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)

The expression of gamma-glutamyl transpeptidase (GGT), a plasma membrane ectoenzyme involved in the metabolism of extracellular reduced glutathione (GSH), is a marker of neoplastic progression in several experimental models, and occurs in a number of human malignant neoplasms and their metastases. Because it favors the supply of precursors for the synthesis of GSH, GGT expression has been interpreted as a member in cellular antioxidant defense systems. However, thiol metabolites generated at the cell surface during GGT activity can induce prooxidant reactions, leading to production of free radical oxidant species. The present study was designed to characterize the prooxidant reactions occurring during GGT ectoactivity, and their possible effects on the thiol redox status of proteins of the cell surface. Results indicate that: (i) in U937 cells, expressing significant amounts of membrane-bound GGT, GGT-mediated metabolism of GSH is coupled with the extracellular production of hydrogen peroxide; (ii) GGT activity also results in decreased levels of protein thiols at the cell surface; (iii) GGT-dependent decrease in protein thiols is due to sulfhydryl oxidation and protein S-thiolation reactions; and (iv) GGT irreversible inhibition by acivicin is sufficient to produce an increase of protein thiols at the cell surface. Membrane receptors and transcription factors have been shown to possess critical thiols involved in the transduction of proliferative signals. Furthermore, it was suggested that S-thiolation of cellular proteins may represent a mechanism for protection of vulnerable thiols against irreversible damage by prooxidant agents. Thus, the findings reported here provide additional explanations for the envisaged role played by membrane-bound GGT activity in the proliferative attitude of malignant cells and their resistance to prooxidant drugs and radiation therapy.
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PMID:Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation. 1049 Feb 84

B16 melanoma (B16M) was used to study the relationship between glutathione (GSH) metabolism and the metastatic activity of malignant cells. GSH content increased in B16M cells during the initial period of exponential growth in vitro, to reach a maximum of 37 +/- 3 nmol/10(6) cells 12 h after plating, and then gradually decreased to control values (10 +/- 2 nmol/10(6) cells) when cultures approached confluency. On the contrary, glutathione disulphide (GSSG) levels (0.5 +/- 0.2 nmol/10(6) cells) and the rate of glutathione efflux (GSH + GSSG) (2.5 +/- 0.4 nmol/10(6) cells per h) remained constant as B16M grew. Changes in enzyme activities involved in GSH synthesis or the glutathione redox cycle did not explain shifts in the glutathione status (GSH/GSSG). However, two facts contributed to explain why GSH levels changed within B16M cells: a) high intracellular levels of GSH induced a feed-back inhibition of its own synthesis in B16M cells from cultures with low cellular density (LD cells); b) transport of cyst(e)ine, whose availability is the major rate-limiting step for GSH synthesis, was limited by cell-cell contact in cultures with high cellular density (HD cells). Intrasplenic injection of B16M cells with high GSH content (exponentially-growing cultures) showed higher metastatic activity in the liver than cells with low GSH content (cells at confluency). However, when low GSH-content cells (HD cells) were incubated in the presence of GSH ester, which rapidly enters the cell and delivers free GSH, their metastatic activity significantly increased. Our results demonstrate that changes in GSH content regulate the metastatic behaviour of B16M cells.
Clin Exp Metastasis 1999
PMID:Growth-associated changes in glutathione content correlate with liver metastatic activity of B16 melanoma cells. 1084 55

A prospective study with a new tumour-seeking agent, 99Tcm-glutathione (GSH), was performed on 17 patients with choroidal melanoma. Planar and SPECT images using 99Tcm-GSH clearly demonstrated melanotic melanoma but failed to show amelonotic melanomas. Following confirmation of our results by concurrent ultrasonography and magnetic resonance imaging or computed tomography, patients were managed by either 125I plaque brachytherapy, diode laser transpupillary thermotherapy or enucleation depending on the site and location. In combination with other diagnostic tests, 99Tcm-GSH scintigraphy may play a role in the detection of uveal melanoma and its possible distant metastases.
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PMID:Scintigraphic imaging of uveal melanoma with 99Tcm-glutathione. 1125 7

B16 melanoma (B16M) cells with high glutathione (GSH) content show rapid proliferation in vitro and high metastatic activity in the liver in vivo. gamma-Glutamyl transpeptidase (GGT)-mediated extracellular GSH cleavage and intracellular GSH synthesis were studied in vitro in B16M cells with high (F10) and low (F1) metastatic potential. GGT activity was modified by transfection with the human GGT gene (B16MF1/Tet-GGT cells) or by acivicin-induced inhibition. B16MF1/Tet-GGT and B16MF10 cells exhibited higher GSH content (35 +/- 6 and 40 +/- 5 nmol/10(6) cells, respectively) and GGT activity (89 +/- 9 and 37 +/- 7 mU/10(6) cells, respectively) as compared (P <.05) with B16MF1 cells (10 +/- 3 nmol GSH and 4 mU GGT/10(6) cells). Metastasis (number of foci/100 mm(3) of liver) increased in B16MF1 cells pretreated with GSH ester ( approximately 3-fold, P <.01), and decreased in B16MF1/Tet-GGT and B16MF10 cells pretreated with the GSH synthesis inhibitor L-buthionine (S,R)-sulphoximine ( approximately 5-fold and 2-fold, respectively, P <.01). Liver, kidney, brain, lung, and erythrocyte GSH content in B16MF1/Tet-GGT- or B16MF10-bearing mice decreased as compared with B16MF1- and non-tumor-bearing mice. Organic anion transporting polypeptide 1-independent sinusoidal GSH efflux from hepatocytes increased in B16MF1/Tet-GGT- or B16MF10-bearing mice ( approximately 2-fold, P <.01) as compared with non-tumor-bearing mice. Our results indicate that tumor GGT activity and an intertissue flow of GSH can regulate GSH content of melanoma cells and their metastatic growth in the liver.
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PMID:gamma-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver. 1178 61

Reduced glutathione (GSH) production by tumour cells has been proposed as a mechanism for resistance to alkylating agents. High levels of paracetamol can deplete intracellular GSH. We conducted a phase I trial of high dose paracetamol and carmustine (BCNU) in patients with advanced malignant melanoma to determine the optimal biological dose and the maximum tolerated dose (MTD) with the goal of increasing sensitivity to BCNU by GSH depletion. Groups of three to five patients received escalating doses of paracetamol (10, 15 or 20 g/m(2)) every 3 weeks. Every other cycle, BCNU (10 mg/m(2)) was given 6.5 h after administration of paracetamol and 45 min before a 20 h infusion of N-acetylcysteine. Once the MTD for paracetamol had been determined, the dose of BCNU was sequentially escalated in subsequent cohorts to 150 mg/m(2). GSH levels were measured in peripheral blood mononuclear cells (PBMCs) and, when available, in tumour biopsies. The MTD of paracetamol was 15 g/m(2). The dose of BCNU was safely escalated to 150 mg/m(2). The most common toxicity was grade II nausea/vomiting. At 15 g/m(2), peak paracetamol levels (median 253 microg/ml) were reached between 1 and 4 h. No changes in GSH levels in PBMCs were seen. There were two partial responses, including a dramatic decrease in hepatic metastases. Treatment of melanoma patients with paracetamol (15 g/m(2)) every 3 weeks and BCNU (150 mg/m(2)) every 6 weeks is safe. The observation of two partial responses has led to a phase II study to evaluate treatment with high dose paracetamol alone or in combination with BCNU.
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PMID:Phase I trial of high dose paracetamol and carmustine in patients with metastatic melanoma. 1269 Mar 4

Raltitrexed (Tomudex; TOM) hepatotoxicity is usually characterized by a transient and self-limiting increase in transaminase levels. How this may condition daily clinical practice is still unclear. The aim of this study was to investigate predictive factors of TOM hepatotoxicity. In total, 130 patients were treated at two medical oncology institutions with TOM (3 mg/m2) (52 patients) or TOM plus oxaliplatin (TOMOX) (100 mg/m2 day 1 or 70 mg/m2 day 1, 8) (78 patients). A multinomial logistic regression (adjusted for multilevel data) was performed (on all administered chemotherapy courses) to assess the dependence of hepatic toxicity on a set of clinical factors correlated with patient, disease and treatment characteristics. Creatinine clearance was calculated by the Cockcroft formula before each chemotherapy course. Most of the patients presented colorectal cancer (95%) and metastatic disease (93%). Out of the 130 patients, 41 were aged 70 or more, while 119 (91.5%) had a good performance status (PS) (ECOG 0 or 1). Before chemotherapy, liver metastases were present in 78 (60%) patients and elevated transaminase in 25 (19%). A total of 584 courses were administered (252 TOM and 332 TOMOX). National Cancer Institute Common Toxicity Criteria grade 1/2 and 3/4 transaminase toxicity was observed in 62 and 20% of patients, respectively. To control transaminase increase, glutathione (GSH) or ademethionine (SAMe) was administered in 96 and 129 cycles, respectively. Hepatotoxicity conditioned delays (a week or more) in 60 (10%) chemotherapy cycles and was the reason for the discontinuation of chemotherapy in eight (6%) patients. Among the factors evaluated with multivariate analysis, sex, age, PS, creatinine clearance, previous chemotherapy treatment, presence of liver metastases and oncology centre were not significantly associated with TOM hepatotoxicity. Elevated baseline transaminase levels (p=0.001), number of chemotherapy cycles (p<0.001), TOM cumulative dose (p=0.018), unprolonged intervals between courses (p<0.001) and TOMOX regimen (p<0.001) emerged as factors predictive of hepatotoxicity. In the same analysis, GSH (p<0.001) and SAMe (p<0.001) were hepatoprotective agents. This study confirmed TOM-based hepatotoxicity as a clinical relevant side-effect and a major factor for treatment delays or discontinuation. Predictive and protective factors listed above could assist the management of this toxicity that has probably been underestimated until now.
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PMID:Raltitrexed-induced hepatotoxicity: multivariate analysis of predictive factors. 1296 Jul 37

Here we describe the isolation of C33/CD82/KAI1 in a screen for apoptosis-inducing genes. C33 is a gene that is downregulated in many metastatic tumor cells and the expression of which can attenuate the process of metastases formation in a variety of tumors. In accordance, we observed cell death induction by C33 in many different cell types. C33 seems to promote cell death by the generation of reactive oxygen intermediates (ROIs). These ROIs, however, are not derived from the mitochondrial respiratory chain as in most other scenarios leading to apoptosis. We observed that C33 renders cells sensitive to ROIs by causing the specific release of the intracellular antioxidant glutathione (GSH) from cells. Moreover, C33 activates the GTPase Cdc42, which mediates GSH release and apoptosis induction and allows to detect the formation of ROIs.
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PMID:The metastasis suppressor gene C33/CD82/KAI1 induces apoptosis through reactive oxygen intermediates. 1459 53

Mitochondrial glutathione (mtGSH) depletion increases sensitivity of Bcl-2-overexpressing B16 melanoma (B16M)-F10 cells (high metastatic potential) to tumor necrosis factor-alpha (TNF-alpha)-induced oxidative stress and death in vitro. In vivo, mtGSH depletion in B16M-F10 cells was achieved by feeding mice (where the B16M-F10 grew as a solid tumor in the footpad) with an L-glutamine (L-Gln)-enriched diet, which promoted in the tumor cells an increase in glutaminase activity, accumulation of cytosolic L-glutamate, and competitive inhibition of GSH transport into mitochondria. L-Gln-adapted B16M-F10 cells, isolated using anti-Met-72 monoclonal antibodies and flow cytometry-coupled cell sorting, were injected into the portal vein to produce hepatic metastases. In l-Gln-adapted invasive (iB16M-Gln+) cells, isolated from the liver by the same methodology and treated with TNF-alpha and an antisense Bcl-2 oligodeoxynucleotide, viability decreased to approximately 12%. iB16M-Gln+ cell death associated with increased generation of O2*- and H2O2, opening of the mitochondrial permeability transition pore complex, and release of proapoptotic molecular signals. Activation of cell death mechanisms was prevented by GSH ester-induced mtGSH replenishment. The oxidative stress-resistant survivors showed an adaptive response that includes overexpression of manganese-containing superoxide dismutase (Mn-SOD) and catalase activities. By treating iB16M-Gln+ cells with a double anti- antisense therapy (Bcl-2 and SOD2 antisense oligodeoxynucleotides) and TNF-alpha, metastatic cell survival decreased to approximately 1%. Chemotherapy (taxol plus daunorubicin) easily removed this minimum percentage of survivors. This contribution identifies critical molecules that can be sequentially targeted to facilitate elimination of highly resistant metastatic cells.
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PMID:Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. 1626 11

Diabetes mellitus (DM) is a chronic disease that is characterized by deteriorating glycemic control. The disease is known to be caused by imbalance between reactive oxygen species (ROS) and antioxidant defense systems. Hyperglycemia is commonly observed in a wide variety of diseases, including cancer. Although, therapy against glycemic control, is used in all these diseases, the diabetic cancer patients are on additional therapy with anticancer drugs. The objective of present study was to study if Glucophage (metformin), a very popular antidiabetic agent can avert the mutagenicity and lipid peroxidation caused by adriamycin (ADR), which is a commonly used cytotoxic drug. The experimental protocol included oral treatment of mice with different doses (62.5, 125 and 250 mg/kg day) of metformin for 7 days. Some mice in each group were injected i.p. with ADR (15 mg/kg). In each case animals were killed, 30 or 24, 48 and 72 h after the last treatment and femurs were excised for cytological studies by micronucleus test. Additional experiments on estimation of glutathione (GSH) and malondialdehyde (MDA) were undertaken in blood and serum, respectively. Twenty-four hour after the treatment, blood from each mouse was collected from heart and preserved for analysis. The results obtained revealed that pretreatment with metformin: (i) reduced the ADR-induced frequency of micronuclei without any alteration in its cytotoxicity and (ii) protected against the ADR-induced increase and decrease of MDA and GSH, respectively. The exact mechanism of action is not known, however, the inhibition of ADR-induced clastogenicity and lipid peroxidation by metformin may be attributed to the antioxidant action of the latter. Our results demonstrate that metformin might be useful to avert secondary tumor risk by decreasing the accumulation of free radicals and inhibition of mutagenicity.
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PMID:Effect of metformin on clastogenic and biochemical changes induced by adriamycin in Swiss albino mice. 1769 28

Octreotide is a somatostatin analogue binding on two receptor subtypes. In previous trials Octreotide showed inhibitory effects on tumour growth and liver metastasis in experimental pancreatic cancer. Thus we evaluated whether the new somatostatin analogue SOM-230 binding on 4 receptor subtypes has superior effects on carcinogenesis in pancreatic carcinoma. About 120 Syrian hamsters were randomised into six groups (n = 20): Gr.1: Aqua/Aqua, Gr.2: BOP/Aqua, Gr.3: Aqua/Octreotide, Gr.4: BOP/Octreotide, Gr.5: Aqua/SOM-230, Gr.6: BOP/SOM-230. Tumour groups 2,4,6 subcutaneously received 10 mg/kg body weight N-nitrosobis-2-oxopropylamin (BOP) weekly for 10 weeks, healthy control Gr.1,3,5 were given aqua. In the 17th week therapy started with Octreotide and SOM-230 for 16 weeks, after 32 weeks animals were sacrificed. Pancreas and liver were histopathologically analysed. Hepatic lipidperoxidation was determined by activities of antioxidative enzymes gluthation-peroxidase (GSH-Px) and superoxiddismutase (SOD) as well as concentration of thiobarbituric-acid reactive substances (TBARS). Incidence of liver metastases was 88.2% in Gr.2 (BOP/Aqua), it was decreased in Gr.4 (BOP/Octreo: 40%) and Gr.6 (BOP/SOM-230: 50%) (P < 0.05). Mean number/animal and mean-2-dimensional size of liver metastases did not differ between tumour groups. Comparing GSH-Px-activity in intrametastatic and extrametastatic hepatic tissue revealed a significant increase extrametastatically in Gr.2 (BOP/Aqua) and Gr.6 (BOP/SOM-230). SOD-activity in liver metastases was decreased in Gr.2 (1,801) (P < 0.05) versus Gr.4 (8,304) and Gr.6 (7,038). Intrametastatic TBARS concentration was increased in Gr.2 compared to Gr.4 (BOP/Octreotid) and Gr.6 (BOP/SOM-230) (P < 0.05). Octreotide and SOM-230 equally reduced liver metastasis in ductal pancreatic adenocarcinoma probably by a reduction of lipidperoxidation.
Clin Exp Metastasis 2009
PMID:Impact of Octreotide and SOM-230 on liver metastasis and hepatic lipidperoxidation in ductal pancreatic adenocarcinoma in Syrian Hamster. 1952 86


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