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PubMed1991

Interaction between dactinomycin and tumor necrosis factor in mesothelioma. Cachexia without oncolysis.

There is no effective therapy for human malignant mesothelioma, and its susceptibility to recombinant cytokines has not been studied extensively. Recombinant human tumor necrosis factor alpha (rHuTNF alpha) was evaluated for its in vitro and in vivo antitumor activity using a human malignant mesothelioma cell line [DeH128(m)], both in culture and heterotransplanted in nude mice. In vitro, rHuTNF alone had no direct antimesothelioma activity assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, but in combination with the transcription inhibitor, dactinomycin (AD), mesothelioma cell metabolic activity was inhibited (80% of control). The effects of this combination of agents were studied on DeH128(m) cells heterotransplanted as subcutaneous tumors in nude mice. In vivo there was no significant inhibition of tumor growth by combined rHuTNF alpha and AD therapy, but the combination produced marked cachexia in doses at which each component (rHuTNF alone or AD alone) was well tolerated. The authors conclude that the well-described in vitro interaction between AD and rHuTNF also operates in vivo to produce cachexia and that the combination of these two agents is likely to have a low therapeutic index in malignant mesothelioma.

Animals↗

PubMed1991

Inhibition of tumour-induced lipolysis in vitro and cachexia and tumour growth in vivo by eicosapentaenoic acid.

Stimulation of lipolysis in murine adipocytes in response to a lipid-mobilizing factor produced by a cachexia-inducing murine adenocarcinoma was inhibited by eicosapentaenoic acid (EPA) with a Ki value of 104 microM. The inhibitory effect was strictly structurally specific, since other related fatty acids of both the (n-3) and (n-6) series were ineffective as inhibitors of the lipolytic process. Induction of lipolysis by both salbutamol and ACTH was also inhibited by EPA, suggesting that the effect is exerted on a step central to the process of lipolysis. Lipolysis induced with the tumour lipid-mobilizing factor was associated with a prolonged elevation of the intracellular level of cyclic AMP in adipocytes, in contrast with ACTH and salbutamol. The elevation of adipocyte cyclic AMP in response to the tumour lipid-mobilizing factor and lipolytic hormones was inhibited by EPA. In vivo, administration of pure EPA to weight losing mice bearing the MAC16 adenocarcinoma completely prevented weight loss and tumour growth rate. In contrast both the other (n-3) fatty acid present in fish oil, docosahexaenoic acid (DHA), and linoleic acid were ineffective in inhibiting weight loss or the growth of the MAC16 tumour. This suggests that inhibition of tumour lipolytic activity accounts for the anticachectic effect of EPA, and that a correlation may exist between the inhibition of cachexia and the inhibition of tumour growth.

Adenocarcinoma↗

PubMed1992

Cancer cachexia is transmissible in plasma.

The cause of cancer cachexia is unclear. Tumors may be competing with the host for ingested nutrients or may be releasing some factor that actively inhibits energy utilization. To explore these questions, plasma was sterilely collected and pooled from 103 terminally cachectic Fischer 344 rats implanted with an experimental sarcoma. Control plasma was collected in similar fashion from 138 nontumor-bearing rats (NTBP). Plasma from tumor-bearing rats (TBP) or NTBP was continuously infused in a randomized, blinded fashion for 4 days into 20 normal rats. During infusion, food intake and nitrogen excretion were measured daily. At sacrifice, body weight and organ masses were determined. Rats receiving TBP demonstrated an immediate and profound anorexia compared with those receiving NTBP. Total food intake during treatment was 31.2 +/- 3.3 (g +/- SEM) in the TBP group versus 48.2 +/- 2.8 in the NTBP group (P less than 0.001 by t test). Likewise, the total decline in body weight was greater in the TBP group as compared with the NTBP group (-35.2 +/- 3.4 versus -14.6 +/- 4.0, P less than 0.001). Mean daily nitrogen balance during treatment was negative in the rats receiving TBP (-14.5 +/- 20.1 mg +/- SEM) while remaining highly positive in the rats receiving NTBP (110.7 +/- 19.3, P less than 0.002). Finally, cardiac and gastrocnemius muscle masses were decreased, while hepatic mass was unaffected. These data demonstrate that the syndrome of cancer-associated cachexia is transmissible in plasma and therefore may be mediated by a circulating molecule or molecules. Identification and purification of the molecule(s) responsible for this effect would have obvious clinical benefits.

Animals↗

PubMed1990

Effects of spontaneous physical exercise on experimental cancer anorexia and cachexia.

The aim of this study was to evaluate whether spontaneous physical exercise can modify cancer anorexia and cachexia in tumour-bearing rats. Two transplantable experimental tumours were evaluated. Tumour-bearing Wistar Furth rats fed ad libitum and with free access to a running wheel had a delayed onset of anorexia compared with their non-exercised tumour-bearing controls, retained normal behaviour and were able to run the same daily distance as non-tumour controls until the onset of cachexia. Exercise resulted in a decreased carcass wet weight and lipid stores but in an increased carcass dry weight in the tumour-bearing animals. Despite increased food intake, physical exercise resulted in a reduced final tumour weight without any change in water content. Skeletal and cardiac muscle tissue did not show any difference in water content but there was an increased RNA/protein quotient in the exercising tumour-bearing animals. Thus the deleterious alterations induced by the malignancy on tumour host metabolism are not inevitable but can be modified by spontaneous physical exercise.

Animals↗

PubMed1991

Anti-interferon-gamma antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia.

C57BL/6N mice bearing Lewis lung tumours were treated with anti-gamma-interferon (IFN-gamma) monoclonal antibodies. Early, but not late, treatment inhibited tumour growth, suggesting that endogenous IFN-gamma promotes initial tumour cell proliferation. Tumour development was associated with failure to gain weight or with progressive weight loss. Anti-IFN-gamma given early or late counteracted this wasting syndrome, which indicates that IFN-gamma production subsists during tumour growth and is directly or indirectly responsible for tumour-associated cachexia. Studies of body composition in cachectic mice revealed fat tissue to be particularly affected. Fat loss was enhanced by IFN-gamma and antagonised by anti-IFN-gamma. Tumour-bearing mice were also hypersensitive to the lethal effect of endotoxin; anti-IFN-gamma was unable to mitigate this sensitisation, suggesting that IFN-gamma does not exert its cachexia-inducing effect through augmentation of the host response to an endogenous endotoxin source.

Animals↗

PubMed1992

Tumour-associated hypoglycaemia in a murine cachexia model.

Animals bearing a cachexia-inducing tumour, the MAC16 adenocarcinoma, showed a progressive decrease in blood glucose levels with increasing weight loss, while animals bearing a histologically similar tumour, the MAC13 adenocarcinoma, showed no change in either body weight or blood glucose levels with growth of the tumour. The effect of the MAC16 tumour on blood glucose levels appeared to be unrelated to food intake, glucose consumption by the tumour, or to the production of increased levels of IGF-I and IGF-II mRNA by the tumour cells. The relationship between the induction of cachexia and alteration in blood glucose levels remains unknown.

Adenocarcinoma↗

PubMed1992

Cachexia and graft-vs.-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice.

Tumor necrosis factor alpha (TNF alpha) orchestrates a wide range of effects that combat severe infections in animals. At lower levels, TNF alpha plays an important protective role in stimulating chemotaxis and antimicrobial activity of neutrophils, macrophages, and eosinophils. During chronic illness, TNF alpha secretion can be elevated markedly, giving rise to cachexia, hemorrhage, necrosis and, ultimately, death. Although TNF alpha may mediate many of its effects through macrophages, 30% of TNF alpha injected into animals concentrates in the skin. In recent years, it has been shown that keratinocytes can be induced to synthesize TNF alpha. To explore the role of TNF alpha synthesis in keratinocytes, we used a keratin-14 (K14) promoter to target human TNF alpha expression in the epidermis and other stratified squamous epithelia of transgenic mice. Most mice expressing the K14-TNF alpha transgene stopped gaining weight within 1 week postbirth, and exhibited retarded hair growth. In the skin, adipose production was profoundly inhibited, whereas signs of fibrosis and immune infiltration were evident in the dermis. Over time, the epidermis exhibited an increased stratum corneum, as signs of necrosis began to appear in the skin. Within 3-5 weeks, the mice displayed features characteristic of cachexia and necrosis. Our results suggest that TNF alpha expression by keratinocytes not only plays a role in inflammatory and graft-versus-host-disease-like responses in the skin, but also in other tissues, apparently by virtue of stratified squamous epithelial-derived TNF alpha entering the bloodstream. Our results have enabled the first evaluation of many of the effects of TNF alpha in transgenic animals.

Animals↗

PubMed1992

HIV-related cachexia: potential mechanisms and treatment.

Involuntary weight loss or wasting indicative of severe protein energy malnutrition is a frequent complication of acquired immune deficiency syndrome (AIDS). Malnutrition, with its associated adverse effects on immunocompetence, may contribute to the progression of AIDS itself. Since death from wasting is ultimately related to the magnitude of tissue depletion, restoration of body cell mass may enhance survival. The mechanism of weight loss in AIDS has not been clearly elucidated. The etiology is likely to be multifactorial, the result of interactions between decreased caloric intake, malabsorption, and alterations in energy expenditure secondary to hormonal and/or metabolic abnormalities. Although weight loss is occasionally reversible with treatment of underlying infections and/or easily identifiable and reversible causes, the majority of patients are not this fortunate. Enteral and parenteral nutrition, which are expensive, cumbersome, and potentially morbid, have been suggested by some as therapeutic options. Megestrol acetate, a synthetic, orally active progestational agent, has been reported to stimulate appetite and weight gain. Data regarding the use of megestrol acetate for the treatment of cachexia related to human immunodeficiency virus (HIV) infection demonstrate convincingly its effectiveness in treating many patients with HIV-related anorexia and cachexia.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Occurrence of hypercalcemia and leukocytosis with cachexia in a human squamous cell carcinoma of the maxilla in athymic nude mice: a novel experimental model of three concomitant paraneoplastic syndromes.

Hypercalcemia and leukocytosis may occur in conjunction as paraneoplastic syndromes associated with malignant disease. Here we describe a human squamous cell carcinoma of the maxilla that was associated with hypercalcemia and leukocytosis, and also cachexia. The primary tumor was surgically removed and established in permanent cell culture. When either primary tumors or cultured tumor cells were inoculated into nude mice, the nude mice developed the same paraneoplastic syndromes as those which occurred in the patient from whom the tumor was originally derived. The plasma calcium was increased two and one-half-fold and the WBC count 30-fold, and the body weight was decreased by 45% in tumor-bearing animals. Each of these paraneoplastic syndromes was alleviated by surgical excision of the tumor, indicating that the paraneoplastic syndromes were due to a factor or factors produced by the primary tumor. The development of each of these paraneoplastic syndromes in nude mice correlated positively with the other two syndromes. We examined the organs of tumor-bearing mice and found striking histopathologic abnormalities in the bones, spleen, and liver, but no infiltration with tumor cells. The bones showed marked evidence of osteoclastic bone resorption. This model of a human tumor associated with the hypercalcemia-leukocytosis paraneoplastic syndrome, together with cachexia, should make it possible to determine the mechanisms responsible for these paraneoplastic syndromes and their relationship to each other.

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↗

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↗

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↗

PubMed1990

Anticachectic activity of 5'-deoxy-5-fluorouridine in a murine tumor cachexia model, colon 26 adenocarcinoma.

Murine colon 26 adenocarcinoma causes a progressive weight loss and physiological changes associated with cachexia when it grows to a certain size. By the use of this tumor model several types of cytostatics were examined for their ability to alleviate cachexia. Among them, 5'-deoxy-5-fluorouridine could reverse a progressive weight loss and improve hypoglycemia, hyperglucocorticism, and hepatic malfunctions, as well as inhibiting the tumor growth. Cyclophosphamide, nimustine, and 2'-deoxy-5-fluorouridine were only slightly effective in reversing the wasting, while 5-fluorouracil, tegafur, mitomycin C, cis-platinum, and doxorubicin were not active. Within 3 days after 5'-deoxy-5-fluorouridine was administered to cachectic mice with large tumor burdens, the wasting was immediately reversed even at doses in which there was increase or no significant reduction in tumor growth. These results indicate that the anticachectic activity of 5'-deoxy-5-fluorouridine is independent of its antiproliferative activity.

Acute-Phase Proteins↗

PubMed1991

Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia.

The aim of this study was to evaluate to what extent tumor necrosis factor alpha (TNF-alpha) and interleukin 1 may explain the development of experimental cancer cachexia. For this purpose, C57BL/6J mice bearing a transplantable low differentiated rapidly growing tumor were passively immunized every other day with rabbit or rat neutralizing immunoglobulins against either TNF-alpha (anti-TNF) or against an interleukin 1 receptor (anti-IL-1r). Anti-IL-1r in itself had no agonistic effect to the type I, T-cell/fibroblast IL-receptor. Tumor-bearing mice receiving either preimmune antiserum or nonimmune rat hybridoma IgG served as controls. Anti-TNF and anti-IL-1r inhibited tumor growth significantly, as measured by a lower wet and dry tumor weight at the end of 11 days of antiserum treatment (P less than 0.05). The acute phase response in tumor-bearing animals, measured as an increase in liver weight, hepatic RNA content, and increases in plasma concentrations of circulating IL-6, serum amyloid P, transferrin, complement (C3), and a decrease in plasma albumin, were unaffected by the specific antiserum treatments. Food intake, which declined significantly in pre/nonimmune injected tumor-bearing controls, was significantly improved in tumor-bearing animals immunized against TNF-alpha or the IL-1r. Whole body lipid content showed a trend to improvement in specifically immunized animals (P less than 0.07). The effects on whole body fat-free dry weight were insignificant, although numerically higher in specifically immunized tumor-bearing animals. The combination of anti-TNF and anti-IL-1r antiserum had no additive effects compared to single antiserum treatment suggesting that the two antibody treatments acted through a common mechanism. Cultured tumor cells, established from growing tumors, were sensitive to anti-TNF and anti-IL-1r, which both reduced tumor growth in vitro. This inhibitory effect by the antiserum could in part be reversed by the addition of recombinant IL-1 alpha and TNF alpha. We conclude that both TNF and IL-1 are involved in tumor growth and thus the progression of cancer cachexia. It seems as if the role of TNF and IL-1 was to promote tumor growth rather than restrict tumor growth in the present model. In this sense both TNF and IL-1 may act as tumor growth factors.

Acute-Phase Proteins↗

PubMed1991

Management of anorexia-cachexia associated with cancer and HIV infection.

The cachexia associated with cancer and AIDS appears to result from a number of processes, most of which impair caloric intake. Although past attempts to reverse anorexia-cachexia have generally been disappointing, several promising new pharmacologic approaches are currently being evaluated, including megestrol acetate, hydrazine sulfate, metoclopramide, and dronabinol.

Anorexia↗

PubMed1991

The roles of gamma-interferon and tumor necrosis factor alpha in an experimental rat model of cancer cachexia.

Administration of repetitive sublethal doses of either recombinant human tumor necrosis factor (TNF) or recombinant murine gamma-interferon (IFN) to non-tumor-bearing (NTB) rats caused a significant decline in food intake and body weight. After 3 days rats became resistant to the anorectic and weight loss effects of TNF but maintained persistent diminished food intake and diminished body weight gain while receiving recombinant murine IFN. Passive immunization against recombinant rat gamma-interferon allowed cachectic tumor-bearing (TB) rats to eat more food, have a lesser decline in body weight, live longer, and tolerate larger tumors than similar TB rats given nonspecific control antibody. TB rats treated with an antisera to recombinant murine TNF, which was 100% protective when given to NTB rats 6 h before a lethal endotoxin challenge, did not differ significantly from TB rats treated with control antibody with respect to food intake, body weight, survival, or tumor size. Serum levels of TNF or IFN were not detectable in cachectic tumor-bearing rats. The data indicate that the administration of exogenous IFN can simulate cachexia in NTB rats and that passive immunization against it can partially reverse the cachectic changes associated with cancer and prolong survival. These findings suggest that gamma-interferon may be an important mediator of cachexia in this rat tumor model.

Animals↗

PubMed1991

[Pre- and postoperative nutritional assessment of cardiac cachexia].

Pre- and postoperative nutritional states were studied in fifty patients undergoing cardiac surgery. Seven of them were cardiac cachectic patients. There was no hospital death except one patient with cardiac cachexia. Preoperative measurements showed decreased %standard body weight (80.7%), %standard AMC (86.1%), and %standard TSF (61.5%) in cachectic patients. Resting energy expenditure (REE) and circulating blood volume were significantly higher in cachectic patients throughout the pre- and postoperative periods, and a significant correlations were admitted between them (p less than 0.05). REE increased to 33.6 kcal/kg/day 1 week after operation. Serum proteins, including rapid turnover proteins (RTP), when expressed in g/dl or mg/dl, did not show any difference between two groups. However by correction with circulating plasma volume and body weight (mg/kg), cardiac cachectic patients had significantly higher protein contents preoperatively and seventh post-operative day (p less than 0.05). There was no difference in urinary excretion of 3-methylhistidine between two groups throughout the study period, but urinary excretion of urea was higher in 1st and 3rd postoperative days in non cachectic patients. Serum cortisol and urinary excretion of vanillymandelic acid were higher, and serum insulin level tended to be lower in cachectic patients postoperatively. These results indicate that, in cardiac cachexia, increased blood volume and hypermetabolic state cause higher energy expenditure, resulting in weight loss and chronic heart failure.

Adult↗