The role of cytokines in muscle wasting: its relation with cancer cachexia.
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The pleiotropic cytokine tumour necrosis factor-alpha (TNF) is thought to play a central role in infectious, inflammatory and autoimmune diseases. Critical to the understanding and management of TNF-associated pathology is the development of highly specific agents capable of modifying TNF activity. We evaluated the ability of a high affinity mouse/human chimeric anti-TNF monoclonal antibody (cA2) to neutralize the in vitro and in vivo biological effects of TNF. cA2 inhibited TNF-induced mitogenesis and IL-6 secretion by human fibroblasts, TNF-priming of human neutrophils, and the stimulation of human umbilical vein endothelial cells by TNF as measured by the expression of E-selectin, ICAM-1 and procoagulant activity. cA2 also specifically blocked TNF-induced adherence of human neutrophils to an endothelial cell monolayer. Receptor binding studies suggested that neutralization resulted from cA2 blocking of TNF binding to both p55 and p75 TNF receptors on the cells. In vivo, repeated administration of cA2 to transgenic mice that constitutively express human TNF reversed the cachectic phenotype and prevented subsequent mortality. These results demonstrated that cA2 effectively neutralized a broad range of TNF biological activities both in vitro and in vivo.
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Rats (weight 150-200 g) bearing Walker-carcinoma showed tumour size dependent hypoglycemia, diminished mobilization of glycogen following glucagon stimulation and elevated values of the enzyme activity of glucose-6-(P)-ase. A further hormonal stimulation of this enzyme activity towards the values observed in normal rats after betamethasone stimulation was not possible. The values of the enzyme fructose-1,6-di-(P)-ase in liver of tumour bearing rats equalled those found in normal controls and did not show any rise after application of betamethasone. The serum levels of free fatty acids did not show any difference between normal controls and tumour bearing rats, and displayed an equal rise after intensive stimulation of peripheral lipolysis.
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The nutritional status of 11 patients with severe mitral valve disease was investigated pre-operatively and 3 months post-operatively. It was shown that they were malnourished pre-operatively, and that this appeared to be related mainly to anorexia.
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Chemotherapy and radiotherapy offer little benefit to patients with advanced pancreatic cancer. Eicosapentaenoic acid (EPA) has anticancer effects both in vitro and in animal models. The dose of EPA that can be administered to cancer patients has previously been limited by the low purity of available preparations and the tolerability of large capsules. A high-purity preparation of EPA as a 20% oil-in-water diester emulsion allowed a small study of the tolerance, incorporation, and effects of EPA in high doses in five patients with advanced pancreatic cancer. Patients underwent assessment at baseline and every 4 wk thereafter. All patients managed to tolerate a dose providing 18 g EPA per day, with doses between 9 and 27 g daily being taken for at least a month. Dosage was limited by a sensation of fullness, cramping abdominal pain, steatorrhea, and nausea. All such symptoms were controlled by dose reduction or pancreatic enzyme supplements. No other adverse effects attributable to the trial agent were observed. Plasma phospholipid EPA content increased from around 1% at baseline to 10% at 4 wk and 20% at 8 wk. Incorporation of EPA into red blood cell phospholipids reached levels of around 10%. The present study has shown that a novel, high-purity, EPA diester emulsion can be tolerated at a dose providing around 18 g EPA per day with side-effects being easily controlled. The acceptibility of large doses of oral EPA should allow larger controlled clinical studies into potential anticancer effects of EPA.
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