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PubMed2004

Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients.

Leptin is a hormone involved in the regulation of body weight and sexual maturation. We previously reported that cancer cachexia was associated with reduced or normal levels of leptin. Here we investigate whether leptin levels are related to cachetic or hormonal status. Circulating leptin and its mRNA from adipose tissue were measured in 87 patients with gynaecological and breast cancers and related to tumour, cachexia and hormonal markers. We found that leptin protein increased in patients with these tumours due to higher mRNA levels. In patients with ovarian cancer, the increased leptin levels were associated with higher circulating follicle-stimulating hormone (FSH). The higher leptin concentrations in patients with endometrial and portio tumours were related to an increase in tissue estrogen receptor (ER) and progesterone receptor (PGR) and, only in the postmenopause, to an increase in circulating estradiol. Patients with breast cancer showed enhanced blood plasma concentrations of progesterone and estradiol, and enhanced tissue levels of ER and PGR associated with increased leptin levels. The data from the present study indicate that, in gynaecological and breast cancers, leptin is related to hormonal status but not to cachexia. We suggest that leptin stimulates the production of sexual hormones, important risk factors for these tumours, and we propose leptin as a novel prognostic marker.

Adipocytes↗
PubMedDate not supplied

Effect of n-3 fatty acids on the antitumour effects of cytotoxic drugs.

BACKGROUND: n-3 fatty acids are increasingly being administered to cancer patients for the treatment of cachexia, and it is thus important to know of any potential interactions with ongoing cytotoxic drug therapy. MATERIALS AND METHODS: For this reason eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were administered to mice bearing the cachexia-inducing MAC16 colon adenocarcinoma, and the effect of epothilone, gemcitabine, 5-fluorouracil and cyclophosphamide on tumour growth and body weight determined. RESULTS: Epothilone alone had a minimal effect on tumour growth rate, but this was potentiated by DH4, while for 5-fluorouracil and cyclophosphamide tumour growth inhibition was enhanced by EPA. The antitumour effect of gemcitabine was not altered by either fatty acid. EPA arrested the development of cachexia, while DHA had no effect and the same was true for their effect on tumour growth rate. The anticachectic effect of EPA was only seen in combination with 5-fluorouracil. CONCLUSION: These results suggest that n-3 fatty acids do not interfere with the action of chemotherapy and may potentiate the effect of certain agents.

Adenocarcinoma↗
PubMed2005

Systemic effects of cancer: role of multiple proteases and their toxic peptide products.

Cachexia, or the loss of skeletal muscle, adipose tissue and immunological competence, is a common systemic condition in advanced cases of cancer, and is a frequent cause of death. There have been many reports that small peptides isolated from tumors induce systemic effects correlated with cachexia upon injection into mice or addition to cell cultures. Only recently has evidence been presented for the origin of these peptides from the large increase in proteolytic enzymes found in tumors. Additional evidence is presented here for a major role of tumor peptides in producing effects associated with cachexia. Such peptides of low molecular weight were found to produce lipolysis in adipose tissue. Fibrinogen degradation products from the plasma of cancer patients and other chronic diseases suppress activation of the immune response. Some proteases of the cathepsin class occur in high concentration at the surface of transformed cells where the pH is low enough to allow digestion of pericellular proteins; other cathepsins elevated in tumors are highly active at physiological pH. Cathepsin L is the major excreted protein of cultured cells transformed by viruses or chemicals and is likely to form toxic peptides by digestion of extracellular proteins. Even normal liver and skeletal muscle of some cancer patients and tumor-bearing animals exhibit significant increases in cathepsins and components of the ubiquitin-proteasesome pathway which would add to circulating peptides. These observations argue for a central role of multiple proteases and their proteolytic products in producing the debilitating systemic effects of cancer.

Adipose Tissue↗
PubMed2006

[Treatment with nutrition and fluids in patients with non-curable cancer].

Patients with non-curable cancer represent a large and heterogeneous group in which malnutrition and weight loss is a frequent finding. This article is based on relevant literature and our own clinical experience. For every patient a thorough examination of possible underlying causes should be explored and corrected as soon as possible (secondary cachexia). However, in many patients primary cachexia is the cause, a catabolic condition where muscle protein and lipids are degraded and even aggressive nutrition will not reverse the process. This condition is very different from starvation. Metoclopramide, corticosteroids and gestagens can relieve symptoms as anorexia, chronic nausea and asthenia which frequently occur in patients with cachexia. Treatments that may maintain or increase muscle function and modulate inflammatory processes are new approaches, such as eicosapentaneoic acid, adenosine triphosphate, specific amino acids and nonsteroidal antiinflammatory drugs. Nutrition is an integrated part of supportive therapy to all cancer patients, unless expected survival is short. At this time in life, nutrition will not influence survival and focus should be on symptom control.

Cachexia↗
PubMed1984

Glucose metabolism in cachectic patients with colorectal cancer.

We have studied a defined group of 12 weight-losing patients with metastatic colorectal cancer to evaluate the occurrence of and possible relationship between those determinants of carbohydrate metabolism which have been reported to occur commonly in cancer cachexia. The rates of endogenous glucose production and recycling via lactate (Cori cycle) were measured following an infusion of 50 to 100 microCi of [1-14C]glucose. Compared to an age-related group of control subjects without cancer, significantly elevated rates of glucose production [136.4 +/- 9.0 (S.E.) versus 101.0 +/- 4.6 mg/kg/hr; p less than 0.01] and recycling (43.0 +/- 7.2 versus 15.4 mg/kg/hr; p less than 0.01) were observed. Values for glucose production and recycling ranged from normal to markedly elevated. Glucose tolerance was then determined following a p.o. glucose load of 40 g/sq m in 10 of the 12 patients. Compared to control subjects, all showed a significantly delayed clearance of glucose (p less than 0.01) and a blunted insulin-secretory responsiveness (p less than 0.025). Increased glucose production and recycling was only observed in the presence of carbohydrate intolerance, but the latter occurred in a manner which seemed independent of the rate of glucose turnover. In order to obtain an estimate of hepatic glycogen reserves, glucagon, 15 ng/kg/min, was infused over 40 min in seven subjects. A significantly blunted glycemic response was observed in the cancer patients compared to controls (delta 25.0 +/- 6.9 versus 57.8 +/- 8.5 mg/dl; p less than 0.025). Neither the rate of glucose production nor the glycemic response to glucagon appeared to correlate with the immediate antecedent caloric intake. An apparent relationship was observed, however, between increased glucose production and recycling and a lack of response to infused glucagon, probably reflecting decreased glycogen stores in the face of an increased glucose requirement by the patient. We have shown that diverse abnormalities of carbohydrate metabolism commonly occur in cancer cachexia and that significant metabolic heterogeneity may be expected, despite a uniform diagnosis. These results should prove useful in the interpretation and development of clinical studies on cancer cachexia.

Adenocarcinoma↗
PubMed1981

Serum sialyltransferase and liver catalase activity in cachectic nude mice bearing a human malignant melanoma.

Cachexia is rare in nude mice bearing human malignant tumors even when the transplanted tumors become as large as the body size of the host. In our series on heterotransplantation of a variety of human malignant tumors into nude mice, a malignant melanoma (SEKI) was found to induce severe body weight loss in the host at the early stage of transplantation. There was no electrolyte disturbance, hyper- or hypoadrenocorticism, hyperthyroidism, or destruction of cells of vital organs to account for the weight loss. Moreover, no evidence was obtained for concomitant infection with bacteria, Mycoplasma or fungi. These cachectic mice revealed remarkably increased levels of serum sialyltransferase and decreased liver catalase activity. The removal of tumor tissues from these mice resulted in prompt recovery of body weight, serum sialyltransferase, and liver catalase activity within 1 to 2 weeks. On the basis of the results obtained, the SEKI melanoma was thought to have produced a pathophysiological state in host nude mice which was very similar to that of cachexia in cancer patients. Nude mice bearing transplants of SEKI melanoma may provide a useful system for the study of cancer cachexia in humans.

Animals↗
PubMed1995

[Diet therapy in cancer].

Cancer cachexia is a syndrome with weight loss, anorexia, and loss of host body cell mass. Tumor cachexia may be an early symptom of a neoplasm. Low food intake is the main reason for weight loss. Surgery, chemotherapy and radiation remain primary therapeutic modalities to overcome cancer cachexia. Artificial nutrition is able to avoid progressive weight loss; nutrition alone may not preserve fat-free body cell mass. Parenteral nutrition reduces perioperative morbidity and mortality. Nutritional support failed to show a benefit in patients with malignancies which are treated with therapeutic radiation or chemotherapy. For patients with unresectable neoplasms of the upper GI-tract conventional palliative regimens (bougienage, laser, etc.) do not support a satisfactory nutritional state. Ambulatory enteral tube feeding via percutaneous endoscopic gastrotomy (PEG) as an adjunct to therapy is useful and safe in providing adequate fluid and substrates.

Cachexia↗
PubMed1997

[Inhibitive effect of umbellatus polyporus polysaccharide on cachexic manifestation induced by toxohormone-L in rats].

OBJECTIVE: To investigate the effect of treatment of cachexia with Umbellatus Polyporus Polysaccharide (UPP). METHODS: UPP was used to treat cachexia induced by toxohormone-L. RESULTS: Toxohormone-L from ascites fluid with primary hepatoma could induce lipolysis in vitro significantly, inhibit the intake behavior, decrease the level of blood zinc, increase that of blood copper (P < 0.01), upp could inhibit these effects. CONCLUSION: Toxohormone-L was closely related with neoplastic cachexia and UPP could inhibit this effect induced by toxohormone-L significantly.

Animals↗
PubMed1987

Physiological responses to cachectin.

Mammals infected with parasitic, bacterial or viral organisms or bearing tumours characteristically display a catabolic state and weight loss which can advance to cachexia (or wasting), shock and death. Although the phenomenon is commonly observed in many parasitic diseases its mechanism is not understood. We have identified and isolated a macrophage protein, cachectin, as the molecule that may be responsible for cachexia and shock. Cachectin is produced by macrophages in response to endotoxin or a number of other bacterial or protozoal products. The released cachectin acts as a hormone, binding to specific high affinity receptors and eliciting biological responses. In the adipocyte anabolic enzymes such as lipoprotein lipase are suppressed through the selective inhibition of mRNA production. An intriguing aspect of cachectin is its pivotal role in the pathogenesis of endotoxin-induced shock. Cachectin causes fever and anorexia and can induce lethal shock and tissue injury in experimental animals. During its chemical characterization cachectin was shown to be identical to tumour necrosis factor (TNF), a macrophage protein that kills tumour cells. This finding emphasizes the extensive range of effects associated with this protein. Cachectin has many properties in common with interleukin 1 but binds to a different receptor and lacks structural homology. Presumably, low levels of cachectin help the host in its battle to remove invasive pathogens, but extensive production of cachectin can lead to shock and catabolic stress hormone responses. These findings have added a new dimension to the biological properties of cachectin, its production, and its role in cachexia and shock.

Animals↗
PubMed2004

Reduction of tumor progression and paraneoplastic syndrome development in murine lung adenocarcinoma by nonsteroidal antiinflammatory drugs.

Mice bearing LP07 lung adenocarcinoma show some characteristics that are similar to those present in patients with NSCLC. LP07 tumor-bearing mice develop the paraneoplastic syndromes of cachexia, leukocytosis and hypercalcemia. These symptoms may be partly due to a systemic inflammatory response. Our aim was to determine if treatment with NSAIDs would lower tumor and metastasis growth and their accompanying syndromes. The nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor celecoxib reduced tumor growth and metastasis outcome in s.c. LP07 tumor-bearing mice. Both drugs also inhibited the development of leukocytosis and the weight loss associated with LP07 progression. Serum levels of the inflammatory cytokines IL-1beta and IL-6, mediators of cachexia, were modulated by NSAIDs. Inhibition of in vitro migration and invasion and reduction in angiogenesis were attained when cells were treated with either indomethacin or celecoxib. MMP-9 activity was also reduced in conditioned media from LP07 cells treated with celecoxib. These data suggest that several processes implicated in tumor progression can be modulated with NSAID treatment. Improvement in performance status through modulation of cachexia may offer a possibility for combining anti-inflammatory treatments with more aggressive therapies.

Adenocarcinoma↗
PubMed1995

CNTF or (-)-deprenyl in immature rats: survival of axotomized facial motoneurons and weight loss.

The application of ciliary neurotrophic factor (CNTF) to the cut ends of transected facial nerves in newborn rats has been reported to reduce the death of facial motoneurons (FMns) axotomized by the transection. Systemically delivered CNTF has been found to cause cachexia in adult mice. We compared the influence of dosage of CNTF and (-)-deprenyl on FMn death, weight loss, and animal survival in rat pups that underwent facial nerve transection at the 14th postnatal day (P14). CNTF was administered by osmotic mini-pumps connected to tubing ending either intrathecally or extrathecally near the craniocervical junction. CNTF caused weight loss and animal death that was similar to the cachexia reported in mice if administered in amounts of 1.1 microgram/day or greater. At the same doses, intrathecal CNTF was more effective than extrathecal CNTF in inducing the cachexia. (-)-Deprenyl did not alter animal survival or weight gain, even at high doses (10 mg/kg every 2 days). Intrathecal CNTF and intraperitoneal (-)-deprenyl, but not extrathecal CNTF, significantly increased the survival of the axotomized FMns. (-)-Deprenyl administered twice daily at 0.01 mg/kg was considerably more effective than CNTF in increasing FMn survival due to the limitation on CNTF dosage caused by the animal death.

Animals↗
PubMed1996

Stimulation of decreased lipoprotein lipase activity in the tumor-bearing state by the antihyperlipidemic drug bezafibrate.

The activity of lipoprotein lipase (LPL), a key regulatory enzyme for triglyceride (TG) clearance from plasma, is reported to decrease as the tumor burden increases in tumor-bearing animals and patients with lung cancer; therefore, it is believed to play a key role in inducing cancer cachexia. We attempted to reverse cancer cachexia by stimulating LPL activity with an antihypertriglyceridemic drug, bezafibrate. Bezafibrate, which reduces circulating TG levels by stimulating tissue LPL activity, has been used clinically in patients with hypertriglyceridemia. Bezafibrate was administered subcutaneously to 24 rats at a dose of 30 mg/kg per day from the 8th day after tumor inoculation with methylcholanthrene-induced sarcoma until they were killed on either the 25th or 33rd day, at the precachectic and cachectic stages, respectively. The animals were divided into the following three groups: treated tumor-bearing rats (treated TBR group), untreated TBRs (untreated TBR group), and a control (CTR) group. LPL activities in both the adipose tissue and cardiac muscle were measured by the method of Nilsson-Ehle and Schotz. Both TG and nonesterified fatty acid (NEFA) became elevated as the size of the tumor increased in the TBRs; however, this increment was quantitatively less in the treated TBR group than in the untreated TBR group. The administration of bezafibrate resulted in preservation of the epididymal fat pad mass at the cachectic stage. A significant decrease in LPL activity in the epididymal fat was observed in the untreated TBR group at the cachectic stage, but this was prevented in the treated TBR group, the values being 2.97 +/- 1.37 U/whole tissue in the untreated TBR group, 4.03 +/- 1.11 in the treated TBR group, and 10.15 +/- 6.61 in the CTR group. Thus, tumor growth in the treated TBR group at the cachectic stage was significantly suppressed compared with that of the untreated TBR group. These results suggest that the decreased LPL activity that occurs in the tumor-bearing state can be stimulated by the antihyperlipidemic drug bezafibrate, which may modulate some of the tumor-bearing state can be stimulated by the antihyperlipidemic drug bezafibrate, which may modulate some of the tumor-induced metabolic alterations leading to cancer cachexia.

Animals↗
PubMed1988

Resting energy expenditure in lung and colon cancer.

Elevated resting energy expenditure (REE) is a possible mechanism of cancer cachexia. We measured REE by whole-body direct calorimetry in patients with colon and non-small cell lung cancer and compared the results with REE in groups of healthy subjects and in patients with anorexia nervosa, with nonmalignant gastrointestinal (GI) disease, with miscellaneous reasons for weight loss, and with chronic lung disease. The mean REE of the cancer patients was not different from healthy subjects, those with GI disease, miscellaneous causes of cachexia, and chronic lung disease, and there was no significant difference in REE between those cancer patients with weight loss and controls with weight loss, except for the anorexia nervosa patients. The REE of the anorexia nervosa patients (female) was significantly lower than the REE of females with lung cancer. Weight loss correlated with REE in female lung cancer patients. Serial comparison of REE of ten cancer patients who lost 5% to 18% of their body weight during study showed no consistent change in REE. We conclude that patients with colon and non-small cell lung cancer, including those with weight loss, have REE similar to normal controls. Relative hypermetabolism may contribute to cancer cachexia, as may absolute hypermetabolism in some subsets of cancer patients.

Anorexia Nervosa↗
PubMed2005

Lifelong exposure to dietary fish oil alters macrophage responses in Walker 256 tumor-bearing rats.

Supplementation of the diet with fish oil (FO) decreases growth of the Walker 256 tumor and decreases the cachexia associated with tumor-bearing. The mechanisms by which FO inhibits tumor growth and cachexia are unknown. Macrophages are very important in host defence against tumors since they produce several anti-tumor agents which in turn have been shown to be modified by dietary FO, but rarely in the setting of tumor bearing and never in relation to lifelong exposure. In this study, we compared the effects of supplementation of the diet of pregnant and lactating rats and subsequent supplementation of the offspring with coconut fat or FO on macrophage activities involved in anti-tumor defence. FO supplementation was able to induce an increase in phagocytosis, in O2-, H2O2, nitric oxide, and TNF-alpha production by macrophages and in lysosomal volume in non-tumor-bearing rats. However, phagocytosis, production of O2- and H2O2 and lysosomal volume were not affected by the FO diet when rats were bearing tumors, although nitric oxide production was higher in these animals. It appears that tumor bearing activates the innate immune system and that dietary FO has little effect on innate immunity in the presence of Walker 256 tumors. Thus, it is still unclear how FO decreases the growth of Walker 256 tumors and the associated cachexia.

Aging↗
PubMed1997

Anorexia, weight loss and increased plasma interleukin-6 caused by chronic intracerebroventricular infusion of interleukin-1beta in the rat.

Pro-inflammatory cytokines produced in the central nervous system (CNS) have been suggested to have a role in the anorexia and cachexia of disease. In the present study, the effects of chronic exposure of the CNS to interleukin-1beta (IL-1beta) on several indicators of cachexia were studied. Rats were prepared with an intracerebroventricular (i.c.v.) cannula and an osmotic minipump that delivered vehicle or 1.56 ng/h recombinant murine IL-1beta for 4 days. Food intake and body weight were determined daily during the 4-day infusion period and plasma IL-6 and corticosterone concentrations were determined from plasma collected postinfusion. Chronic i.c.v. infusion of IL-1beta resulted in a chronic reduction in food intake. Rats infused i.c.v. with IL-1beta ate less food each day compared to vehicle controls and, at the end of the 4-day infusion period, consumed an average of 17.2 g less. Intracerebroventricular infusion of IL-1beta also caused an immediate and substantial loss of body weight that was sustained throughout the infusion period. In addition, rats infused with IL-1beta had plasma levels of IL-6 double those of vehicle controls (401 pg/ml vs. 185 pg/ml). Plasma corticosterone concentrations were similar between treatments. These results suggest that chronic exposure of the CNS to cytokines such as IL-1beta may be sufficient to induce anorexia and cachexia.

Animals↗
PubMed2002

Chronic heart failure and skeletal muscle catabolism: effects of exercise training.

Although the clinical picture of cardiac cachexia is well-known in patients with advanced chronic heart failure (CHF) the factors that determine who is at risk for this progressive catabolic syndrome and who is not remain unclear. Different endocrine systems have been accused of being involved in this process: an imbalance between catabolic and anabolic steroids with an elevated cortisol/dihydroepiandrosterone ratio, an increased resting metabolic rate due to high levels of circulating catecholamines, various cytokines are activated in CHF (i.e. TNF-alpha, IL-6, IL-1beta and others), and elevated levels of growth hormone (GH) with inappropriately normal or low serum levels of insulin-like growth factor-I (IGF-I) have been described in cardiac cachexia. These catabolic factors contribute to peripheral muscle atrophy, augment the expression of the inducible nitric oxide synthase (iNOS), which in turn inhibits the aerobic cellular metabolism. The present review examines whether the catabolic factors can be influenced by a classical anabolic intervention: regular physical exercise training. Long-term training programs increase skeletal muscle cytochrome c oxidase activity and are associated with reduced local expression of pro-inflammatory cytokines as well as iNOS, and augment local IGF-I production. In concert, these beneficial effects of exercise training may help to retard the catabolic process in CHF finally leading to cardiac cachexia and death.

Chronic Disease↗
PubMed1998

Tumor growth and food intake in interleukin-6 gene knock-out mice.

Interleukin (IL)-6 has potential antitumor activity and at the same time is responsible for tumor-derived cachexia. Using IL-6 gene knock-out (GKO) mice, we investigated the effect of IL-6 deficiency on the survival time, tumor growth and daily food intake of mice inoculated with Ehrlich ascites carcinoma. IL-6 GKO mice gained weight due to tumor growth more rapidly than the wild-type mice. The daily food intake of wild-type mice declined on day 2 after tumor inoculation and was only 37% on day 8. In contrast, the daily food intake of IL-6 GKO mice was constant for the first 7 days after tumor inoculation. Although wild-type mice suffered from cachexia, their survival time was significantly longer than that of IL-6 GKO mice. We propose that both IL-6 secretion and cancer cachexia syndrome may be involved in the defense mechanism against tumor progression.

Animals↗
PubMed1996

Novel anti-tumour activity of 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4- benzoquinone (CV-6504) against established murine adenocarcinomas (MAC).

2,3,5-Trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase and thromboxane A2 synthase and a scavenger of active oxygen species, has been shown to exhibit profound anti-tumour activity against three established murine adenocarcinomas (MACs) that are generally refractory to standard cytotoxic agents. For the cachexia-inducing MAC16 tumour, optimal anti-tumour activity was seen at dose levels of 10 and 25 mg kg-1 day-1, together with a reversal of cachexia and a doubling of the time to sacrifice of the animals through cachexia from 8 days to 17 days. The remaining tumour fragments showed extensive necrosis in regions distal from the blood supply. Growth of the MAC13 tumour was also effectively suppressed at dose levels between 5 and 50 mg kg-1 day-1, resulting in a specific growth delay between 1.0 and 1.2. Growth of the MAC26 tumour was also inhibited a concentration-related manner, with doses of 25-50 mg kg-1 day-1 being optimal. Anti-tumour activity towards all three tumours at low dose levels of CV-6504 was effectively suppressed by concurrent administration of linoleic acid (1 g kg-1 day-1), suggesting that inhibition of linoleate metabolism was responsible for the anti-tumour effect. Tumour sensitivity may be correlated with increased DT-diaphorase that are required to metabolise CV-6504 to the active hydroquinone, which inhibits 5-lipoxygenase activity.

Adenocarcinoma↗