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PubMed1995

Muscle wasting associated with cancer cachexia is linked to an important activation of the ATP-dependent ubiquitin-mediated proteolysis.

Rats bearing the Yoshida AH-130 ascites hepatoma for 7 days showed an important decrease in muscle mass--over 30% in gastrocnemius and extensor digitorum longus (EDL)--in relation to non-tumour-bearing controls, which is associated with an increased proteolytic rate in in vitro incubation. In order to identify the precise biochemical process which was involved, we measured different proteolytic systems in incubated EDL muscles. The capacity for intralysosomal proteolysis, as measured by sensitivity to methylamine, was not increased in tumour-bearing rats, suggesting that the mechanism involved in the increased proteolytic rate was extralysosomal. Incubations using the Ca2+ ionophore A23187 revealed no change in the activity of calcium-dependent proteases as a consequence of tumour growth. Finally, muscle incubation in an ATP-depleted medium allowed us to conclude that energy-dependent proteases were involved in the activation of muscle proteolysis in tumour-bearing rats. In particular, the ubiquitin-dependent proteolytic system is involved, since there is an important increase in ubiquitin conjugates in the skeletal muscle of tumour-bearing rats. It may thus be suggested that extralysosomal ATP- and ubiquitin-dependent proteases underlie the biochemical mechanism of muscle wastage associated with cancer cachexia.

Adenosine Triphosphate↗

PubMed1994

Diminished visceral adipose tissue in cancer cachexia.

To estimate the relationship between the visceral adipose tissue (AT) area and cancer cachexia, 13 cachectic patients (7 males, 6 females; age 65.2 +/- 11.0 years; body mass index 20.8 +/- 4.1 kg/m2) were examined by computed tomography (CT) scanning. Cachectic cancer patients who had a 10% decrease of body weight and died within 6 months because of gastrointestinal carcinoma had a significantly smaller visceral AT area than control subjects (mean +/- sd: 43.9 +/- 42.2 cm2 vs. 93.4 +/- 56.0 cm2, P < 0.05, P = 0.014). Otherwise, there were no significant differences between the visceral AT areas of cachectic cancer patients and those of cancer patients with resectable tumors treated by curative operation (mean +/- sd: 68.8 +/- 57.7 cm2) (NS, P = 0.206). There was, however, a tendency for cachectic cancer patients to have a smaller visceral AT area than those with resectable tumors. This result suggests that the visceral AT area is not preserved in the cachectic state associated with cancer.

Adipose Tissue↗

PubMed2006

Mass-dependent decline of skeletal muscle function in cancer cachexia.

CD2F1 mice were inoculated with C26 adenocarcinoma cells, followed by assessment of ex vivo muscular function. Muscles from tumor-bearing mice had a significantly lower force output during a single maximal contraction and during repeated contractions than control muscles. The relative force output, however, did not differ when corrected for muscle mass. Thus, cachexia significantly reduces absolute skeletal muscle function, but muscle "quality" appears unaltered.

Adenocarcinoma↗

PubMed1997

Mechanism of depletion of liver glycogen in cancer cachexia.

Mice transplanted with a cachexia-inducing colonic adenocarcinoma (MAC16) show a progressive decrease in liver glycogen in direct proportion to the loss of body weight. Such tumours elaborate a lipid mobilizing factor (LMF), which produces a dose-dependent stimulation, not only of adipocyte adenylate cyclase, but also of hepatocyte adenylate cyclase in a GTP-dependent manner. These results suggest that LMF has the capacity to initiate hepatic glycogenolysis through an increase in cyclic AMP.

Adenocarcinoma↗

PubMed2002

Molecular regulation of muscle cachexia: it may be more than the proteasome.

Muscle cachexia induced by sepsis, severe injury, cancer, and a number of other catabolic conditions is mainly caused by increased protein degradation, in particular breakdown of myofibrillar proteins. Ubiquitin-proteasome-dependent proteolysis is the predominant mechanism of muscle protein loss in these conditions, but there is evidence that several other regulatory mechanisms may be important as well. Some of those mechanisms are reviewed in this article and they include pre-, para-, and postproteasomal mechanisms. Among preproteasomal mechanisms, mediators, receptor binding, signaling pathways, activation of transcription factors, and modification of proteins are important. Several paraproteasomal mechanisms may influence the trafficking of ubiquitinated proteins and their interaction with the proteasome, including the expression and activity of the COP9 signalosome, the carboxy terminus of heat shock protein 70-interacting protein (CHIP) and valosin-containing protein (VCP). Finally, because the proteasome does not degrade proteins completely into free amino acids but into peptides, postproteasomal degradation of peptides by the giant protease tripeptidyl peptidase II (TPP II) and various aminopeptidases is important in muscle catabolism. Thus, multiple mechanisms and regulatory steps may influence the breakdown of ubiquitinated muscle proteins by the 26S proteasome.

Adenosine Triphosphatases↗

PubMed1993

Prevention of runting and cachexia by a chimeric TNF receptor-Fc protein.

Tumor necrosis factor alpha (TNF) is an important mediator of septic shock and cachexia. A soluble form of the human type 2 TNF receptor, constructed by joining the Fc region of human IgG1 to the TNF receptor, prevents weight loss in nude mice bearing a TNF-secreting tumor. This soluble receptor was also used to treat TNF transgenic mice which were runting and died before reaching reproductive age. After continuous treatment with soluble TNF receptor, the TNF transgenic mice grew to normal size and reproduced. Thus, soluble TNF may be useful in counteracting the detrimental systemic effects of TNF in a clinical setting.

Animals↗

PubMed1976

[Biochemical investigations of cancer cachexia. II. Depletion of glycogenolysis and stimulation of gluconeogenesis in Walker carcinoma 256 bearing rats (author's transl)].

150-200 g heavy, Walker-carcinoma bearing, male Sprague-Dawley-rats showed rapid, tumour weight dependent, loss of liver glycogen until complete depletion in tumour groups heavier than 40 g/animal. Simultaneously the glycogen mobilization after massive glucagon stimulation, was successivly diminished and finally abolished in different groups with increasing tumor weight. Concomitantly the spontaneous and stimulated activity of liver phosphorylase a was found markedly reduced in advanced tumour cachexia, the extent of stimulation of liver phosphorylase a activity by intracardial injections of epinephrine not being altered. Tumour induced inhibition of glycogen mobilization thus appears to have been excluded. To account for the relative late pronounced hypoglycemia in peripherial rat blood in face of the early loss of liver glycogen, accelerated gluconeogenesis has been postulated. In accord with this spontaneous rise in liver tyrosine amino transferase was found in tumour bearing rats along with a doubled maximal stimulation value after medrol injection as compared to control groups. This behavior could not be shown for liver alanine aminotransferase and liver fructose 1,6-di-phosphatase. The former showed no differences between control and tumour groups neither of spontaneous nor of stimulated activity. The latter showed only a very reluctant rise after massive stimulation by triamcinolone for 3 days in the control groups, the tumour bearing groups showing no deviation from spontaneous control values.

Alanine Transaminase↗

PubMed1981

Sympathetic activation of brown-adipose-tissue thermogenesis in cachexia.

Tumour-bearing mice spontaneously lose weight 8-9 weeks after implantation of a human hypernephroma, in spite of a normal food intake. Resting oxygen consumption was up to 40% higher in these animals than in sham-operated controls, but was significantly reduced by beta-adrenergic blockade with propranolol in the former group. The injection of noradrenaline caused a marked stimulation of the metabolic rate in all the animals, but the greatest response was seen in the cachectic mice. The brown-adipose-tissue mass was similar for both groups, but guanosine diphosphate binding to brown-adipose-tissue mitochondria (an index of thermogenic capacity) was significantly increased in tumor-bearing mice, and the injection of noradrenaline 1 h prior to sacrifice caused the greatest stimulation of binding in the cachectic group. These data suggest that the rapid weight loss of tumor-bearing animals may be due to a high metabolic rate which results from sympathetic stimulation of brown-adipose-tissue metabolism. The relevance of these results to cancer-induced cachexia in man is discussed.

Adipose Tissue, Brown↗

PubMed1996

Macrophage-derived tumor necrosis factor and tumor-derived of leukemia inhibitory factor and interleukin-6: possible cellular mechanisms of cancer cachexia.

BACKGROUND: The cellular basis for augmented cytokine production in the tumor-bearing host is not known. Recently leukemia inhibitory factor (LIF) and interleukin (IL)-6, produced by a variety of tumors, have been implicated as mediators of cachexia. METHODS: Five murine tumor cell lines were tested for the production of these cytokines. 4JK tumor was further tested to determine if IL-1, tumor necrosis factor (TNF), or cocultivation with RAW 264 cells augmented IL-6 or LIF production. RESULTS: 4JK from in vivo tumors produced significantly more IL-6 than did 4JK from culture, indicating that tumor production of IL-6 and LIF is potentially augmented by infiltrating macrophages. When 4JK was cocultured with RAW 264 cells, TNF, or IL-1 in vitro, a three- to 15-fold increase in tumor production of LIF and IL-6 was noted (p2 < or = 0.03). Conversely, in coculture experiments performed with a neutralizing TNF antibody, a 50% reduction in tumor production of LIF ad IL-6 was noted (p2 < 0.04). Resting RAW cells produced only minimal quantities of TNF; however, when RAW cells were exposed to tumor-conditioned supernatant from 4JK, their TNF production was markedly increased. CONCLUSIONS: In the tumor microenvironment, host macrophages may be activated and produce inflammatory cytokines such as TNF. Local TNF then appears to act on tumor cells to stimulate production of IL-6 and LIF. Enhanced tumor production of cytokine mediators may contribute to deleterious effects of neoplastic growth on the host.

Animals↗

PubMed1994

Effect of fish oil on cancer cachexia and host liver metabolism in rats with prostate tumors.

The aim of this study was to investigate whether tumor-induced cachexia and aberrations in host liver metabolism, induced by the MAT-LyLu variant of the Dunning prostate tumor, could be prevented by omega 3 fatty acids from fish oil. On day 0, adult Copenhagen-Fisher rats fed normal chow ad libitum were inoculated with 10(6) MAT-LyLu cells (n = 14) or saline (n = 9). On day 7, when tumors were palpable, four tumor-bearing (TB) and four nontumor-bearing (NTB) rats were put on isocaloric diets with 50% of total energy as fish oil. The introduction of fish oil-enriched diets caused a reduction in energy intake to less than half of the energy intake by animals fed normal diets during days 7-14 (difference by dietary group: NTB, P < 0.001; TB, P < 0.001). During days 14-21, energy intake in fish oil-fed animals returned to approximately 75% of energy intake by animals fed normal diets (difference by dietary group: NTB, P < 0.003; TB, P = 0.001). Carcass weight of animals on day 21, when the study was terminated, was significantly related to initial weight (P = 0.05) and mean food intake during the study (P = 0.01). When data were adjusted for these variables using analysis of covariance, with NTB animals on normal diets being the reference group, significant loss of carcass weight was observed in TB animals on normal diets only (mean +/- SEM 58 +/- 10 g loss, P < 0.001), but not in TB animals on fish oil diets (8 +/- 18 g loss, P = 0.67).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Diabetic neuropathic cachexia.

A case of diabetic neuropathic cachexia is presented. This unusual syndrome within the broad group of diabetic neuropathies is characterized by extreme loss of body mass and severe neuropathic pain. The loss of body weight is unassociated with glycosuria or ketoacidosis. Initially, the patient may present a confusing picture suggestive of carcinomatous neuropathy.

Cachexia↗

PubMed1999

Pancreatic cancer as a model: inflammatory mediators, acute-phase response, and cancer cachexia.

Patients with pancreatic cancer frequently develop the syndrome of cancer cachexia. Pro-inflammatory cytokines have been strongly implicated in the pathogenesis of this syndrome. In patients with pancreatic cancer an acute-phase response (an index of pro-inflammatory cytokine activity) is associated with accelerated weight loss, hypermetabolism, anorexia, and a shortened duration of survival. However, little is known about the primary significance of the acute-phase response in terms of altered hepatic export protein synthesis rates and its potential impact on the body's nitrogen economy. In a recent series of studies on weight-losing pancreatic cancer patients with hypoalbuminemia we have demonstrated albumin synthesis to be unaltered whereas fibrinogen synthesis is increased two- to threefold compared with healthy controls. Because of the mismatch in amino acid composition between the body's main labile amino acid reserve (skeletal muscle) and that of acute-phase proteins, these results lend support to the concept that in pancreatic cancer the reprioritization of body protein metabolism during an acute-phase response may well be a significant factor in the loss of lean tissue in these patients.

Acute-Phase Proteins↗

PubMed1999

The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction.

AIMS/HYPOTHESIS: Although retinoid X receptor (RXR) and peroxisome proliferator activated receptor-gamma (PPARgamma) agonists have antidiabetic effects in hyperinsulinaemic animals, little information exists on their effects after pancreatic beta-cell failure. Thus, we examined if RXR and PPARgamma agonists alter distinct metabolic pathways in animals suffering from impaired insulin secretion. METHODS: Adverse side effects and antidiabetic responses were measured in db/db mice treated from 14-16 weeks of age with the RXR agonist, LG100268, and/or the PPARgamma agonists, BRL49653 or GW1929. RESULTS: In animals treated with LG100268 or BRL49653, serum glucose, glycohaemoglobin and the cardiovascular risk factor, fibrinogen, decreased to the same extent. Both of these agonists were equally effective at increasing insulin accumulation in beta cells, although neither agent had an effect on serum insulin concentrations. In contrast, the RXR agonist was less effective than the PPARgamma agonists at lowering serum triglycerides and non-esterified fatty acids and increasing interscapular brown fat and body weight. Further, LG100268 increased serum alkaline phosphatase and liver mass, hepatic fat accumulation, lauric acid hydroxylase activity, catalase-immunostaining and peroxisomal number more than the PPARgamma agonists. Moreover, co-treatment with the RXR and PPARgamma agonists reduced glucose, triglycerides, non-esterified fatty acids and cholesterol more than either agent alone. CONCLUSION/INTERPRETATION: These data suggest 1) RXR and PPARgamma agonists decrease islet degeneration, cardiovascular risk and cachexia during later stages of diabetes, 2) RXR agonists are less effective than PPARgamma agonists at decreasing serum lipids and causing weight gain and 3) RXR agonists have a more pronounced effect on liver metabolism (e.g. peroxisome accumulation and hepatomegaly) than PPARgamma agonists.

Animals↗

PubMed2005

Prospective evaluation of carboplatin AUC dosing in patients with a BMI>or=27 or cachexia.

When determining the carboplatin dosage from the Calvert formula, there are a lack of data when evaluating patients with cachexia or body mass index (BMI)>or=27. If the Cockcroft and Gault (C-G) creatinine clearance (CrCl) equation is utilized and substituted for glomerular filtration rate in the Calvert formula, the chance for inaccurate dosing occurs especially in these populations. Therefore, the purpose of this study is to evaluate and compare the target carboplatin area under the concentration (AUC) with the actual AUC achieved in cachectic or BMI>or=27 patients. In a prospective manner, we evaluated 19 patients with a BMI>or=27 and nine cachectic patients. In the C-G equation to determine creatinine clearance, the adjusted body weight was used for BMI>or=27 patients and serum creatinine value of 70.7 microM (0.8 mg/dl) for the cachectic patients. The carboplatin dose was calculated, administered to the patients, and subsequent carboplatin blood samples were obtained for pharmacokinetic determination. Once the AUC was determined, the results were compared with the expected outcomes from the modified C-G CrCl equation for the Calvert formula, Chatelut and Bénézet equations. The results demonstrated that the modified C-G CrCl equation for the Calvert formula had less bias and more precision than using actual weight in the C-G CrCl equation or using the Chatelut and Bénézet equations. Using the actual weight in overweight and especially obese patients and using a serum creatinine<70.7 microM in cachectic patients will lead to overestimation of the carboplatin clearance and thus AUC.

Adult↗

PubMed2004

Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model.

BACKGROUND: Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice. METHODS: Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1-11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated. RESULTS: Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss. CONCLUSION: Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.

Adenocarcinoma↗

PubMed2004

Nutrition intervention improves outcomes in patients with cancer cachexia receiving chemotherapy--a pilot study.

GOALS OF THE WORK: The aim of this study was to examine the effect of nutrition intervention on outcomes of dietary intake, body composition, nutritional status, functional capacity and quality of life in patients with cancer cachexia receiving chemotherapy. PATIENTS AND METHODS: Patients received weekly counselling by a dietitian and were advised to consume a protein- and energy-dense oral nutritional supplement with eicosapentaenoic acid for 8 weeks. The medical oncologist determined the chemotherapy protocol. Eight patients enrolled and seven completed the study. MAIN RESULTS: There were significant improvements in total protein intake (median change 0.3 g/kg per day, range -0.1 to 0.8 g/kg per day), total energy intake (median change 36 kJ/kg per day, range -2 to 82 kJ/kg per day), total fibre intake (median change 6.3 g/day, range -3.4 to 20.1 g/day), nutritional status (patient-generated subjective global assessment score, median change 9, range -5 to 17), Karnofsky performance status (median change 10, range 0-30) and quality of life (median change 16.7, range 0-33.3). There were clinically significant improvements in weight (median change 2.3 kg; range -2.7 to 4.5 kg) and lean body mass (median change 4.4 kg, range -4.4 to 4.7 kg), although these were not statistically significant. Change in nutritional status was significantly associated with change in quality of life, change in Karnofsky performance status and change in lean body mass. CONCLUSIONS: Nutrition intervention together with chemotherapy improved outcomes in patients with pancreatic and non-small-cell lung cancer over 8 weeks. Supplement intake does not inhibit meal intake.

Antineoplastic Agents↗

PubMed1998

Pharmacological treatment of cachexia: any progress?

In view of the renewed interest in pharmacological treatment of anorexia-cachexia in cancer patients over the past 3 years, both the established drugs used in its treatment and the emerging new drugs still being tested for it are reviewed. Results of trials that have already been evaluated are reported, and possible areas for further research are indicated.

Adrenal Cortex Hormones↗

PubMed1987

Preoperative insulin reverses cachexia and decreases mortality in tumor-bearing rats.

As a model of surgical stress in the cancer-bearing animal, we resected large flank sarcomas from cachectic rats under ether anesthesia and closed wounds primarily. The metabolic cost of tumor resection was measured using a long-term continuous indirect calorimeter. In the immediate postresection period energy balance decreased and host energy expenditure increased significantly (P less than 0.005). In animals with similar tumor weights, mortality following resection was determined by the degree of cachectic depletion. We then considered whether improvement of preoperative host nutritional status with insulin treatment might improve a subsequent surgical outcome. Insulin, when administered exogenously to cachectic tumor-bearing rats, has been shown to stimulate food intake and preserve host weight and does not stimulate tumor growth. When individual rats bearing a cachexia-producing flank sarcoma demonstrated a decline in food intake to less than 75% of predicted (approximately 25 days after tumor implantation), they were randomized to receive either daily injections of NPH insulin (2 units/100 g/day) for 5 days or no treatment for 5 days. Animals then underwent tumor resection and 14-day survival was measured. All resections were performed in an unbiased manner without the surgeon's knowledge of each rat's treatment status. In an experiment using 59 rats, insulin-treated rats had a threefold higher 5-day preoperative food intake and did not lose weight in the preoperative period, while untreated rats lost 17 g (P less than 0.001). Mortality in the insulin-treated group was 10% versus 28% in the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗