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PubMed2006

Clodronate alleviates cachexia and prolongs survival in nude mice xenografted with an anaplastic thyroid carcinoma cell line.

Cancer cachexia is one of the most common manifestations of advanced malignant disease and is frequently associated with decreased survival. Previously, we reported the establishment of a new anaplastic thyroid carcinoma cell line, Thena, and its mouse xenograft, Thena-Nu, which induced cachexia in athymic nude mice. Subsequent studies showed that the addition of clodronate to Thena-Nu cultures reduced cell proliferation as well as cytokine production in a dose- and time-dependent manner. Weekly administration of clodronate induced tumor cytostasis, attenuation of cachexia, as well as prolongation of survival in Thena-Nu-bearing mice. Reduced serum interleukin 6, tumor necrosis factor-alpha, and granulocyte colony stimulating factor levels were detected, whereas, serum leukemia inhibitory factor levels were not reduced. Liver necrosis, observed in tumor-bearing mice, was also improved following clodronate treatment. Discontinuation of clodronate treatment, however, resulted in progressive tumor growth and weight loss. Our results demonstrated that clodronate could exert therapeutic efficacy on amelioration of cancer cachexia in the hosts. Nevertheless, this study also points out that a longer period of treatment is required to maintain these effects.

Animals↗
PubMed1998

A review of the drug treatment of cachexia associated with cancer.

In the past 20 years, cachexia in cancer patients has attracted increasing interest from both clinicians and basic researchers. It is now clear that the cachexia is secondary to major metabolic abnormalities due to tumour by-products and cytokine release. These metabolic abnormalities produce numerous symptoms such as cachexia, anorexia and asthenia. There are now effective drugs such as corticosteroids and progestational drugs that have been shown to improve appetite, food intake and sensation of well-being, and which elicit bodyweight gain. While hydrazine (hydrazine sulfate) has received much attention, unfortunately it has been shown to be ineffective in improving the symptoms of the patient with cancer cachexia. A new group of drugs, such as thalidomide and melatonin because of their effects on tumour necrosis factor-alpha, and beta 2-adrenoceptor agonists because of their effects on muscle metabolism, and other agents, is presently reaching the clinical trial stage. There is now the possibility of addressing this fascinating syndrome at a different level and an opportunity for combined therapy to try to improve the quality of life of these patients.

Cachexia↗
PubMed2004

[Pathogenesis and treatment of cancer anorexia-cachexia, with special emphasis on aged patients].

Cachexia is among the most debilitating and life-threatening aspects of cancer and is more common in children and elderly patients. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. This could be caused by persistent inhibition of the feeding-stimulatory circuitry including neuropeptide Y. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a 3-6-month period. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life.

Aged↗
PubMedDate not supplied

Cancer anorexia-cachexia syndrome: current issues in research and management.

Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a six-month period. The two major options for pharmacological therapy have been either progestational agents, such as megestrol acetate, or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide--all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life.

Anorexia↗
PubMedDate not supplied

Pernicious cachexia: a different view of cancer.

Despite intensive effort to cure breast cancer, treatment generally fails, as evidenced by the age adjusted mortality from breast cancer. For 60 years, breast cancer mortality remained virtually constant. As treatment failed to improve the life prospect of the average patient, it is based on false premises, e.g., Halsted's hypothesis, according to which the tumor is the only threat to the patient. Yet there is more to cancer than just the tumor. Two hallmarks of cancer, cachexia, and paraneoplasia, are usually ignored, since it is assumed that they are caused by the tumor. But, what if it is the other way around, and cancer is first of all a cachexia accompanied by a tumor? At least this could explain why in most cancers treatment fails. Cancer is a chronic systemic disease with local manifestations. Like arteriosclerosis, that is also systemic and manifested solely by its local manifestations, e.g., stroke and myocardial infarction. In the same way as treatment of an ailing heart does not cure the underlying arteriosclerosis, tumor removal does not cure cancer, since being "metabolically" systemic. It is proposed here that carcinogens deplete a vital substance and induce a metabolic deficiency that ends in cachexia. In order to survive, the organism grows a protective organ, the tumor, that replenishes the missing substance. During pre-clinical phase of cancer, deficiency is slight and compensated even by a minute tumor. With time it gets worse and the tumor has to grow more and more in order to make up for the loss, causing pain and secondary damage to vital functions. The patient seeks help and the disease starts its clinical course. When deficiency worsens, the patient becomes cachectic and dies. Such a metabolic relationship exists in pernicious anemia, that illustrates how a tumor might be protective. Cancer is viewed here as pernicious cachexia induced by the loss of a vital metabolite and compensated by the tumor. Until the discovery of the missing substance, treatment ought to preserve the tumor and alleviate its secondary manifestations.

Cachexia↗
PubMed2001

Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid.

Cancer cachexia is characterized by selective depletion of skeletal muscle protein reserves. Soleus muscles from mice bearing a cachexia-inducing tumor (MAC16) showed an increased protein degradation in vitro, as measured by tyrosine release, when compared with muscles from nontumor-bearing animals. After incubation under conditions that modify different proteolytic systems, lysosomal, calcium-dependent, and ATP-dependent proteolysis were found to contribute to the elevated protein catabolism. Treatment of mice bearing the MAC16 tumor with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), attenuated loss of body weight and significantly suppressed protein catabolism in soleus muscles through an inhibition of an ATP-dependent proteolytic pathway. The ATP-ubiquitin-dependent proteolytic pathway is considered to play a major role in muscle catabolism in cachexia, and functional proteasome activity, as determined by "chymotrypsin-like" enzyme activity, was significantly elevated in gastrocnemius muscle of mice bearing the MAC16 tumor as weight loss progressed. When animals bearing the MAC16 tumor were treated with EPA, functional proteasome activity was completely suppressed, together with attenuation of the expression of 20S proteasome alpha-subunits and the p42 regulator, whereas there was no effect on the expression of the ubiquitin-conjugating enzyme (E2(14k)). These results suggest that EPA induces an attenuation of the up-regulation of proteasome expression in cachectic mice, and this was correlated with an increase in myosin expression, confirming retention of contractile proteins. EPA also inhibited growth of the MAC16 tumor in a dose-dependent manner, and this correlated with suppression of the expression of the 20S proteasome alpha-subunits in tumor cells, suggesting that this may be the mechanism of tumor growth inhibition. Thus EPA antagonizes loss of skeletal muscle proteins in cancer cachexia by down-regulation of proteasome expression, and this may also be the mechanism for inhibition of tumor growth.

Adenocarcinoma↗
PubMedDate not supplied

In vivo gene transfer of murine interleukin-4 inhibits colon-26-mediated cancer cachexia in mice.

Cancer cachexia has been suggested to be mediated by various cytokines derived either from tumor or host tissue. In the murine colon-26 (C-26) adenocarcinoma model IL-1, secreted by tumor-infiltrating mononuclear phagocytes, has an important role in induction of cancer cachexia. In order to suppress production of IL-1 in peritoneal macrophages we have used liposome-mediated gene transfer of the anti-inflammatory cytokine mIL-4, known as a potent inhibitor of IL-1 production. Balb/c mice were transfected by intraperitoneal inoculation of C-26 tumor cells. The mIL-4 transfected animals showed increased survival rate, delayed symptoms of cachexia and reduced anorexia in comparison with tumor-bearing control groups. However, tumor growth inhibition was not seen in mIL-4-transfected animals. Peritoneal macrophages from surviving mIL-4-transfected mice, when stimulated with LPS ex vivo, showed decreased IL-1 alpha production, 1672 +/- 202 pg/2 x 10(6) cells in contrast to tumor-bearing control animals, 3975 +/- 89 pg/2 x 10(6) cells, mock-transfected tumor-bearing animals 4004 +/- 174 pg/2 x 10(6) cells and tumor-free animals, 3142 +/- 60 pg/2 x 10(6) cells (p < 0.004). The present study demonstrates that in vivo gene transfer of an anti-inflammatory cytokine reduces cancer-associated cachexia by inhibition of IL-1 alpha production of tumor surrounding peritoneal macrophages, without a significant effect on tumor growth.

Adenocarcinoma↗
PubMed2004

[The role of proteasome in pathophysiology of cancer cachexia].

Cancer cachexia is a serious and life-treating syndrome that appears in most solid tumor patients. The syndrome is associated with anorexia, loss of protein mass, wasting of lipids, and disturbances of carbohydrate metabolism. Moreover, psychological distress and lower quality of life are often seen in patients with cancer cachexia. The latter is a multimodality process in which cytokine interactions, action of enzymes playing a key role in lipid metabolism, and activity of proteolytic proteinases are the complex net that are responsible for destruction of an organism suffering from cancer cachexia. Recently, it has been shown a growing role of ubiquitin-proteasome pathway in cachexia. Biochemical interactions are crucial for further study, mainly, when a novel target therapy appears to treat cancer in different modalities. In case of proteasome, PS-341 (bortezomib, Velcade) an inhibitor of proteasome is under investigation in clinical trials phase I.

Boronic Acids↗
PubMed2005

Chemotherapy under cachectic conditions and the possibility of cachexia-controlled chemotherapy.

We studied the role of chemotherapy in cancer cachexia, which is well known to lower QOL and responsiveness to chemotherapy. In BALB/c mice we used two clones derived from the murine colon 26 adenocarcinoma cell line; clone 5, a non-cachexigenic tumor and clone 20, a cachexigenic tumor, in which IL-6 mRNA was selectively detected. While maximum tolerated dose (MTD) of CPM and CPT-11 showed significantly smaller tumor weight and higher survival than 1/2 MTD in both drug groups with clone 5, the results were reversed with clone 20. The tumor weights with MTD of CPM or CPT-11 in combination with anti-IL-6 antibody treatment, which decreases serum IL-6 level and improves cachexia status, were significantly smaller than those in the MTD treatment-alone group with clone 20, but not with clone 5. From these results, we suggest that lower dose chemotherapy or cachexia-controlled chemotherapy, such as some chemotherapeutic agents with neutralizing cachexia-related cytokine effects, elicit anti-tumor effects in cachectic individuals that are superior to conventional MTD chemotherapy.

Animals↗
PubMed2006

Muscle wasting in cancer and ageing: cachexia versus sarcopenia.

Muscle wasting during cancer and ageing share many common metabolic pathways and mediators. Due to the size of the population involved, both cancer cachexia and ageing sarcopenia may represent targets for future promising clinical investigations. Cancer cachexia is a syndrome characterized by a marked weight loss, anorexia, asthenia and anemia. In fact, many patients who die with advanced cancer suffer from cachexia. The degree of cachexia is inversely correlated with the survival time of the patient and it always implies a poor prognosis. In recent years, age-related diseases and disabilities have become of major health interest and importance. This holds particularly for muscle wasting, also known as sarcopenia that decreases the quality of life of the geriatric population, increasing morbidity and decreasing life expectancy. The cachectic factors (associated with both depletion of fat stores and muscular tissue) can be divided into two categories: of tumour origin and humoural factors. In conclusion, more research should be devoted to the understanding of muscle wasting mediators, both in cancer and ageing, in particular the identification of common mediators may prove as a good therapeutic strategy for both prevention and treatment of wasting both in disease and during healthy ageing.

Aging↗
PubMed2006

[Pharmacological therapy of cancer anorexia-cachexia].

Anorexia is one of the most common symptoms of patients with advanced cancer and it presents as loss of appetite due to satiety. On the other hand, cachexia is described in those patients with unwanted weight loss. Cancerous processes produce an energy unbalance by decreased food intake and increased catabolism, resulting in a clearly negative balance. Several factors determining cachexia are observed, from metabolic unbalances produced by tumoral products and endocrine impairments or the inflammatory response produced by cytokines, all of them leading to higher lipolysis, loss of muscle protein, and anorexia. Besides, causes of anorexia are multiple, from chemotherapy agents, radiotherapy, or immunotherapy, which may produce different degrees of nausea, vomiting, diarrhea, and also leading to impairments of taste and smell, to obstruction of the digestive tract, pain, depression, constipation, etc. From the knowledge of the different mechanisms producing the anorexia-cachexia syndrome, hypercaloric diets for artificial nutrition have been studied with varying success, and different drugs with a positive effect on appetite gain such as progestogens, steroids, and with lesser clinical evidence cannabinoids, cyproheptadine, mirtazapine (antidepressant), and olanzapine (antipsychotic). Other drugs have been studied because of their anti-inflammatory properties, anti-cytokine, such as melatonin, polyunsaturated omega-3 fatty acids, pentoxifylline, and thalidomide; with the exception of the latter, clinical data are still scant for daily usage. Similarly happens with testosterone-derived anabolic drugs or with metabolism inhibitors such as hydrazine sulfate. With no doubt, progestogens, especially megestrol, and corticosteroids will be first-line therapies for anorexia-cachexia syndrome to stimulate the appetite and increase weight (megestrol), and have an effect on quality of life improvement and comfort in patients with advanced cancer.

Anorexia↗
PubMed2006

[Physiology of sarcopenia. Similarities and differences with neoplasic cachexia (muscle impairments in cancer and ageing)].

Muscle wasting during cancer and ageing share many common metabolic pathways and mediators. Due to the size of the population involved, both cancer cachexia and ageing sarcopenia may represent targets for future promising clinical investigations. Cancer cachexia is a syndrome characterized by a marked weight loss, anorexia, asthenia and anemia. In fact, many patients who die with advanced cancer suffer from cachexia. The degree of cachexia is inversely correlated with the survival time of the patient and it always implies a poor prognosis. In recent years, age-related diseases and disabilities have become of major health interest and importance. This holds particularly for muscle wasting, also known as sarcopenia, that decreases the quality of life of the geriatric population, increasing morbidity and decreasing life expectancy. More research should be devoted to the understanding of muscle wasting mediators (associated with both depletion of fat stores and muscular tissue), both in cancer and ageing, in particular the identification of common mediators may prove as a good therapeutic strategies for both prevention and treatment of wasting both in disease and during healthy ageing.

Aging↗
PubMed2006

[Cardiac cachexia].

Chronic heart failure (CHF), especially affecting the right heart, frequently leads to malnutrition. If the latter is severe and is combined to other factors, it may lead to cardiac cachexia. This one is associated to increased mortality and lower survival of patients suffering from it. The causes of cardiac cachexia are diverse, generally associated to maintenance of a negative energy balance, with increasing evidence of its multifactorial origin. Neurohumoral, inflammatory, immunological, and metabolic factors, among others, are superimposed in the patient with CHF, leading to involvement and deterioration of several organs and systems, since this condition affects both lean (or active cellular) mass and adipose and bone tissue osteoporosis. Among all, the most pronounced deterioration may be seen at skeletal muscle tissue, at both structural and functional levels, the heart not being spared. As for treatment, it should be based on available scientific evidence. Assessment of nutritional status of any patient with CHF is a must, with the requirement of nutritional intervention in case of malnutrition. In this situation, especially if accompanied by cardiac cachexia, it is required to modify energy intake and oral diet quality, and to consider the indication of specific complementary or alternative artificial nutrition. Besides, the causal relationship of the beneficial role of moderate physical exertion is increasing, as well as modulation of metabolic and inflammatory impairments observed in cardiac cachexia with several drugs, leading to a favorable functional and structural response in CHF patients.

Cachexia↗
PubMed2005

Clinical impact of cachexia on survival and outcome of cancer patients.

Approximately one half of all cancer patients experience a complex metabolic status involving progressive exhaustion of adipose and skeletal muscle tissue. This condition, known as cachexia, is responsible for more than 20% of the overall deaths in cancer patients. Although its main mechanisms remain unknown, several hypotheses have been proposed. One of the pathogenic mechanisms involves leptin and hypothalamic neuropeptide-containing pathways. Orexigenic and anorexigenic neuropeptides are down-regulated respectively upregulated as a result of cancer. Other pathogenic theories consider tumour derived factors, such as LMF (Lipid Mobilising Factor) and PIF (Proteolysis-inducing Factor), to be responsible for the weight losing pattern of cancer patients via activation of various catabolic pathways (e.g. ubiquitin-proteasome proteolytic-pathway, etc.). Despite the controversial discussion of cachexia-inducing mechanisms it is clear that proinflammatory cytokines, such as TNFalpha, IFNgamma, IL-1, IL-6 and IL-8, are linked to all pathways that induce cachexia. Although only limited treatment exists for patients with cancer cachexia, recent studies with eicosapaentanoic acid showed promising effects in reversing weight losing pattern of cachectic patients. Cytokine targeted monoclonal antibodies, cytokine traps and genetic therapies are also evaluated for future therapeutic strategies.

Cachexia↗
PubMed2006

[Cachexia in chronic cardiac disease. Ancient syndrome new idea?].

Cachexia has long been recognized as serious complication of chronic illness. Cardiac cachexia is a syndrome of generalised wasting which carries a poor prognosis of the chronic heart disease. Characteristic features of cachexia include the activation of the immune system associated with raised plasma concentriations of tumor necrosis factor alpha (TNF(alpha) and other plasma cytokines. Another crucial issue is muscle wasting through the ubiquitin proteasome pathway. The prevention or attenuation of disease related skeletal muscle degeneration has been a common goal in the treatment of cardiac cachexia.

Animals↗
PubMed1991

Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor.

Melanoma-derived lipoprotein lipase inhibitor (MLPLI) is a factor purified from the conditioned medium of a human melanoma cell line, SEKI, which induced severe cachexia in tumor-bearing nude mice. Amino acid sequencing revealed that the amino-terminal portion was identical to that of leukemia-inhibitory factor (LIF). To determine whether MLPLI is actually LIF, the expression of LIF mRNA was examined in the SEKI melanoma cell line. Northern blot analyses revealed that the cell line displayed an intense hybridizable band with a molecular size of 3.8 kilobases, suggesting that MLPLI is identical to LIF. The relationship between the development of the cancer cachexia syndrome and the expression of LIF mRNA was examined in four melanoma xenografts, SEKI, G361, A375 and MEWO, in nude mice. SEKI- and G361-bearing nude mice developed cancer cachexia syndrome, and their body weights decreased by the 25th day after the transplantation to 73.6% and 73.8% of the control, respectively. A375- and MEWO-bearing nude mice, however, did not develop the syndrome. Northern blot analyses revealed that G361 as well as SEKI expressed a large amount of LIF mRNA, but A375 and MEWO did not, suggesting a close relationship between the expression of LIF mRNA and the development of the syndrome. These data support the concept that MLPLI, or LIF, plays an important role in the development of the cancer cachexia syndrome observed in melanoma-bearing nude mice.

Animals↗
PubMed1988

Studies of high-dose megestrol acetate: potential applications in cachexia.

Cachexia can be a severe problem in the management of patients with cancer and other illnesses because it produces an ever-increasing spiral of anorexia, undernutrition, loss of tissue mass, muscle wasting, and increased susceptibility to infection and treatment toxicity. Megestrol acetate has been observed to produce weight gain in patients with hormone-sensitive tumors and has recently been noted to produce a similar degree of weight gain in those with hormone insensitive tumors. A review of our experience in a phase I-II study of escalating doses of megestrol acetate for advanced breast cancer revealed that weight gain occurred in more than 80% of all treated patients and in 90% of those patients who received treatment for 6 or more weeks. The median maximum weight gain was 5.5 kg, with a range of -5.6 to 44 kg. Subjective improvement in appetite occurred in most patients. These data provided the impetus for a series of further studies of the role of megestrol acetate in the control of cachexia, including a randomized study in cancer cachexia, AIDS cachexia, and anorexia nervosa. In addition, a number of laboratory trials seeking the mechanism of action have been initiated, as well as whole-animal studies to define the compartment of increased weight. Our data and the preliminary observation of weight gain in patients with hormone insensitive tumors suggest that megestrol acetate has a potential role in producing a possibly dose-related subjective improvement and an increase in appetite and weight. Further research is necessary to understand the mechanism of appetite stimulation and anabolic effect.

Body Weight↗
PubMed1993

Mechanisms of experimental cancer cachexia. Local involvement of IL-1 in colon-26 tumor.

In the colon-26 (C-26) tumor model, the cytokine IL-6 is an important factor involved in experimental cancer cachexia. Recent in vitro data indicated that IL-1 plays a role in the interaction between host macrophages and C-26 cells that express IL-1R, resulting in the amplification of tumor IL-6 production. To investigate the role of IL-1 on the development of C-26 cachexia in vivo, the effect of specific blockade of the action of IL-1 with reagents against IL-1R was evaluated. Both IL-1R antagonist (IL-1RA) and the mAb 35F5 directed against IL-1R type I, prevented binding of radioactive IL-1, and inhibited IL-1-induced IL-6 synthesis by the C-26 cell line. Whereas a systemic administration of these reagents did not reverse weight loss in C-26-bearing mice, intratumoral injections of IL-1RA significantly reduced cachexia. Furthermore, body composition analysis confirmed that this treatment improved lean tissue and fat, as well as hypoglycemia and serum IL-6 level. The fact that the treatment did not change the tumor burden suggests that it affected the host directly. These results support the hypothesis that, at the microenvironment of the C-26 tumor, IL-1 is involved in the cachexia endured by the host.

Animals↗