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PubMed1995

Effects of nandrolone propionate on experimental tumor growth and cancer cachexia.

We studied the tumor host response to excessive doses of an anabolic steroid (nandrolone propionate, 2.5 mg 20 g intraperitoneally every second day for 11 days) with respect to body composition and tumor cell kinetics in MCG 101 sarcoma-bearing mice (C57BL/6J) with progressive cachexia. Although survival and food intake were not affected, a significant weight gain was observed that was essentially attributed to water retention. Net protein content was increased only to a minor extent (15%), of which only the liver accounted for a significant part of the body compartments. Hepatic protein accumulation was obviously caused by decreased protein degradation, since hepatic RNA content was unchanged. After anabolic steroid administration, reduced histochemical staining of succinate dehydrogenase was observed in skeletal muscles rich in oxidative type 1 fibers, but it was not different from that of tumor-bearing control animals, which was also confirmed by measurements of citrate synthase and cytochrome c oxidase activities in skeletal muscle and liver tissue. The anabolic steroid had no significant effect on tumor growth in terms of weight progression, energy state, polyamine synthesis rate, cell division rate, and cell cycle cytocompartments. We conclude that anabolic steroid supplementation is not therapeutically beneficial in counteracting progressive weight loss in experimental cancer.

Anabolic Agents↗

PubMed1991

Changes in activity of lipoprotein lipase, plasma free fatty acids and triglycerides with weight loss in a cachexia model.

The effect of weight loss during cancer cachexia on the plasma levels of free fatty acids (FFA) and triglycerides, and on the tissue levels of lipoprotein lipase (LPL), has been studied in mice bearing an experimental colon adenocarcinoma (MAC16). Despite extensive mobilisation of host body fat reserves, plasma levels of triglycerides were reduced irrespective of the extent of weight loss. The plasma levels of FFA also showed an initial decrease with weight loss, followed by a rise peaking at a weight loss of about 2 g, and thereafter the levels decreased with increasing weight loss. The level of LPL in both heart and adipose tissue showed an initial rise with increasing weight loss also peaking at a weight loss of approximately 2.5 g, followed by a decrease with further weight loss. The increased LPL would provide an increased level of fatty acids for oxidation in the cachectic state and would account for the effect on plasma FFAs and triglycerides.

Adenocarcinoma↗

PubMed1992

Weight loss in a murine cachexia model is not associated with the cytokines tumour necrosis factor-alpha or interleukin-6.

Daily administration of an escalating dose of tumour necrosis factor-alpha (TNF-alpha) to female NMRI mice caused a progressive loss of body weight representing 12% of the original weight over a 6-day period. Weight loss was associated with a decreased food intake and pair-fed controls exhibited a weight loss of similar magnitude to that caused by TNF-alpha. However, weight loss in animals bearing a murine adenocarcinoma (MAC16) occurred without a change in energy intake and thus differed from that produced by TNF-alpha. Anti-TNF-alpha monoclonal antibodies at levels capable of protecting mice against lethal endotoxaemia were ineffective in reversing weight loss in animals bearing the MAC16 tumour and had no effect on the increase in tumour volume. Circulating levels of interleukin-6 were not elevated in animals bearing the MAC16 tumour and with a weight loss between 1.8 and 5.4 g. These results suggest that these cytokines are not involved in the cachexia produced by this murine tumour.

Adenocarcinoma↗

PubMed1993

Detection of serum cytokine levels in experimental cancer cachexia of colon 26 adenocarcinoma-bearing mice.

The aim of this study was to evaluate the correlations between tumor size and cachexia parameters including cytokine levels in serum. In transplantable colon 26 adenocarcinoma-bearing mice, parameters having negative correlations with tumor size were host weight changes, epididymal adipose tissue weight, glucose and interleukin 3 (IL-3) concentration in serum. Parameters having a positive correlation with tumor size were the number of circulating white blood cells and immunosuppressive acidic protein (IAP), interleukin 6 (IL-6) and transforming growth factor beta (TGF-beta) concentration in serum.

Adenocarcinoma↗

PubMed1995

Lack of effect of eicosapentaenoic acid in preventing cancer cachexia and inhibiting tumor growth.

It has been recently reported that a diet enriched in n-3 polyunsaturated fatty acids reduces the growth of different kinds of tumors as well as the host tissue hypercatabolic state frequently associated. The rat ascites hepatoma Yoshida AH-130 is a fast growing tumor that causes a rapid and progressive body weight loss in the host and tissue waste associated with a hypercatabolic condition. Plasma levels of classical hormones and humoral mediators (prostaglandin E2 and tumor necrosis factor-alpha) are early perturbed after tumor transplantation (Tessitore, L., Costelli, P. and Baccino, F.M. (1993) Humoral mediation for cachexia in tumour-bearing rats. Br. J. Cancer, 67, 16-23). Enhanced protein degradation rates and alteration of lipoprotein lipase activity mainly account for the wasting of protein and adipose mass, respectively. However, the daily intragastric administration of eicosapentaenoic acid (1.5 g/kg body wt) to AH-130 bearing rats was completely ineffective either in preventing tissue waste or in reducing tumor growth. The low degree of differentiation and the high growth rate of the AH0130 hepatoma probably account for this lack of effect.

Animals↗

PubMed1996

Cancer, cancer cachexia, and diet: lessons from clinical research.

Cachexia is a common cause of morbidity and mortality in cancer patients. Successful nutritional repletion might enhance treatment results, quality of life, and survival. In the past, attempts at nonvolitional feeding (enteral and parenteral techniques) have not been as successful as initially hoped. The cachectic cancer patient's loss of lean body mass has been very difficult to restore, although fat can be repleted. Laboratory and epidemiologic investigations have suggested that dietary calories and dietary fat may play a promotional role in cancer. Overfed animals and obese humans both have an increased tendency for development of malignancy. Breast cancer has been investigated extensively for its relationship to diet. Certain fatty acids appear to stimulate breast cancer, as do obesity-related changes in circulating hormones. Obesity in breast cancer and weight gain on adjuvant therapy may therefore be adverse prognostic signs. Clinical trials of decreasing dietary fat as an adjuvant to breast cancer therapy are in progress. The current challenge in nutritional management of the cancer patient is to incorporate laboratory, epidemiologic, and clinical data into a successful repletion strategy. It seems unlikely that traditional methods of supplying excess calories will succeed, so that other, more specific nutritional manipulations should be evaluated in clinical trials.

Animals↗

PubMed1993

Mechanism of lipid mobilization associated with cancer cachexia: interaction between the polyunsaturated fatty acid, eicosapentaenoic acid, and inhibitory guanine nucleotide-regulatory protein.

During a study of the mechanism of cancer cachexia, a debilitating condition in which catabolism of host muscle and adipose tissue occurs, it has been observed that the process can be effectively reversed in vivo by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), but not by other PUFA of either the n-3 or n-6 series. In vitro studies showed that EPA blocked the action of a tumour-produced catabolic factor at the level of the adipocyte, and that the effect of EPA also extended to beta-adrenergic stimuli and polypeptide hormones. Again the effect was specific to EPA and appeared to arise from an inhibition of the elevation of cyclic AMP levels in adipocytes in response to varied stimuli. Using isoprenaline stimulated lipolysis as a model system we have shown that EPA has a direct inhibitory effect on isoprenaline-stimulated adenylate cyclase in isolated plasma membrane fractions with half maximal inhibition at a concentration of 165 microM. The inhibitory effect was specific for EPA and was not shown by docosahexaenoic or arachidonic acids. The inhibitory effect of EPA on adenylate cyclase showed properties similar to hormonal inhibition of the enzyme in that it was (i) GTP-dependent, (ii) non-competitive with isoprenaline, (iii) eliminated following treatment of either adipocytes or plasma membrane fractions with pertussis toxin, which is known to ADP-ribosylate the alpha-subunit of an inhibitory guanine nucleotide-regulatory protein (Gi), thus leading to its inactivation. This suggests that inhibition of cyclic AMP formation by EPA was due, at least in part, to a Gi-mediated inhibition of adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMed1994

Alterations in plasma and tumour levels of fatty acids with weight loss in an experimental cachexia model.

Growth of the MAC16 tumour in NMRI mice was accompanied by a decrease in host body weight, adipose tissue and liver weight in proportion to the tumour mass. The total plasma concentration of fatty acids also increased with increasing weight loss, while the linoleic acid: arachidonic acid ratio decreased. The liberated fatty acids were taken-up both by the tumour and the liver. However, since liver weight decreased in proportion to weight loss the accumulation of fatty acids increased as liver weight decreased. This suggests that the small liver mass had an increased capacity to accumulate fatty acids. The concentration of stearic, palmitic, oleic, palmitoleic and arachidonic acids all increased with increasing tumour weight, while the stearic acid: oleic acid ratio, a measure of unsaturation in the tumour increased. Thus mobilization of adipose tissue reserves during cancer cachexia ensures a constant availability of essential fatty acids for tumour growth.

Adenocarcinoma↗

PubMed2004

Suppression of cancer cachexia by 20S,21-epoxy-resibufogenin-3-acetate-a novel nonpeptide IL-6 receptor antagonist.

While screening for novel IL-6 inhibitors, we synthesized 20S,21-epoxy-resibufogenin-3-acetate (ERBA). ERBA dose-dependently suppressed IL-6-induced cell growth with an IC(50) value of 5.3 microM and caused a parallel rightward shift of dose-response curves to IL-6. Analysis of data yields a pA2 of 5.83 and a slope of 0.99. ERBA did not affect IL-2-, IL-3-, and GCSF-dependent cell growth, or tumor necrosis factor alpha-induced growth suppression, nor did ERBA affect osteoclast formation induced by IL-11, leukemia inhibitory factor, and 1alpha,25-dihydroxyvitamin D(3). Receptor assay showed that ERBA dose-dependently suppressed IL-6 binding to IL-6 receptor (IL-6R). Furthermore, no band existing at the position of IL-6R in Western blots of ERBA-treated cells when stimulated with IL-6:ERBA suppresses IL-6 activity by blocking the binding of IL-6 to IL-6R. In an experimental model of colon 26-induced cancer cachexia, ERBA markedly inhibited body weight loss. ERBA is a specific small molecule with IL-6R-antagonist activity.

Animals↗

PubMed2006

Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure.

Chronic heart failure is a complex catabolic state that carries a devastating prognosis. The transition from stable disease to cardiac cachexia is not well understood. Mechanisms that maintain the wasting process involve neurohormones and pro-inflammatory cytokines, which contribute to an imbalance in anabolic and catabolic pathways. A decrease in food intake alone rarely triggers the development of a wasting process, but dietary deficiencies in micronutrients and macronutrients contribute to the progression of the disease. Malabsorption from the gut as a result of bowel wall edema and decreased bowel perfusion also plays an important role. This article describes the complex interplay of hormonal systems in energy balance in patients with chronic heart failure as well as other factors such as malabsorption and dietary deficiencies that contribute to the wasting process. Finally, therapeutic approaches are discussed. These include dietary advice, ongoing studies, and future possibilities.

Adrenergic beta-Antagonists↗

PubMed2005

Prevention and treatment of cancer cachexia: new insights into an old problem.

Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, accounting for at least 20% of deaths in neoplastic patients. CC significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of CC and the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways. Most therapeutic strategies to CC have proven to be only partially effective . The inhibition of catabolic processes in muscle has been attempted pharmacologically with encouraging results in animal models. However, data in the clinical setting are still scanty and contradictory. Stimulation of muscle anabolism could represent a promising and valid therapeutic alternative for cancer-related muscle wasting. This goal may be currently achieved with the conventional, short-acting and adverse side effect-rich anabolic steroids. Insulin-like growth factor-1 (IGF-1) plays a critical role in muscle homeostasis, hypertrophy and regeneration. IGF-1 overexpression at the muscular level by gene therapy reverses muscle hypotrophy secondary to catabolic conditions and induces muscle hypertrophy increasing muscle mass and strength. This allows the speculation that this approach could also prove effective in modulating cancer-induced muscle wasting, while avoiding the potentially hazardous side effects of systemic IGF-1 administration. The present review will focus on the potential biochemical and molecular targets of CC therapy, and will define the rationale for a novel, gene therapy-based approach.

Cachexia↗

PubMed2006

The AP-1/CJUN signaling cascade is involved in muscle differentiation: implications in muscle wasting during cancer cachexia.

The aim of the present study was to investigate a possible role of the AP-1 signaling cascade in the process of wasting associated with cancer cachexia at the level of skeletal muscle. The injection of virus containing the TAM67 protein (a blocker of the AP-1 protein) to the gastrocnemius muscle of tumour-bearing rats resulted in a significant recovery of the muscle mass (which is dramatically reduced as a result of tumour burden), therefore suggesting that AP-1 is certainly involved in the signaling associated with muscle protein accretion. In conclusion, the gene therapy approach presented here clearly suggests an important role for AP-1 in muscle signaling during catabolic states.

Animals↗

PubMed2004

Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome.

This study aimed to assess the efficacy and safety of megestrol acetate (MA) in anorexia-cachexia syndrome (ACS). Literature and relevant databases were searched for randomized controlled trials of MA to treat ACS in patients with cancer, AIDS, or other pathologies. Data were extracted by two independent reviewers, and meta-analyses were performed where possible. Twenty-six studies were included (n=3,887). Compared to placebo, MA increased appetite in oncology patients [RR=2.31 (95% CI 1.52-3.59)], led to weight gain [RR=1.88 (95% CI 1.43-2.47)] and improved HRQOL [RR=1.52 (95% CI 1.00-2.30)]. In AIDS patients, it increased weight [RR=2.16 (95% CI 1.45-3.21)]. MA showed significant benefits over dronabinol in improving appetite, but no statistically significant advantages over other drugs for treating ACS were observed. There were no appreciable differences between lower (<800 mg/day) and higher (>800 mg/day) doses of MA. Few serious adverse events were recorded. MA is an effective and safe treatment for ACS in cancer and AIDS patients, particularly in terms of improvement in appetite and weight gain.

Anorexia↗

PubMed2006

Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism.

A review-based hypothesis is presented on the energy flow in cancer patients. This hypothesis centres on the hypoxic condition of tumours, the essential metabolic consequences, especially the gluconeogenesis, the adaptation of the body, and the pathogenesis of cancer cachexia. In growing tumours the O(2) concentration is critically low. Mammalian cells need O(2) for the efficient oxidative dissimilation of sugars and fatty acids, which gives 38 and 128 moles of ATP per mole glucose and palmitic acid, respectively. In the absence of sufficient O(2) they have to switch to anaerobic dissimilation, with only 2 moles of ATP and 2 moles of lactic acid from 1 mole of glucose. Since mammalian cells cannot ferment fatty acids, in vivo tumour cells completely depend on glucose fermentation. Therefore, growth of these tumour cells will require about 40 times more glucose than it should require in the presence of sufficient O(2). Since lactic acid lowers the intracellular pH, it decreases the activity of pyruvate dehydrogenase, stimulates fermentation, and thus amplifies its own fermentative production. Compensatory glucose is provided by hepatic gluconeogenesis from lactic acid. However, the liver must invest 3 times more energy to synthesize glucose than can be extracted by tumour cells in an anaerobic way. The liver extracts the required energy from amino acids and especially from fatty acids in an oxidative way. This may account for weight loss, even when food intake seems adequate. In the liver 6 moles of ATP are invested in the gluconeogenesis of one mole of glucose. The energy content of 4 out of these 6 moles of ATP is dissipated as heat. This may account for the elevated body temperature and sweating experience by cancer patients.

Adenosine Triphosphate↗

PubMed2005

Mediators involved in the cancer anorexia-cachexia syndrome: past, present, and future.

The cachectic syndrome, characterized by a marked weight loss, anorexia, asthenia, and anemia is invariably associated with the presence and growth of the tumor and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumor and the host leads to an accelerated starvation state, which promotes severe metabolic disturbances in the host, including hypermetabolism, which leads to an increased energetic inefficiency. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. Present investigation is devoted to revealing the different signaling pathways, in particular transcriptional factors involved in muscle wasting. The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (both humoral and tumoral) involved in cancer cachexia since they may represent targets for future promising clinical investigations.

Cachexia↗

PubMed2005

Effect of eicosapentaenoic acid (EPA) on expression of a lipid mobilizing factor in adipose tissue in cancer cachexia.

Adipose tissue of mice bearing a cachexia-inducing murine tumour (MAC16) shows increased expression of zinc-alpha(2)-glycoprotein (ZAG), a lipolytic factor thought to be responsible for the increased lipolysis. The anti-cachectic agent eicosapentaenoic acid (EPA) (0.5 g/kg) attenuated the loss of body weight in mice bearing the MAC16 tumour, and this was accompanied by downregulation of ZAG expression in both white and brown adipose tissue, as determined by Western blotting. Glucocorticoids may be responsible for the increased ZAG expression in adipose tissue. Dexamethasone (1.68 microM) stimulated lipolysis in 3T3-L1 adipocytes, and this effect was attenuated by EPA (50 microM). In addition the lipolytic action of dexamethasone was attenuated by anti-ZAG antibody, suggesting that the induction of lipolysis was mediated through an increase in ZAG expression. This was confirmed by Western blotting, which showed that dexamethasone (1.68 microM) induced a two-fold increase in ZAG expression in both cells and media, and that this was attenuated by EPA (50 microM). These results suggest that EPA may preserve adipose tissue in cachectic mice by downregulation of ZAG expression through interference with glucocorticoid signalling.

3T3-L1 Cells↗

PubMed2005

Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes.

Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-kappaB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.

Animals↗

PubMed1983

Chronic erosive gastritis resulting in cachexia.

Nine patients are reported who presented with severe weight loss of up to 13.6 kg (30 lb) as a result of chronic erosive gastritis. In many the cachexia was sufficient to prompt a search for malignancy but no other lesion was found. The importance of the radiological pursuit of this diagnosis is emphasised. Illustrative case histories are presented.

Adult↗