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PubMed1999

Differential reconstitution of mitochondrial respiratory chain activity and plasma redox state by cysteine and ornithine in a model of cancer cachexia.

The mechanism of wasting, as it occurs in malignant diseases and various etiologically unrelated conditions, is still poorly understood. We have, therefore, studied putative cause/effect relationships in a murine model of cancer cachexia, C57BL/6 mice bearing the fibrosarcoma MCA-105. The plasma of these mice showed decreased albumin and increased glutamate levels, which are typically found in practically all catabolic conditions. Skeletal muscles from tumor-bearing mice were found to have an abnormally low mitochondrial respiratory chain activity (mito.RCA) and significantly decreased glutathione (GSH) levels. The decrease in mito.RCA was correlated with an increase in the i.m. GSH disulfide/GSH ratio, the plasma cystine/thiol ratio, and the GSH disulfide/GSH ratio in the bile. This is indicative of a generalized shift in the redox state extending through different body fluids. Treatment of tumor-bearing mice with ornithine, a precursor of the radical scavenger spermine, reversed both the decrease in mito.RCA and the change in the redox state, whereas treatment with cysteine, a GSH precursor, normalized only the redox state. Treatment of normal mice with difluoromethyl-ornithine, a specific inhibitor of ornithine decarboxylase and spermine biosynthesis, inhibited the mito.RCA in the skeletal muscle tissue, thus illustrating the importance of the putrescine/spermine pathway in the maintenance of mito.RCA. Ornithine, cysteine, and N-acetyl-cysteine (NAC) also reconstituted the abnormally low concentrations of the GSH precursor glutamate in the skeletal muscle tissue of tumor-bearing mice. Higher doses, however, enhanced tumor growth and increased the plasma glucose level in normal mice. In the latter, cysteine and NAC also decreased i.m. catalase and GSH peroxidase activities. Taken together, our studies on the effects of ornithine, cysteine, and NAC illuminate some of the mechanistic pathways involved in cachexia and suggest targets for therapeutic intervention.

Acetylcysteine↗

PubMed1999

[Cachexia in cancer: disturbances in the protein and aminoacid metabolism].

Cancer induced cachexia is characterized by complex changes in the intermediary metabolism. There is a raised basal metabolism with increased turnover of lipids, carbohydrates and proteins. In this altered metabolic milieu, protein catabolism occurs in peripheral tissue resulting in release of amino acids for the benefit of visceral organs. These as a rule increase in protein mass and also produce more plasma proteins. The amino acid glutamine plays a central part in this. It is released in large amounts from muscle tissue and is consumed to a high degree by visceral organs and immune cells. Although biochemically glutamine is not an essential amino acid, in cancer-induced cachexia it appears to be a 'conditionally' essential amino acid. Changes in the protein metabolism appear to be controlled by chronically increased neuroendocrine and inflammatory activity (exerted among other things by tumour necrosis factor alpha, interleukins 1 and 6 and catecholamines). Fundamental research, animal experiments and certain clinical trials show that the metabolism altered by these mediators can be corrected using hormonal preparations such as growth hormone, beta 2-adrenergic agonists and insulin. In the future it may conceivably be possible to correct the metabolic disturbance with drugs and the depletion of nutrients with specific nutritional supplements.

Amino Acids↗

PubMed1999

Cancer anorexia-cachexia syndrome: are neuropeptides the key?

Progressive wasting is common in many types of cancer and is one of the most important factors leading to early death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response, although the weight loss in the patients differs from that found in simple starvation. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight. It has been demonstrated that leptin, a hormone secreted by adipose tissue, is an integral component of the homeostatic loop of body weight regulation. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the loop and induce behavioral and metabolic responses. A number of cytokines, including tumor necrosis factor-alpha, interleukins 1 and 6, IFN-gamma, leukemia inhibitory factor, and ciliary neurotrophic factor have been proposed as mediators of the cachectic process. Cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin. This could be done by persistent stimulation of anorexigenic neuropeptides such as corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network that consists of opioid peptides and galanin, in addition to the newly identified melanin-concentrating hormone, orexin, and agouti-related peptide. Information is being gathered, although it is still insufficient, on such abnormalities in the hypothalamic neuropeptide circuitry in tumor-bearing animals that coincide with the development of anorexia and cachexia. Characterization of the feeding-associated gene products have revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown.

Animals↗

PubMed2000

The cancer anorexia-cachexia syndrome.

The cancer anorexia-cachexia syndrome is one of the most common causes of death among cancer patients and is present in 80% at death. It is a complex example of metabolic chaos effecting protein, carbohydrate, and fat metabolism. Tumors produce both direct and indirect abnormalities, resulting in anorexia and weight loss. The disease burden does not correlate with the degree of cachexia. Although there is no treatment to control or reverse the process, appetite stimulants may promote increased food intake and enhance quality of life.

Cachexia↗

PubMed2001

The cancer cachexia syndrome.

The provision of additional calories and protein alone has not been shown to be efficacious in patients with cancer cachexia. Although primary research continues to unravel the complex metabolic derangements and diverse mediator pathways underlying cancer cachexia, the future lies in drugs and neutracenticals that may modulate this altered metabolism and enable conventional nutritional support to effectively replenish vital lean tissue.

Acute-Phase Proteins↗

PubMed2001

[Molecular and cellular biological analysis on cancer cachexia syndrome].

About half of patients with cancer will suffer from wasting syndrome, called cancer cachexia, which shows abnormality of homeostasis, nutrition, endocrine function, metabolism, immunity et al. This syndrome is characterized with anorexia and weight loss caused by degradation of skeletal muscle and adipose tissue. Progressive weight loss is responsible not only for a poor quality of life and poor response to anti-cancer drug, but also shorter survival time comparing patient without weight loss. Various factors have been found as mediators of this syndrome base on the development of immunology, biochemistry and molecular and cellular biology. These include several cytokines, proteolysis-inducing factor (PIF), lipid-mobilizing factor (LMF), apoptosis-inducing factor and another factors. Recentry, molecular biological analysis makes clear more detail mechanisms of cancer cachexia syndrome, for example, ubiqutin/proteasome pathway, activation of nuclear transcriptional factors and others. These progresses will contribute not only to establish new treatment but also to carry out "order-made palliative oncology" using DNA-chip and/or Protein-chip in near future.

Animals↗

PubMed2003

Malnutrition, muscle wasting and cachexia in chronic heart failure: the nutritional approach.

Malnutrition, muscle wasting and cachexia are often present in chronic heart failure (CHF). However, malnutrition in CHF patients is not always as severe as muscle wasting. Data in the literature show that 24% of CHF patients have malnutrition (albumin < 3.5 mg/dl) but 68% have muscle atrophy. This apparent discrepancy can be explained by considering the metabolic role of the striate muscle. In fact, the striate muscle maintains the body metabolic performance by continuous exchanges of fuels (amino acids) with the liver. This happens in case of malnutrition or starvation. In such situations, glucose is produced by gluconeogenesis when amino acids are metabolized in the liver. Malnutrition, muscle wasting and the frequent progression through cachexia can be reduced by specific therapy such as cytokine and/or catabolic hormone antagonists. This is because cytokines and catabolic hormones, with consequent insulin resistance, cause muscle wasting. An alternative and/or complementary therapy may be exogenous amino acid supplementation. In fact, amino acids: a) are rapidly absorbed regardless of pancreatic activity, b) reduce insulin resistance, c) induce the hepatic synthesis of anabolic molecules such as growth hormone and insulin-like growth factor, and d) modulate the catabolic hormonal-mediated effects on adipocytes. Research on the best suitable qualitative and quantitative amino acid composition for an alternative and/or complementary therapy is still being studied in different research centers.

Amino Acids↗

PubMed2003

Selective up-regulation of tumor necrosis factor receptor I in tumor-bearing rats with cancer-related cachexia.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) are important mediators in cancer cachexia; however, the expression of these cytokines and their receptors in tumor-bearing animals is poorly characterized. We analyzed expression of TNF-alpha, IL-6, tumor necrosis factor (TNF-RI, TNF-RII) and interleukin 6 (IL-6R) receptors in the brain, kidney, spleen, liver, muscle, ascite tumors and serum, from Yoshida AH-130 hepatoma-bearing rats. TNF-alpha increased in the brain, spleen, liver, and muscle of cachectic animals; IL-6 increased in the liver and muscle. AH-130 cells expressed a good level of TNF-alpha; on the contrary, no TNF-alpha or IL-6 protein was detected in the serum of either tumor-bearing or control animals. TNF-RI mRNA was up-regulated in the spleen, liver and muscle of tumor-bearing rats. TNF-RI protein levels confirmed up-regulation in the spleen and liver, but failed to detect any increase in the muscle. Western blotting against TNF-RI revealed two bands of lower molecular weight in cachectic muscle, suggesting proteolysis involving TNF-RI. No significant increase of either TNF-RII or IL-6R was observed. This is the first demonstration of a selective up-regulation of TNF-RI in cancer cachexia and suggests that local production of TNF-alpha and IL-6 is a corner-stone in the induction/maintenance of this syndrome.

Animals↗

PubMed1992

Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor.

OBJECTIVE: To investigate body composition and serum tumor necrosis factor (TNF) levels in a series of 24 patients with rheumatoid arthritis (RA). METHODS: Body composition assessment by anthropometric measures and bioelectrical impedance. Cytokine determination in serum by ELISA: RESULTS: When compared to United States population norms, 16 of the subjects (67%) were cachectic. In regression models, lean body mass (LBM) was inversely associated with the number of swollen joints (p < 0.025). Elevated TNF-alpha was found in 3 of 5 flaring patients vs 0 of 18 patients with less active disease (p = 0.001). These 3 were all cachectic, while the 2 flaring patients without detectable TNF had normal LBM (p < 0.03). Among the whole group, there was a trend toward increasing disability with decreased LBM after adjusting for joint pain and disease duration (p < 0.07). CONCLUSION: Cachexia is common in RA, and may be cytokine driven. Given the prognostic impact of LBM wasting in other diseases, the effect of rheumatoid cachexia on outcome in RA deserves further study.

Adult↗

PubMedDate not supplied

Pathogenesis of cancer cachexia.

Cachexia is a progressive wasting syndrome characterized by extensive loss of adipose tissue and skeletal muscle. It occurs in about half of all cancer patients. While anorexia also may be present, the energy deficit alone does not explain the pathogenesis of cachexia. The presence of an acute phase response (APR) has been linked to accelerated weight loss and a shortened survival time. The APR is thought to be initiated by cytokines such as interleukin (IL)-6 and IL-8, production of which is induced by a tumor factor, proteolysis inducing factor (PIF). Cachectic cancer patients also show an increased expression of uncoupling protein-3 in muscle, which may act as an energy sink, increasing energy expenditure. Loss of adipose tissue appears to be due to an increase in degradation of triglycerides, rather than a decrease in synthesis. One candidate for this effect is a tumor lipid mobilizing factor, which stimulates lipolysis directly through a cyclic AMP-mediated process via interaction with a beta3-adrenergic receptor. Loss of skeletal muscle arises from both a depression in protein synthesis and an increase in protein degradation. The major proteolytic pathway involved in intracellular protein breakdown in cachectic muscle is the ATP-ubiquitin-dependent proteolytic pathway. Both PIF and tumor necrosis factor-alpha, but not other cytokines, can induce expression of the key regulatory components of this pathway. Eicosapentaenoic acid, found in oily fish, effectively attenuates protein degradation in cachectic muscle by inhibiting the increased proteasome expression and can stabilize body weight in cachectic cancer patients.

Adipose Tissue↗

PubMedDate not supplied

[Cachexia].

Cachexia is a frequent syndrome in patients suffering from advanced cancer; it is characterized by anorexia, weight loss, and malnutrition, which combined with other psychic and social consequences lead to a deterioration in a patient's quality of life. Various factors play a role in the development of cachexia; these depend on the patient, the type of tumor, and the treatments received. Its complexity warrant the intervention of an interdisciplinary team, in which nursing plays an essential role. Up to present time, the results of pharmaceutical treatment have been rather unfavorable; therefore, nutritional treatments based on advise for concrete problems and dietary supplements gain importance; enteral or parenteral nutrition are reserved for selected cases. Other important aspects are psychological support, control of associated symptoms and the prevention and treatment of any complication which may appear.

Cachexia↗

PubMed1992

Insulin action on glucose and branched-chain amino acid metabolism in cancer cachexia: differential effects of insulin.

In addition to the maintenance of glucose homeostasis, insulin plays a major role in the regulation of branched-chain amino acid (BCAA) metabolism. We investigated insulin action on glucose turnover rates, arterial BCAA concentrations, and forearm BCAA flux in cancer cachexia. Six weight-losing patients with localized gastrointestinal malignancy and five age-matched control subjects underwent sequential 120-minute euglycemic insulin infusions. Steady-state insulin concentrations were 50 +/- 5, 97 +/- 14, and 435 +/- 14 microU/ml in patients and 44 +/- 4, 95 +/- 6, and 495 +/- 42 microU/ml in control subjects at the insulin infusion rates of 0.5, 1.0, and 4.0 mU/kg.min, respectively. During the 0.5 and 1.0 mU/kg.min insulin infusions, a primed, continuous infusion of D-[3-3H] glucose was used to quantify endogenous glucose production. Total body glucose uptake was decreased in patients with cancer compared with control subjects at the 0.5 mU/kg.min (2.9 +/- 0.4 vs 3.6 +/- 1.2 mg/kg.min), 1.0 mU/kg.min (5.3 +/- 0.3 vs 8.7 +/- 0.8 mg/kg.min; p less than 0.05), and 4.0 mU/kg.min (10.9 +/- 0.9 vs 13.7 +/- 1.1 mg/kg.min) insulin infusion rates, consistent with a state of insulin resistance. Progressive euglycemic insulin infusion induced a marked, comparable insulin-dependent decrease in arterial plasma BCAA concentrations in both patients with cancer and control subjects. There was no change in postabsorptive forearm BCAA flux with progressive hyperinsulinemia. Insulin-induced branched-chain hypoaminoacidemia is unimpaired in this group of patients manifesting resistance to insulin action on glucose metabolism, thereby providing evidence of a differential resistance to insulin action on glucose metabolism versus insulin action on BCAA concentrations in cancer cachexia. Peripheral BCAA flux is not affected by systemic insulin infusion, suggesting that skeletal muscle is not a major site of BCAA disposal during insulin-mediated hypoaminoacidemia.

Amino Acids↗

PubMed1992

[A case report of Russel's diencephalic cachexia].

The case of an infant admitted for evaluation of severe emaciation with intermittent ocular anomalies including strabismus and nystagmus is reported. This case demonstrates the value of magnetic resonance imaging and transfontanellar ultrasonography for the diagnosis of diencephalic syndrome of infancy. The prognosis of this condition is usually grim, in particular because of the severe emaciation which is disproportionate with the tumour spread. Pathophysiologic hypotheses put forward to explain this cachexia are reviewed. Although cytokines such as TNF alpha are currently incriminated in the pathophysiology of cachexia induced by a number of conditions, they have not yet been studied in diencephalic syndrome of infancy. TNF alpha is a potent lipolytic agent. Excessive production of TNF alpha may be involved in the genesis of the emaciation characteristic of diencephalic syndrome. Inappropriate production of TNF alpha may respond to the administration of specific anti-TNF monoclonal antibodies. This approach may be considered as a means for treating emaciation in patients with diencephalic syndrome of infancy.

Astrocytoma↗

PubMed2005

Can progressive resistance training reverse cachexia in patients with rheumatoid arthritis? Results of a pilot study.

OBJECTIVE: . A Phase II trial was performed as a preliminary test of the efficacy and safety of progressive resistance training (PRT) as adjunct treatment for rheumatoid cachexia. METHODS: Ten mildly disabled patients with well-controlled rheumatoid arthritis (RA) trained, on average, 2.5 times per week for 12 weeks. Ten age and sex matched RA patients with similar disease characteristics were non-randomly assigned to a control group. Body composition, physical function, and disease activity were assessed pre and post intervention period. RESULTS: Between group comparisons at followup by ANCOVA using baseline scores as covariate showed significant increases in fat-free mass (+1253 g, p = 0.004), total body protein (+1063 g, p = 0.044), and arm (+280 g, p = 0.005) and leg (+839 g, p = 0.001) lean mass (a proxy measure of total body skeletal muscle mass) in response to PRT with no exacerbation of disease activity. There was also a trend for loss of fat mass in the trunk (-752 g, p = 0.084) and a significant reduction in percent body fat (-1.1%, p = 0.047). Changes in body composition were associated with improvements in various measures of physical function. CONCLUSION: Intense PRT with adequate volume seems to be an effective and safe intervention for stimulating muscle growth in patients with RA. Pending confirmation of these results in a larger randomized controlled trial that includes patients with more active and severe disease, a similar PRT program should be included in the management of RA as adjunct treatment for cachexia.

Arthritis, Rheumatoid↗

PubMed2005

Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia.

Muscle wasting in experimental cancer cachexia has been associated with increased ubiquitin proteasome proteolytic system activity and increased uncoupling protein (UCP) expression. Increased ubiquitin proteasome pathway activity has also been found in gastric, but not lung, cancer patients. It therefore remains unclear in which patients modulation of this proteolytic system could be a therapeutic target. We investigated markers of systemic inflammation, hypermetabolism and expression of ubiquitin and uncoupling proteins 2 and 3 in muscle of pancreatic cancer patients. Rectus abdominis muscle was sampled from 15 weight-losing pancreatic cancer patients and 11 controls. UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting. Resting energy expenditure and plasma IL-6, sTNF-R and C-reactive protein (CRP) were also measured. Cancer patients had lost 18% of pre-illness stable weight, but were not significantly hypermetabolic compared with controls. IL-6, sTNF-R and CRP levels and ubiquitin 2.4 kb, but not 1.2 kb, mRNA expression were increased in cancer patients. UCP-2 and 3 mRNA and UCP-3 protein were similar in both groups. Weight loss correlated with systemic inflammation and ubiquitin 1.2 and 2.4 kb mRNA expression. Weight loss in pancreatic cancer is associated with systemic inflammation and increased mRNA expression for ubiquitin but not uncoupling proteins in skeletal muscle. The pro-inflammatory network and ubiquitin proteasome pathway may be targets for intervention in pancreatic cancer cachexia.

Aged↗

PubMedDate not supplied

[Pathogenesis of cachexia in malignant tumors].

The review of the literature covers major publications on the topic in 2000-2004. The role of acute phase reactions and hypermetabolism in cancer cachexia, problems of energy expenditure, influence of cancer wasting on adipose tissue and skeletal muscle as well as some therapeutic approaches delaying the development and progression of cancer cachexia are discussed.

Cachexia↗

PubMed2006

[Pathophysiology of neoplasic cachexia].

The regulation of food intake is mediated by different psicological, gastrointestinal metabolic, nutritional and endocrine mechanisms. The cancer patient suffers from anorexia which results in early saciety and a reduction of appetite. Sometimes, the causes of the anorectic response are derived from the antitumoral treatment (chemotherapy, radiotherapy or immunotherapy), in some cases vomiting resulting in altered food intake. Alterations in the food taste and smell perception in addition to psychological dearrangements might also lead to the anorexia. Sometimes the tumour may play a direct effect when it is localised in either the hypothalamus or the digestive apparatus. However, in the majority of cases the origin of the anorexia associated with cancer cachexia seems to be due to the metabolic alterations induced by tumour burden. Different factors of both humoral and tumoral origin play a role in cancer anorexia. For instance, tumour necrosis factor (TNF-), a cytokine responsible for a great part of the metabolic alterations characteristic of cancer cachexia seems to be involved. In conclusion, the cancer anorexia seems to be more an effect than the cause of the weight loss and in fact the decrease in food intake might take place after weight loss is evident. In any case, the malnutrition associated with a decrease of food intake worsens the cachectic state, favouring a kind of a positive feed-back mechanism that finally leads to the patient's death.

Cachexia↗

PubMed1991

Reversal of cancer cachexia in rats by cimaterol and supplemental nutrition.

The anabolic beta 2-agonist cimaterol was used in conjunction with supplemental nutrition to reverse cancer-induced cachexia and malnutrition in tumor-bearing rats. Cimaterol was administered to tumor-bearing rats receiving total parenteral nutrition or enteral nutrition for 10 days, beginning 2 weeks after subcutaneous transplantation of methylcholanthrene sarcoma. A significant increase occurred in both muscle weight and muscle protein in animals receiving cimaterol in conjunction with either enteral or parenteral feeding, compared to food fed tumor-bearing animals. Muscle protein content was increased significantly by 16% in cimaterol-treated rats maintained on parenteral nutrition and by 11% in cimaterol-treated enterally fed rats compared with the respective tumor-bearing controls. Urinary concentrations of 3-methylhistidine, an estimation of muscle turnover or catabolism, were significantly reduced in both tumor-bearing groups treated with cimaterol compared to 3-methylhistidine levels of the untreated tumor-bearing groups. The anabolic effects of cimaterol were expressed in the presence of a large tumor burden resulting in reversal of muscle depletion and muscle breakdown regardless of the route of supplemental nutrition. Thus, beta 2-agonists may be considered as a possible therapy for cancer cachexia.

Adrenergic beta-Agonists↗