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 semicarbazide-sensitive amine oxidases constitute a group of copper-containing enzymes whose physiological function is unclear. The enzymes are present in various tissues, including blood plasma. At present, the source of the plasma enzyme in humans is not known. Results of a recent study suggested that semicarbazide-sensitive amine oxidase is expressed in the skeleton, e.g. in the spine. Using an indirect autoradiographic method in mice, we provide evidence that semicarbazide-sensitive amine oxidase is present in high abundance in bone tissue. Specific activities of semicarbazide-sensitive amine oxidase were estimated in blood samples from subjects with femoral bone fractures. Moreover, enzyme activities were also measured in patients suffering from prostate cancer with skeletal metastases. The level of specific semicarbazide-sensitive amine oxidase activity in serum was significantly elevated in patients with skeletal metastases compared with both healthy controls and patients having prostate cancer without signs of skeletal metastases. Based on the results of the present study, we propose that semicarbazide-sensitive amine oxidase in blood plasma may originate, at least in part, from the skeleton.
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PMID:Elevated activity of semicarbazide-sensitive amine oxidase in blood from patients with skeletal metastases of prostate cancer. 1036 2

Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15-20% of baseline. The level III dose of TM (120 mg/ day) was effective in reaching the target Cp without added toxicity. TM-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.
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PMID:Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study. 1065 25

Semicarbazide-sensitive amine oxidases (SSAOs) are widely expressed copper-containing enzymes. One enzyme of this family have high specific activity towards benzylamine and is present in human blood plasma. This enzyme is altered in several diseases, for instance in diabetes. Presently it is unclear where the plasma SSAO is synthesized. Previous autoradiographic studies have suggested that SSAO may be expressed in bone tissue. In the current study we have analyzed levels of SSAO in serum from cases with 'skeletal disease', i.e. patients with severe skeletal metastases of prostate cancer and subjects having recent fractures. Interestingly, subjects with metastases showed significantly elevated levels of SSAO in serum compared to individuals having prostate cancer without skeletal metastases. It is speculated that, at least in part, SSAO in the blood stream may be derived from bone tissue.
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PMID:Is semicarbazide-sensitive amine oxidase in blood plasma partly derived from the skeleton? 1106 Dec 10

Insufficient blood flow within colo-rectal hepatic metastases is a factor which may limit drug delivery to, and thus the response of, these tumours to regional chemotherapy. Loco-regional flow may be manipulated pharmacologically to enhance the tumour blood flow relative to that of the normal liver. However, as yet, only transient effects have been studied. Patients receiving regional chemotherapy for unresectable hepatic disease were given a 45 min regional infusion of the vasoconstrictor Angiotensin II. Intrahepatic blood flow distribution was assessed serially by Positron Emission Tomography (PET) imaging together with the trapping tracer copper(II) pyruvaldehyde bis(N-4-methylthiosemicarbazone) (Cu-PTSM) labelled using copper-62. Eleven lesions in nine patients were studied, with no adverse effects. Prior to Angiotensin II administration tumour blood flow was generally found to be greater than that of liver (10/11 lesions; 8/9 patients; median TNR 1.3, iqr 0.9-2.5). A significant increase in relative flow to tumour was seen in response to 10 min Angiotensin II infusion in most cases (7/11 lesions; 7/9 patients; median TNR 2.1, iqr 1.4-4.1; P = 0.008), which appeared to be sustained throughout the 45 min infusion period (median TNR 1.85, iqr 1.3-3.8; P = 0.03). These effects were accompanied by transient elevation of mean arterial pressure, but no change in pulse rate. These observations suggest that prolonged regional vasoconstrictor administration could prove useful in the management of unresectable colo-rectal hepatic metastases, and that further development of vascular manipulation to enhance tumour targeting and drug delivery is warranted.
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PMID:Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases. 1174 81

Plasma fibronectin-mediated invasion of human DU145 prostate cancer cell line was efficaciously inhibited in a rat tumor model by treatment with Ac-PHSCN-NH(2) peptide. Invasion of DU145 cells was stimulated by the PHSRN sequence of plasma fibronectin. However, PHSCN acts as a competitive inhibitor of PHSRN-mediated invasion. In the current study, we determined whether PHSCN could inhibit the recurrence and metastasis of DU145 tumors after excision of the primary tumor in an athymic nude mouse model. We demonstrated that mice treated thrice weekly with intravenous Ac-PHSCN-NH(2) peptide survived tumor-free for more than 30 weeks post-primary tumor excision, whereas their untreated counterparts succumbed to recurrence and/or metastatic disease in significantly less time. Because of the universal requirement for angiogenesis in solid tumor growth, we tested the efficacy of copper deficiency induced by tetrathiomolybdate (TM) to retard tumor growth in the Dunning prostate cancer model. Significant reduction in size of the primary tumor was observed in mice rendered copper deficient. We sought to reduce tumor growth at the primary and metastatic sites by combining the anti-invasion Ac-PHSCN-NH(2) peptide with TM. Improved survival, fewer metastatic lesions, and excellent tolerability were observed with the combination therapy.
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PMID:Suppression of tumor recurrence and metastasis by a combination of the PHSCN sequence and the antiangiogenic compound tetrathiomolybdate in prostate carcinoma. 1219 95

Long-Evans Cinnamon (LEC) rats, an inbred mutant strain which accumulates copper due to an aberrant copper-transporting ATPase gene, develop acute hepatitis, chronic liver injury and liver tumors as a result of copper-induced oxidative stress, lipid peroxidation and DNA damage. Curcumin, an antioxidant and anti-inflammatory agent, has shown anticancer properties in many rodent models. We investigated the modulating role of curcumin in liver and kidney carcinogenesis in LEC rats. Two groups of 4-week-old LEC rats (n = 60 each) were fed either a standard diet (control) or received 0.5% curcumin in the diet for life. In untreated LEC rats, the rate of acute liver failure, the incidence of liver tumors and of kidney tumors were 32, 100 and 10% respectively, which was not altered by curcumin treatment. However, curcumin reduced tumor incidence at other organ sites (15% versus 0%; P = 0.025) and suppressed formation of metastases (18% versus 0%; P = 0.01). Median survival time was decreased from 88.7 to 78.1 weeks in curcumin-treated rats (P = 0.002). The lack of chemoprevention of liver and kidney tumors in LEC rats by curcumin may be caused by enhanced toxicity and oxidative stress due to excess copper. We conclude that curcumin should be contra-indicated for patients suffering from inherited and acquired metal storage diseases that include patients with hepatitis C virus infection.
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PMID:No prevention of liver and kidney tumors in Long-Evans Cinnamon rats by dietary curcumin, but inhibition at other sites and of metastases. 1262 10

We studied the serum levels of vitamins A, E, zinc and copper in two hundred and twenty-five subjects of both sexes. They were divided into two groups: 87 healthy subjects who served as controls and 138 patients with neoplastic disease. The patients were subdivided according to the absence (n = 79) or the presence of metastatic disease (n =59). In 59 patients with cancer, who were in therapy with scavenger drugs of free radical such as calcium antagonists and the antagonists of receptors H2, we also studied the possible effect of the same therapy on the serum levels of vitamins, on the concentrations of the microelements and on membrane lipid peroxidation. We found that membrane lipid peroxidation, evaluated from the time of in vitro formation in the blood of so-called "Heinz bodies," decreased in all patients treated with scavenger drugs. In these patients the permeability of the erythrocyte membrane was similar to the controls and the serum levels of the vitamins were equal to the levels in patients who did not receive these therapies. Zinc concentration increased while copper remained unchanged. We also studied the levels of vitamins in some organs. The results are discussed considering the role of free radicals. We underline the importance of vitamins A and E in the protection from membranous peroxidation and from free radicals and the need to consider cancer as a systemic morbid event, apart from the contingent actual location.
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PMID:Vitamins A, E, microelements and membrane lipid peroxidation in patients with neoplastic disease treated with calcium antagonists and antagonists of receptors H2. 1527 9

We report the case of a 56-year-old woman with a 7-year history of metastatic cancer who presented with severe copper deficiency following self-treatment with the copper-chelating agent tetrathiomolybdate. This compound was used with the aim of inhibiting tumour angiogenesis and was obtained from the USA by placing an order on the internet. The patient exhibited severe neutropenia as her serum copper concentration fell from 19.8 micromol/L to 3.3 micromol/L and her caeruloplasmin concentration from 35 mg/dL to 4 mg/dL.
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PMID:Iatrogenic copper deficiency following information and drugs obtained over the Internet. 1533 97

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.
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PMID:Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. 1536 99

Tumor growth and metastasis depend on the formation of blood vessels, angiogenesis, to supply the developing mass with nutrients, oxygen, and waste removal. The proteasome, a massive multisubunit catabolic body, exerts a regulatory influence on angiogenesis. Inhibition of the proteasome activity has been found to inhibit angiogenesis and induce apoptosis in human cancer cells with limited toxicity to normal cells. Therefore, the dual action of angiogenesis inhibition and cell death induction makes proteasome inhibition an attractive modality for chemotherapy. A variety of proteasome inhibitors have been studied including: antibiotics such as lactacystin, the green tea polyphenols, and the boronic acid Velcade (MLN-341). Most recently, certain classes of copper compounds have been found to act as potent proteasome inhibitors. The potential of particular organic compounds, such as 8-hydroxyquinoline, to spontaneously bind with tumor cellular copper and form proteasome inhibitors provides a new modality of anti-proteasome and anti-angiogenesis chemotherapy. This review examines angiogenesis, the proteasome, representative proteasome inhibitors, and the emerging role of copper. The formation of new blood vessels, or angiogenesis, is an important and necessary function in both embryonic development and wound repair. Therefore, the ability to regenerate or form new vessels for blood flow is essential. The control of angiogenic pathways is tightly regulated in normal differentiated adult cells, which generally do not stimulate blood vessel growth unless injury occurs. However, cancerous tissues stimulate angiogenesis that in turn leads to increased tumor formation and possible metastases. Many of the factors involved in angiogenesis are regulated by the proteasome, which recently has become a focus in anti-cancer therapies due to its involvement in cell cycle and apoptosis control. Here we discuss angiogenesis and its relation to the proteasome. Additionally, current modalities of anti-angiogenic treatment, mainly proteasome inhibitory strategies, are reviewed. Furthermore, proteasome inhibitors, both natural and synthetic, and their anti-angiogenic effects as well as future approaches to anti-angiogenic chemotherapies are also discussed.
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PMID:Anti-angiogenic and anti-tumor properties of proteasome inhibitors. 1630 49


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