patients. Correlation between the SUV of FdUrd-PET and FDG-PET or the tissue proliferation index, respectively, was not significant. FdUrd was a suitable tracer for imaging malignant tumors only in exceptional cases: Sarcoma, NHL, and some lung carcinomas were detected. FdUrd-PET was less effective than FDG-PET. In this group of patients, it was not useful in measuring tissue proliferation.
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PMID:[18F]5-fluoro-2-deoxyuridine-PET for imaging of malignant tumors and for measuring tissue proliferation. 1295 20

Pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) activity may be related of the antitumor effect of 5'-deoxy-5-fluorouridine (5'-DFUR). To select patients for adjuvant setting of 5'-DFUR, we assessed PyNPase and DPD activity in 41 primary tumors (PTs) and 227 lymph nodes (LNs) of breast cancer patients. Fifty-one patients were involved in this investigation (mean age 54 +/- 12 years). LN metastasis was positive in 23 cases (node-positive group). Metastatic cancer cells were positive in 65 lymph nodes (In + group). PyNPase and DPD activity were measured by ELISA. PyNPase activity in PTs of the node-positive group was significantly higher than in the node-negative group. PyNPase activity in LNs of In + group was also significantly higher than in the negative metastatic cancer cell group. However, no significant differences were noted between these groups in DPD activity. PyNPase/DPD ratio in LNs of the In + group was marginally higher than in the negative metastatic cancer cell group. These data suggest that 5'-DFUR is preferably sensitive in breast cancer patients with lymph node metastasis.
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PMID:[PyNPase and DPD expression potentially predict response to 5'-DFUR treatment for node-positive breast cancer patients]. 1451 22

Neo-angiogenesis seems to play an important role in the progression of ovarian cancer and in formation of distant metastases. Data from literature on role of phosphorylase in neoplasmatic disease and in neo-angiogenesis are controversial. In mammalian cytosole there are two different pirymidine nucleosyde phosphorylases: thymidine (PT) and uridine (PU). Both of them play important role in the metabolism of nucleosides as well as in the recycling of pyrimidine base. Recently thymidine phosphorylase is identified with platelet derived endothelial cell growth factor (PD-ECGF). It has been demonstrated, that PD-ECGF/PT influence on neo-angiogenesis and correlates with degree of neoplasmatic invasion. In literature the data about thymidine phosphorylase activity and its correlation with neoplasmatic angiogenesis in ovarian tumors are controversial. The aim of the study was to evaluate the activity of PT together with the intensity of angiogenesis in epithelial ovarian tumors. 42 patients with ovarian cancer were included into the study. The enzyme activity was measured in ovarian cancer tissue and in the serum in the spectrophotometer. Intratumoral microvessel density (IMD) was evaluated in tumor using immunohistochemical methods. 10 woman with normal ovaries, treated surgically due to non-oncological reasons served as a control. Activity of PT in ovarian tumor and in serum was compared to the control group. Correlation between the intensity of angiogenesis and PT activity in ovarian cancer was also investigated. Significantly higher PT activity was stated both in tumor and serum when compared to the control. Positive correlation between enzyme activity in the serum and neoplasmatic tissue was found. Surprisingly, the negative correlation between neo-angiogenesis and PT activity in ovarian cancer was observed. Neo-angiogenesis is higher in ovarian cancer, when compared to the group of borderline malignancy tumors. Positive correlation between PT activity and staging in ovarian cancer was observed. No correlation between grading and histopathological type of epithelial cancer was observed. PT activity and neo-angiogenesis evaluation might be useful in diagnostics of ovarian cancer.
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PMID:[Thymidine phosphorylase activity and neo-angiogenesis in ovarian cancer]. 1467 44

Mononuclear ruthenium-dmso compounds showed interesting antimetastatic properties on experimental models of solid tumours. In line with the interesting results with multinuclear platinum complexes, which proved to overcome cisplatin resistance, we thought it worthwhile to test the pharmacological properties of some dinuclear ruthenium complexes to ascertain the possible advantages due to the introduction of a second metal centre over NAMI-A and its mononuclear analogues. These compounds belong to the general formula X2[[RuCl4(dmso-S)]2(mu-L)] or [X][[RuCl4(dmso-S)](mu-L)[RuCl3(dmso-S)(dmso-O)]] where L is a nitrogen donor ligand (pyrazine; pyrimidine; 4,4'-bipyridine; 1,2-bis(4-pyridyl)ethane; 1,2-bis(4-pyridyl) ethylene; 1,3-bis(4-pyridyl)propane) and X a counterion. We focused on parameters related to metastatic ability such as gelatinase activity, detected by zymography, and invasive potential, measured by means of a transwell chamber. These activities were correlated to the ability to inhibit tumour metastases in vivo. All dinuclear complexes, except compound D8 ([NH4]2[[RuCl4(dmso-S)]2(mu-pyz]), decrease the number of tumour cells that cross a matrigel barrier, and inhibit MMP-9 gelatinolytic activity at concentrations lower than that of NAMI-A and of other mononuclear ruthenium complexes. In vivo compounds D5 (Na2[[RuCl4(dmso-S)]2(mu-ethylbipy)]) and D7 ([NH4][[RuCl4(dmso-S)](mu-pyz)[RuCl3(dmso-S) (dmso-O)]]) show anti-metastasis activity, at two dose levels, with mild or null effect on primary tumour growth; compound D8 is the weakest active. All compounds tend to accumulate in liver and kidneys, rather than in tumour and lungs. However, compound D5, the most active in vitro on invasion and gelatinases and active in vivo on metastasis, is better concentrated in the lungs than compound D8 which is less active or inactive in vitro and in vivo. Histological analysis show liver, as well as kidney toxicities that limit in vivo activity. These data thus suggest dinuclear ruthenium complexes as promising anti-invasive agents for cancer treatment.
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PMID:Reduction of in vivo lung metastases by dinuclear ruthenium complexes is coupled to inhibition of in vitro tumour invasion. 1471 14


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