Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.5 (5'-nucleotidase)
3,167 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of tumor cells with extracellular-matrix components is suspected to play an important role in tumorigenesis induction. The tumorigenicity of a poorly tumorigenic human colon-adenocarcinoma cell line (BCS-TC2) was induced by co-injection with Matrigel. A new cell sub-line, BCS-TC2.1, was isolated and established from these tumors. Implantation of these cells in nude mice in the absence of Matrigel-generated tumors which allowed the establishment of another tumorigenic cell sub-line, BCS-TC2.2. Matrigel and laminin, but not collagens, promote the tumorigenicity of BCS-TC2 cells, probably due to specific interactions of a pre-existing minor cell sub-population with laminin, which facilitate the initial growth of these cells in vivo. Cytogenetic analysis reveals that both sub-lines originate from the parental one, but a new marker in chromosome 9 is observed. These sub-lines present a lower degree of differentiation, as deduced from the lower CEA content, 5'-nucleotidase and alkaline-phosphatase activities. No variation is observed in the mRNA and protein expression of the 67-kDa laminin-binding protein. However, an increase in beta1 integrins and a parallel decrease in beta4 integrin were detected. Thus, the new sub-lines, compared to the parental cells, present karyotypic and phenotypic differences such as the expression of a distinctive integrin pattern. This system represents a useful model for understanding the development and progression of tumorigenicity in cancer cells.
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PMID:Characterization of tumorigenic sub-lines from a poorly tumorigenic human colon-adenocarcinoma cell line. 878 56

The purine nucleoside adenosine (9-beta-D-ribofuranosyladenine) inhibits a number of lymphocyte functions in vitro, including the ability of activated T lymphocytes and natural killer cells to adhere to and kill tumor targets. Solid tumors, such as adenocarcinomas of the lung and colon, are frequently hypoxic and are, therefore, likely to exhibit increased adenine nucleotide breakdown through the 5'-nucleotidase pathway, yielding adenosine. We examined whether the concentration of adenosine in the extracellular fluid of such tumors is adequate to cause immunosuppression. Murine tumors grown in syngeneic hosts or human tumors grown in immunodeficient nu/nu mice were subjected to microdialysis, and adenosine levels in the microdialysate were measured by high-performance liquid chromatography. Treatment of the tumor microdialysates with adenosine deaminase eliminated the adenosine peak. Recovery of adenosine ranged from 15 to 29%, depending on the microdialysis probe, and concentrations of adenosine in tumors ranged from 0.2 to 2.4 microM with a mean of 0.5 microM. In contrast, the adenosine concentration measured s.c. at the same location was 30 +/- 5 nM (mean +/- SE). Inclusion of the adenosine deaminase inhibitor coformycin (10 microM) and the adenosine kinase inhibitor 5'-iodotubercidin (0.1 microM) in the microdialysis perfusion buffer increased extracellular adenosine concentration in tumors to as high as 13 microM. These data show that extracellular adenosine levels in solid tumors are sufficient to suppress the local antitumor immune response and that interference with pathways of adenosine metabolism causes marked increases in tumor extracellular adenosine concentration.
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PMID:The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. 920 63

The role of iron in anthracycline toxicity was studied in rats in vivo in intact animals and in vitro in heart cell cultures. In animals treated with 8 mg/kg doxorubicin, iron loading resulted in severe weight loss and a twofold increase in rate of mortality. Studies in cultured heart cells aimed at defining the subcellular target of interaction between iron and anthracycline toxicity showed no evidence of anthracycline-induced damage to sarcolemmal thiolic enzymes represented by 5'-nucleotidase and only a limited increase in lysosomal fragility as monitored by an increase in beta-hexosaminidase activity in cell homogenates and its release into the culture medium. By contrast, doxorubicin treatment resulted in a marked inhibition of mitochondrial function as monitored by a decrease in carbon 14-labeled palmitate utilization, to 33% +/- 4% of controls, and prior iron loading resulted in a further decrease in palmitate utilization, to 18% +/- 3% of controls. Conversely, iron-chelation treatment by either deferoxamine or deferiprone (L1) eliminated the harmful effects of iron loading and resulted in a partial inhibition of doxorubicin toxicity in both normal and iron-loaded cells. Our studies represent the first demonstration in intact animals of the potentiation of anthracycline toxicity by iron overload. They also indicate that mitochondria represent an important target of combined iron-anthracycline toxicity. These observations provide new insights into the mechanism of anthracycline cardiotoxicity and may be useful in developing better strategies for tumor therapy.
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PMID:Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction. 927 60

Tumour cell drug resistance is a major problem in cancer chemotherapy. Essential fatty acids have been shown to be cytotoxic to a variety of tumour cells in vitro. But, the effect of these fatty acids on tumour cell drug resistance has not been well characterized. Gamma-linolenic acid (GLA) of the n-6 series and eicosapentaenoic acid (EPA) of the n-3 series potentiated the cytotoxicity of anti-cancer drugs: vincristine, cis-platinum and doxorubicin on human cervical carcinoma (HeLa) cells in vitro. Alpha-linolenic acid (ALA), GLA, EPA and docosahexaenoic acid (DHA) enhanced the uptake of vincristine by HeLa cells. In addition, DHA, EPA, GLA and DGLA were found to be cytotoxic to both vincristine-sensitive (KB-3-1) and -resistant (KB-ChR-8-5) human cervical carcinoma cells in vitro. Pre-incubation of vincristine-resistant cells with sub-optimal doses of fatty acids enhanced the cytotoxic action of vincristine. GLA, DGLA, AA, EPA and DHA enhanced the uptake and inhibited the efflux of vincristine and thus, augmented the intracellular concentration of the anti-cancer drug(s). Fatty acid analysis of KB-3-1 and KB-ChR-8-5 cells showed that the latter contained low amounts of ALA, GLA, 22:5 n-3 and DHA in comparison to the vincristine-sensitive cells. The concentrations of GLA and DHA were increased 10-15 fold in the phospholipid, free fatty acid and ether lipid cellular lipid pools of GLA and DHA treated cells. These results coupled with the observation that various fatty acids can alter the activity of cell membrane bound enzymes such as sodium-potassium-ATPase and 5'-nucleotidase, levels of various anti-oxidants, p53 expression and the concentrations of protein kinase C suggest that essential fatty acids and their metabolites can reverse tumour cell drug-resistance at least in vitro.
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PMID:Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites? 948 65

Extracellular ATP, when added as a single dose at concentrations higher than 0.1 mM to the culture medium, was growth inhibitory or even cytotoxic for human epidermoid carcinoma cells (A431). Adenosine at the same concentrations was much less potent. The molecular mechanism underlying the inhibitory effect of extracellular ATP has been investigated. The cytostatic as well as the cytotoxic effects of ATP could be prevented by supplying uridine as a pyrimidine source and, alternatively, by simultaneous addition of dipyridamole, which inhibits the uptake of adenosine. The data suggest that the long-term production and continuous uptake of adenosine, which is enzymatically generated from the ATP in the medium, led to an intracellular nucleotide imbalance with pyrimidine starvation. This triggered suicidal processes ending up in apoptosis of the cells. The tumor cells have been adapted to extracellular ATP with the aim to obtain cells which are more resistant to ATP. Therefore, growing cells were periodically treated with extracellular ATP. These cells were characterized by an enlargement of cell size, a decreased proliferation rate, and a reduced but not abolished sensitivity to cytostatic and cytotoxic ATP doses. The calcium response of adapted cells was shortened. The nucleotide hydrolyzing ectoenzyme activities (ecto-ATPase, ecto-ADPase, ecto-AMPase, ecto-Ap4Aase) were simultaneously upregulated. All phenotypic alterations of the adapted cells disappeared after cultivation for several generations in the absence of extracellular ATP. Considering ATP as a potential chemotherapeutic agent the adaptive phenomena of treated cells might be important.
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PMID:Nucleotide metabolizing ectoenzymes are upregulated in A431 cells periodically treated with cytostatic ATP leading to partial resistance without preventing apoptosis. 973 53

The activities of 2-chlorodeoxyadenosine (2-CdA) metabolizing enzymes, deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase (5'-NT) were measured in control and bryostatin 1 treated CLL cells using an EBV-negative WSU-CLL cell line. This cell line was established from a patient with CLL resistant to fludarabine. The results revealed a significant increase in dCK activity in bryostatin 1 treated cells at 48 and 72 h compared with the control. 5'-NT activity decreased significantly at 48 h. The ratio of dCK to 5'-NT activity was significantly increased in bryostatin 1 treated WSU-CLL cells after 48 h. WSU-CLL cells treated with bryostatin 1 exhibited an increase in the percentage of apoptotic and dead cells from control levels of 16% to 40%. This percentage was further increased to 67% following the addition of 11.2 microM 2-CdA to WSU-CLL cells pretreated with bryostatin 1. Results from Western blot analysis indicate that WSU-CLL cells express high levels of Bcl-2, Bcl-xL and c-myc, and a low level of Bax. p53 in untreated WSU-CLL cells is undetectable. WSU-CLL cells treated with bryostatin 1 showed a significant increase in the ratio of Bax to Bcl-2. To demonstrate that the bryostatin 1 mediated enhancement of 2-CdA efficacy was not restricted to in vitro cell culture, we have studied the tumor growth delay of WSU-CLL xenografts treated with placebo, bryostatin 1, 2-CdA, and bryostatin 1 followed by 2-CdA. SCID mice given bryostatin 1 at 75 microg x kg(-1) x d(-1) for 5 days followed by 30 mg x kg(-1) x d(-1) 2-CdA for 5 days in two cycles, had significantly improved tumor growth delay (P = 0.05). We conclude that bryostatin 1 is not only capable of inducing apoptosis by itself, but also sensitizes de novo resistant WSU-CLL cells to the chemo-therapeutic effects of 2-CdA. The bryostatin 1-induced increased ratio of dCK/5'-NT activity and an increased ratio of Bax/Bcl-2 are at least two mechanisms through which this natural compound is able to potentiate the anti-tumor activity of 2-CdA in otherwise resistant CLL cells.
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PMID:Potentiation of 2-chlorodeoxyadenosine activity by bryostatin 1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5'-NT and Bax/Bcl-2. 982 May 86

Curcumin, the active constituent of Curcuma longa, which itself possesses antitumour activity against experimental tumours, enhances the antitumour effect of the widely used anticancer drug cisplatin, when used in combination against fibrosarcoma. Tumour marker enzymes such as aminotransferases, lactate dehydrogenase, gamma-glutamyl transpeptidase, alkaline phosphatase, 5'-nucleotidase were analysed in liver and kidney homogenates of experimental rats. All these enzyme activities were markedly increased in tumour bearing animals. On cisplatin administration, the enzyme levels were decreased but not to near normal values. Curcumin, when treated along with cisplatin brought back the enzyme levels to near the control values. Thus curcumin and cisplatin combination may be worth trying against tumours like fibrosarcoma.
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PMID:Dietary curcumin with cisplatin administration modulates tumour marker indices in experimental fibrosarcoma. 1009 41

We studied the value of alkaline phosphatase (AP), gamma-glutamyl transpeptidase (GGT), and 5'-nucleotidase (5'-NU) activities in the diagnosis of intrahepatic (IHC) versus extra-hepatic cholestasis (EHC). Eighty patients were included prospectively. All presented with cholestasis as defined by a concomitant increase in at least two of three cholestatic enzymes (AP, GGT, 5'-NU), a low cytolytic ratio (alanine aminotransferase/AP [xN/xN] < or = 5), and no evidence for associated liver tumor. We compared 43 patients with IHC due to chronic liver disease to 37 patients with EHC due to main bile duct obstruction. Fasting blood samples for activity determination (AP, GGT, 5'-NU) were taken before performing liver biopsy in cases of IHC and before endoscopic or surgical management in cases of EHC. Enzyme activities were compared using univariate and multivariate analysis. AP (276 IU/L [35-3,140] vs. 123 IU/L [37-699]: p < 0.0001), GGT (595 IU/L [98-5,200] vs. 211 IU/L [38-925]; p < 0.0001), and 5'-NU (32 IU/L [10-142] vs. 16 IU/L [4-107]: p < 0.0003) were significantly higher in EHC when compared to IHC. Only in GGT and 5'-NU activities were independent variables significantly linked to the mechanism of cholestasis. In IHC, the ratio GGT/5'-NU (xN/xN) was significantly lower than in EHC (2.8 [0.7-7.2] vs. 3.7 [1.8-10.5]: p < 0.006). A threshold of GGT/5'-NU < 1.9 had a sensitivity of 40% and a specificity of 100% for the diagnosis of IHC. Although such hepatobiliary enzymes cannot be regarded as diagnostic, they can provide useful information to orientate the clinician in the diagnosis of cholestasis.
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PMID:Respective value of alkaline phosphatase, gamma-glutamyl transpeptidase and 5' nucleotidase serum activity in the diagnosis of cholestasis: a prospective study of 80 patients. 1077 84

In order to characterize human colorectal cancer, much attention has been paid to enzyme studies. However, little is known about the correlation between the levels of key enzymes of purine nucleotide pathway and some clinical and biological indicators of tumor invasiveness and aggressiveness. Adenosine deaminase (ADA) and 5'-nucleotidase (5'-NT) were measured in cancerous and cancer-free adjacent large bowel tissues from 38 patients with colorectal carcinoma. We have analyzed the relationship between the enzyme levels and some clinical and pathological parameters. The enzymes' activities were markedly higher in primary tumors than in corresponding normal mucosae. The ADA level in tumor tissue was significantly correlated with lymph node metastasis, histologic type, tumor location, and patient's age, whereas the 5'-NT level showed a significant correlation with tumor grade and tumor location. ADA activity in tumor tissues was significantly higher in patients whose clinical course remained stable than in those with recurrent diseases. The purine metabolism and salvage pathway activity of purine nucleotides are accelerated in the cancerous human colorectal tissue. Although our findings suggest that these enzymes' activities are most likely related to the same histomorphological architecture of the tumor, the authors believe that long-term follow-up studies are needed to evaluate the prognostic value of purine enzymes for colorectal cancer.
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PMID:Activities of adenosine deaminase and 5'-nucleotidase in cancerous and noncancerous human colorectal tissues. 1111 12

Lymphagenesis in gastrointestinal tumors is not well described. To clarify its presence and regulation, we assessed the microlymphatic count (MLC) in colorectal cancer patients. Lymphatic vessels were evaluated by enzyme-histochemistry for 5'-nucleotidase (5'-NA). Since vascular endothelial growth factor (VEGF)-C is reportedly associated with lymphagenesis, the expression of VEGF-C protein was immunohistochemically assessed by the catalyzed signal amplification (CSA) method. MLC of peritumoral lesions was significantly higher than that of non-cancer and intratumoral lesions (p<0.01); it increased where VEGF-C was highly expressed (p<0.01) and increased with the depth of invasion in peritumoral lesions. These results indicate significant findings at peritumoral lesion: that lymphagenesis may be elicited by tumor spread; that VEGF-C expression is associated with lymphagenesis and is a potent factor stimulating lymphagenesis.
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PMID:Lymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer. 1279 49


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