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PubMed2003

Rapid progression of advanced "hormone-resistant" prostate cancer during palliative treatment with progestins for cancer cachexia.

We report three patients with advanced "hormone-resistant" prostate cancer, each of whom had rapid progression of the disease during treatment with megestrol acetate for cancer cachexia. All patients had been previously treated with total androgenic deprivation. With progression of the disease, megestrol acetate was given to palliate the cancer-related wasting syndrome. No other antineoplastic drugs were contemporaneously given, and no concomitant condition that could favor the progression of the disease was present. The worsening observed while receiving megestrol acetate, and the atypical withdrawal syndrome occurring after the treatment was stopped, seem to suggest a promoting role of megestrol acetate in advanced "hormone-resistant" prostate cancer. The risk of rapid disease progression overwhelming the anti-cachectic palliative effect should be kept in mind when progestins are administered as a palliative treatment of cancer cachexia in patients with advanced "hormone-resistant" prostate cancer.

Aged↗

PubMed1996

Cachexia and anorexia in malignancy.

The cancer cachexia syndrome may be present in up to 80% of patients with cancer. Malnutrition resulting from cancer cachexia is a significant cause of morbidity and mortality. Anorexia, tissue wasting, and weight loss appear to be the result of metabolic abnormalities caused by host cytokine production in response to the tumor. The host cytokines include TNF-alpha, IL-1, IL-6, IFN-gamma, and D-factor. Nutritional support in the patient with cancer has been controversial, with the belief that tumor growth may be augmented; however, human studies fail to confirm that tumor growth occurs in excess of normal tissue growth. The efficacy of nutritional support in the cancer has not been adequately studied. Considerable interest exists in providing nutritional support pharmacologically to modify the response to malignancy.

Anorexia↗

PubMed1999

Neuropeptide Y: a key molecule in anorexia and cachexia in wasting disorders?

Anorexia and body weight loss are characteristic of many diseases, including cancer and AIDS. Recent studies indicate that inflammatory cytokines, such as interleukin 1, the interleukin 6 subfamily and tumor necrosis factor, induce anorexia and cachexia by inhibiting the normal adaptive feeding response to energy deficits. Here, I discuss the evidence for and against a central role for neuropeptide Y and leptin in anorexia and cachexia.

Animals↗

PubMed2003

Catabolic mediators as targets for cancer cachexia.

The cachexia syndrome, characterized by a marked weight loss, anorexia, asthenia and anaemia, is invariably associated with the growth of a tumour and leads to a malnutrition status caused by the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host results in an accelerated catabolism state, which promotes severe metabolic disturbances in the patient. The search for the cachectic factor(s) started a long time ago, and many scientific and economic efforts have been devoted to its discovery, but we are still a long way from a complete answer. The present review aims to evaluate the different molecular mechanisms and catabolic mediators (both humoural and tumoural) that are involved in cancer cachexia and to discuss their potential as targets for future clinical investigations.

Animals↗

PubMed1999

Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats.

The development of pharmacological approaches for preventing the loss of muscle proteins would be extremely valuable for cachectic patients. For example, severe wasting in cancer patients correlates with a reduced efficacy of chemotherapy and radiotherapy. Pentoxifylline (PTX) is a very inexpensive xanthine derivative, which is widely used in humans as a haemorheological agent, and inhibits tumor necrosis factor transcription. We have shown here that a daily administration of PTX prevents muscle atrophy and suppresses increased protein breakdown in Yoshida sarcoma-bearing rats by inhibiting the activation of a nonlysosomal, Ca(2+)-independent proteolytic pathway. PTX blocked the ubiquitin pathway, apparently by suppressing the enhanced expression of ubiquitin, the 14-kDa ubiquitin conjugating enzyme E2, and the C2 20S proteasome subunit in muscle from cancer rats. The 19S complex and 11S regulator associate with the 20S proteasome and regulate its peptidase activities. The mRNA levels for the ATPase subunit MSS1 of the 19S complex increased in cancer cachexia, in contrast with mRNAs of other regulatory subunits. This adaptation was suppressed by PTX, suggesting that the drug inhibited the activation of the 26S proteasome. This is the first demonstration of a pharmacological manipulation of the ubiquitin-proteasome pathway in cachexia with a drug which is well tolerated in humans. Overall, the data suggest that PTX can prevent muscle wasting in situations where tumor necrosis factor production rises, including cancer, sepsis, AIDS and trauma.

Adenosine Triphosphatases↗

PubMed1999

Adaptation of the ubiquitin-proteasome proteolytic pathway in cancer cachexia.

The ubiquitin-proteasome proteolytic pathway is of major importance in the breakdown of skeletal muscle proteins. The first step in this pathway is the covalent attachment of polyubiquitin chains to the targeted protein. Polyubiquitinylated proteins are then recognized and degraded by the 26S proteasome complex. In this review, we critically analyze recent findings in the regulation of ubiquitinylation of protein substrates and of their subsequent proteasome-dependent degradation in animal models of cancer cachexia. In particular, we discuss the influence of various mediators (anorexia, hormones, prostaglandins, cytokines, and proteolysis-inducing factor) in signaling the activation of ubiquitin-proteasome proteolysis in skeletal muscle. These findings have lead to new concepts that are starting to be used for preventing cachexia in cancer and other wasting diseases.

Animals↗

PubMed2003

Lymphosarcoma-induced alterations in hepatic adrenergic receptors: implications to the hypoglycemia of cancer cachexia.

A highly malignant transplantable rat lymphosarcoma was studied to determine the involvement of hepatic adrenergic receptors in the development of the hypoglycemia of cancer cachexia. Following inoculation of Fischer 344 rats with lymphosarcoma cells, rats were examined at 2 and 4 weeks, at the pre-cachexic stage; 6 weeks, at the transitional stage; and 7 weeks, at the cachexic hypoglycemic stage of lymphosarcoma progression. Death occurred by the 8th week. Blood glucose levels in lymphosarcoma-bearing rats relative to control rats were: unaffected at week 2; significantly reduced 8% at weeks 4 and 6; and reduced 24% at week 7. Alpha1 adrenergic receptor binding to plasma membranes isolated from the livers of lymphosarcoma-bearing rats was: 114, 89, 67 and 30% of control at weeks 2, 4, 6, and 7, respectively. Kinetic analysis indicated that the lymphosarcoma-induced decrease at week 7 was due to a decrease in numbers of receptors with no change in affinity: B(max)(control): 1411.1 fmol/mg: Kd(control): 0.44 nm; B(max)(lympho): 345.5 fmol/mg; Kd(lympho): 0.50 nm. Alpha2 adrenergic receptor binding to plasma membranes isolated from the livers of lymphosarcoma-bearing rats was: 130, 137, 243 and 212% of control at weeks 2,4, 6, and 7, respectively. The pattern of changes in hepatic alpha1, alpha2 and beta adrenergic receptors at week 6 was comparable to that of 17 day fetal liver: a decrease in alpha1 and beta and an increase in alpha2. Hepatic adrenergic receptor changes occurred in the absence of liver damage and were not due to contamination of the liver plasma membrane fractions with lymphosarcoma cells. Plasma insulin levels displayed modest (10-15%), but not statistically significant, increases post-inoculation after week 4. Plasma glucagon levels fluctuated post-inoculation until week 7 where they were significantly increased: 202% of control. Plasma T3 and T4 levels displayed an early and steady decline after lymphosarcoma inoculation: T3: unchanged at week 2 and significantly decreased 14, 44 and 50% at weeks 4, 6 and 7, respectively. T4 increased 20% at week 1; decreased 9% at week 4 and significantly decreased thereafter: 55 and 49% at weeks 6 and 7, respectively. We propose that the development of the hypoglycemia of cancer cachexia in this lymphosarcoma model is due primarily to an early and progressive thyroid hormone dependent decrease in the number of hepatic alpha1 adrenergic receptors, compounded by an increase and decrease, respectively, in the hepatic beta and alpha2 adrenergic receptors.

Alanine Transaminase↗

PubMed1986

Metabolic substrate utilization by a tumour cell line which induces cachexia in vivo.

The MAC 16 is a transplantable murine carcinoma of the colon producing extensive weight loss in tumour-bearing animals. The weight loss is proportional to the size of the tumour and occurs without a reduction in food intake when compared with non tumour-bearing control mice. Weight loss produced by the MAC 16 tumour is accompanied by hypoglycaemia which becomes more extensive as the tumour mass increases. In order to understand the mechanism of the cachexia produced by the MAC 16 tumour the rate of substrate utilization and CO2 formation from both glucose and palmitate has been compared in vitro, with other colon carcinoma cell lines known not to produce cachexia as well as a range of murine and human tumour cell lines. The rate of glucose consumption, lactate production and CO2 formation from both glucose and palmitate is much higher for the MAC 16 than for the other tumour cells. For all cell lines in vitro the consumption of glucose exceeds that of palmitate by a factor of 10(3). Excessive consumption of glucose by the MAC 16 tumour may account for the hypoglycaemic effect on the host. The level of 3 oxo acid CoA transferase, an initiator of ketone body utilization, was found to be much lower in the MAC 16 tumour than non-involved colon. This suggests that the tumour may not be able to metabolize ketone bodies effectively.

Adenocarcinoma↗

PubMed1987

Reduction of weight loss and tumour size in a cachexia model by a high fat diet.

An attempt has been made to reverse cachexia and to selectively deprive the tumour of metabolic substrates for energy production by feeding a ketogenic regime, since ketone bodies are considered important in maintaining homeostasis during starvation. As a model we have used a transplantable mouse adenocarcinoma of the colon (MAC 16) which produces extensive weight loss without a reduction in food intake. When mice bearing the MAC16 tumour were fed on diets in which up to 80% of the energy was supplied as medium chain triglycerides (MCT) with or without arginine 3-hydroxybutyrate host weight loss was reduced in proportion to the fat content of the diet, and there was also a reduction in the percentage contribution of the tumour to the final body weight. The increase in carcass weight in tumour-bearing mice fed high levels of MCT was attributable to an increase in both the fat and the non-fat carcass mass. Blood levels of free fatty acids (FFA) were significantly reduced by MCT addition. The levels of both acetoacetate and 3-hydroxybutyrate were elevated in mice fed the high fat diets, and tumour-bearing mice fed the normal diet did not show increased plasma levels of ketone bodies over the non-tumour-bearing group despite the loss of carcass lipids. Both blood glucose and plasma insulin levels were reduced in mice bearing the MAC16 tumour and this was not significantly altered by feeding the high fat diets. The elevation in ketone bodies may account for the retention of both the fat and the non-fat carcass mass. This is the first example of an attempt to reverse cachexia by a diet based on metabolic differences between tumour and host tissues, which aims to selectively feed the host at the expense of the tumour.

Adenocarcinoma↗

PubMed1988

A comparison of long-chain triglycerides and medium-chain triglycerides on weight loss and tumour size in a cachexia model.

A comparison has been made between the ability of long-chain triglycerides (LCT) and medium-chain triglycerides (MCT) to prevent weight loss induced by the cachexia-inducing colon adenocarcinoma (MAC16) and to reduce tumour size. There was no difference in calorie consumption or nitrogen intake between the various groups. When compared with a normal control high carbohydrate, low fat diet, animals fed MCT showed a reduced weight loss and a marked reduction in tumour size. In contrast neither weight loss nor tumour size differed significantly from the controls in animals fed the LCT diet. An elevated plasma level of 3-hydroxybuturate was found only in the animals fed the MCT diets. Administration of LCT caused an increase in the plasma level of FFA, which was not observed in the MCT group. These results suggest that diets containing MCT would provide the best ketogenic regime to reverse the weight loss in cancer cachexia with a concomitant reduction in tumour size.

3-Hydroxybutyric Acid↗

PubMed1988

Comparison of weight loss induced by recombinant tumour necrosis factor with that produced by a cachexia-inducing tumour.

A comparison has been made of the cachectic effects produced by the transplantable murine adenocarcinoma of the mouse colon (MAC16) with tumour necrosis factor-alpha (cachectin). Tumour necrosis factor-alpha (TNF-alpha) produced a dose-related weight reduction that was accompanied by a decrease in both food and water intake. The degree of weight loss was directly proportional to the decreased food and water intake. In contrast weight loss produced by the MAC16 tumour occurred without a reduction in fluid or nutrient intake. Both the MAC16 tumour and TNF-alpha produced hypoglycaemia and a reduction in the circulatory level of free fatty acids (FFA), but had opposite effects on the level of plasma triglycerides with the MAC16 tumour-induced cachexia causing a decrease and TNF-alpha producing an increase. The MAC16 tumour elaborated a lipolytic factor which caused an immediate release of FFA from adipose tissue. In contrast TNF-alpha had no effect on mobilization of adipose triglycerides over a short time period. Both TNF-alpha and extracts from the MAC16 tumour caused an enhanced release of amino acids from mouse diaphragm, which was suppressible with indomethacin and heat labile. No TNF was detected in the MAC16 tumour or in the serum of tumour-bearing animals. Both tumour and non-tumour-bearing animals responded with a similar elevation of their serum TNF levels 90 min after a single injection of endotoxin. It is concluded that weight loss produced by TNF-alpha arises from an anorexic effect and that this differs from the complex metabolic changes associated with cancer cachexia.

Adenocarcinoma↗

PubMed1990

Effect of megestrol acetate on weight loss induced by tumour necrosis factor alpha and a cachexia-inducing tumour (MAC16) in NMRI mice.

The effect of the synthetic progesterone, megestrol acetate, on weight loss induced by both tumour necrosis factor alpha (TNF) as a model for the cachexia accompanying the acquired immunodeficiency syndrome and by a cachexia-inducing tumour (MAC16) has been studied in NMRI mice. Megestrol acetate was effective in preventing weight loss in both model systems with treated animals having an increase in intake of both food and water. Megestrol acetate was unable to prevent loss of body weight in animals pair-fed with TNF treated animals, suggesting that the increase in food and water intake was responsible for the increase in body weight. Analysis of body composition showed that the major contribution to the increase in body weight in animals treated with megestrol acetate was an increase in water content, although there was also an increase in carcass fat in animals bearing the MAC16 tumour given the high dose of megestrol acetate. Animals bearing the MAC16 tumour had a significant increase in tumour weight after treatment with megestrol acetate, possibly owing to the increased plasma glucose levels. These results suggest that an increase in appetite and weight gain alone are not sufficient to justify the anticachectic effect of a particular agent and that body composition analysis and tumour growth rate are very important parameters.

Adenocarcinoma↗

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↗

PubMed1993

Mechanism of muscle protein degradation in cancer cachexia.

Depletion of skeletal muscle mass in animals bearing an experimental model of cachexia, the MAC16 adenocarcinoma, occurs by a reduction in protein synthesis accompanied by a large increase in protein degradation. Serum from mice bearing the MAC16 tumour produced an increased protein degradation in isolated gastrocnemius muscle, as measured by tyrosine release, with a maximal effect occurring with serum from animals with a weight loss of between 11 and 20%. The response was specific to the cachectic state, since serum from mice bearing the MAC13 adenocarcinoma, which does not produce weight loss, did not increase tyrosine release from gastrocnemius muscle above that observed with serum from non tumour-bearing animals. The circulatory proteolysis-inducing factor was stable to heating at 60 degrees C for 5 min and was not inhibited by phenylmethylsulfonyl fluoride, suggesting that it was not a serine protease. The level of prostaglandin E2 (PGE2) in gastrocnemius muscle was significantly elevated after incubation with serum from cachectic mice bearing the MAC16 tumour. Both indomethacin and the polyunsaturated fatty acid eicosapentaenoic acid (EPA) inhibited the rise in muscle PGE2 content in response to serum from cachectic mice and also inhibited muscle protein degradation. These results suggest that muscle protein degradation in cancer cachexia is associated with a rise in PGE2 content.

Adenocarcinoma↗

PubMed1997

Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients.

Urine from cancer patients with weight loss showed the presence of an antigen of M(r) 24,000 detected with a monoclonal antibody formed by fusion of splenocytes from mice with cancer cachexia. The antigen was not present in the urine of normal subjects, patients with weight loss from conditions other than cancer or from cancer patients who were weight stable or with low weight loss (1 kg month(-1)). The antigen was present in the urine from subjects with carcinomas of the pancreas, breast, lung and ovary. The antigen was purified from urine using a combination of affinity chromatography with the mouse monoclonal antibody and reversed-phase high-performance liquid chromotography (HPLC). This procedure gave a 200,000-fold purification of the protein over that in the original urine extract and the material isolated was homogeneous, as determined by silver staining of gels. The N-terminal amino acid sequence showed no homology with any of the recognized cytokines. Administration of this material to mice caused a significant (P<0.005) reduction in body weight when compared with a control group receiving material purified in the same way from the urine of a normal subject. Weight loss occurred without a reduction in food and water intake and was prevented by prior administration of the mouse monoclonal antibody. Body composition analysis showed a decrease in both fat and non-fat carcass mass without a change in water content. The effects on body composition were reversed in mice treated with the monoclonal antibody. There was a decrease in protein synthesis and an increase in degradation in skeletal muscle. Protein degradation was associated with an increased prostaglandin E2 (PGE2) release. Both protein degradation and PGE2 release were significantly reduced in mice pretreated with the monoclonal antibody. These results show that the material of M(r) 24,000 present in the urine of cachectic cancer patients is capable of producing a syndrome of cachexia in mice.

Adenocarcinoma↗

PubMed2005

The role of glucocorticoids in the induction of zinc-alpha2-glycoprotein expression in adipose tissue in cancer cachexia.

Loss of adipose tissue in cancer cachexia in mice bearing the MAC16 tumour arises from an increased lipid mobilisation through increased expression of zinc-alpha2-glycoprotein (ZAG) in white (WAT) and brown (BAT) adipose tissue. Glucocorticoids have been suggested to increase ZAG expression, and this study examines their role in cachexia and the mechanisms involved. In mice bearing the MAC16 tumour, serum cortisol concentrations increased in parallel with weight loss, and the glucocorticoid receptor antagonist RU38486 (25 mg kg(-1)) attenuated both the loss of body weight and ZAG expression in WAT. Dexamethasone (66 microg kg(-1)) administration to normal mice produced a six-fold increase in ZAG expression in both WAT and BAT, which was also attenuated by RU38486. In vitro studies using 3T3-L1 adipocytes showed dexamethasone (1.68 microM) to stimulate lipolysis and increase ZAG expression, and both were attenuated by RU38486 (10 microM), anti-ZAG antibody (1 microg ml(-1)), and the beta3-adrenoreceptor (beta3-AR) antagonist SR59230A (10 microM). Zinc-alpha2-glycoprotein also increased its own expression and this was attenuated by SR59230A, suggesting that it was mediated through the beta3-AR. This suggests that glucocorticoids stimulate lipolysis through an increase in ZAG expression, and that they are responsible for the increase in ZAG expression seen in adipose tissue of cachectic mice.

3T3 Cells↗

PubMed2005

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia.

Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E2(14k), has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E2(14k) were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E2(14k) mRNA and protein levels in gastrocnemius muscle with increases of 6-8-fold for C2 and two-fold for E2(14k) between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25-27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18-20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E2(14k) mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss.

Animals↗

PubMed1999

Role of a proteolysis-inducing factor (PIF) in cachexia induced by a human melanoma (G361).

Human melanoma, G361, which induces cachexia in nude mice, has been shown to produce a proteolysis-inducing factor (PIF) of Mr 24000, which is immunologically identical to that isolated from a cachexia-inducing murine tumour (MAC16). Biosynthetic labelling of G361 cells using a combination of [35S]sulphate and [6-3H]glucosamine gave a single component of Mr 24000 after affinity chromatography employing a murine monoclonal antibody. The material contained both radiolabels and, after digestion with peptide N-glycosidase F, two fragments were produced of Mr 14000 and 10000 also containing both radiolabels. Digestion with O-glycosidase produced three fragments of Mr 14000, 6000 and 4000, the first two of which contained both radiolabels, while the third only contained 3H. This digestion pattern is the same as that previously observed with PIF from the MAC16 tumour and is commensurate with one N-linked sulphated oligosaccharide chain of Mr 10000, one O-linked sulphated oligosaccharide chain of Mr 6000 and a central polypeptide chain of Mr 4000 with some residual carbohydrate. When PIF from G361 cells was administered to female NMRI mice (20 g) a pronounced depression of body weight (1.36+/-0.36 g; P < 0.0001 from control) was observed over a 24 h period without a decrease in either food or water consumption. Body composition analysis showed a significant decrease in the non-fat carcass mass without a change in carcass fat or body water. This result suggests that depletion of lean body mass in mice bearing G361 melanoma arises from the production of PIF.

Animals↗