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PubMed2004

Indomethacin and ibuprofen preserve gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma.

Skeletal muscle wasting is a prominent feature of cancer cachexia and involves decreased muscle protein synthesis and increased activity of the ubiquitin-proteasome pathway of protein degradation. We report that both indomethacin and ibuprofen improved body weight and weight of the gastrocnemius muscle in tumor-bearing mice. Ibuprofen increased the soluble protein content of the muscle without affecting muscle levels of phosphorylated p70 S6 kinase, a ribosomal kinase involved in protein synthesis. Paradoxically, indomethacin increased levels of ubiquitin-conjugated proteins. Further study is needed to understand the mechanism of action by which indomethacin and ibuprofen preserve body weight and muscle mass in the tumor-bearing mice. The data suggest that ibuprofen may have beneficial effects in the treatment of cancer cachexia.

Adenocarcinoma↗
PubMed2002

Overexpression of interleukin-15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders.

Interleukin-15 (IL-15) is a novel anabolic factor for skeletal muscle which inhibits muscle wasting associated with cancer (cachexia) in a rat model. To develop a cell culture system in which the mechanism of the anabolic action of IL-15 on skeletal muscle could be examined, the mouse C2 skeletal myogenic cell line was transduced with a retroviral expression vector for IL-15 and compared to sister cells transduced with a control vector. Overexpression of IL-15 induced fivefold higher levels of sarcomeric myosin heavy chain and alpha-actin accumulation in differentiated myotubes. Secreted factors from IL-15-overexpressing myogenic cells, but not from control cells, induced increased myofibrillar protein accumulation in cocultured control myotubes. IL-15 overexpression induced a hypertrophic myotube morphology similar to that described for cultured myotubes which overexpressed the well-characterized anabolic factor insulin-like growth factor-I (IGF-I). However, in contrast to IGF-I, the hypertrophic action of IL-15 on skeletal myogenic cells did not involve stimulation of skeletal myoblast proliferation or differentiation. IL-15 induced myotube hypertrophy at both low and high IGF-I concentrations. Furthermore, in contrast to IGF-I, which stimulated only protein synthesis under these culture conditions, IL-15 both stimulated protein synthesis and inhibited protein degradation in cultured skeletal myotubes. These findings indicate that IL-15 action on skeletal myogenic cells is distinct from that of IGF-I. Due to the ability of IGF-I to stimulate cell division and its association with several forms of cancer, controversy exists concerning the advisability of treating cachexia or age-associated muscle wasting with IGF-I. Administration of IL-15 or modulation of the IL-15 signaling pathway may represent an alternative strategy for maintaining skeletal muscle mass under these conditions.

Actins↗
PubMed1993

Weight loss in patients with hematological neoplasias is associated with immune system stimulation.

Weight loss is the main symptom of so-called tumor cachexia. The pathogenetic mechanisms underlying cachexia are poorly understood; however, it appears that enhanced formation of cytokines such as interferon-gamma and tumor necrosis factor-alpha are involved. In 94 patients suffering from hematological neoplasias we compared body weight changes with serum neopterin, tryptophan, and kynurenine. Biochemical changes, the formation of neopterin, the degradation of tryptophan are closely related to interferon-gamma activity. The majority of our patients had increased neopterin and decreased tryptophan concentrations. Weight loss was seen particularly in patients with higher neopterin and lower tryptophan values. An association between higher neopterin levels and greater weight loss was apparent at study entry and during the follow-up of patients. Our data support the concept that weight loss is closely linked to endogenous interferon-gamma activity.

Biomarkers↗
PubMed1993

The effects of a biological response modifier, OK-432, on tumor-induced alterations in the host metabolism.

The effects of multicytokine inducer, OK-432, on tumor-induced metabolic alterations were studied by assessing three key regulatory enzymes of gluconeogenesis, de novo fatty acid synthesis and the triglyceride clearance pathways. Two Klinish Einheit (KE) of OK-432 was subcutaneously injected on alternate days, for 10 days, into Fischer 344 rats with or without methylcholanthrene-induced sarcoma. At the time of sacrifice, the tumors accounted for approximately 23% of their total body weight. The injections of OK-432 did not affect the amount of food intake in either the tumor bearers or the controls. The tissue lipoprotein lipase activities in the epididymal fat pads of the tumor bearers were significantly decreased compared with the controls (P < 0.01). Phosphoenolpyruvate carboxykinase activity in the liver was significantly increased (P < 0.01), while malic enzyme activity tended to be decreased in the tumor bearers compared with the controls. However, there were no significant differences in those activities depending on the OK-432 injections, even though OK-432 induced tumor necrosis factor (TNF) and increased cytotoxic activities in the mesenteric lymph nodes as well as in the spleen. Thus, although the role of monokines in inducing cancer cachexia is not yet clearly understood, OK-432 was not able to revert the tumor-induced metabolic alterations which lead to tissue wasting and cancer cachexia.

Animals↗
PubMed1996

The possible role of TNF-alpha and IL-2 in inducing tumor-associated metabolic alterations.

This study was conducted to investigate the role of tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) in inducing cancer cachexia, and the results were compared with those obtained from our previous study on Fisher 344 rats with methylcholanthrene-induced sarcoma. Three groups of male Fisher 344 rats received one of the following regimens: 4 x 10(4) IU of human recombinant TNF-alpha per rat per day subcutaneously (sc) for 5 consecutive days (n = 5), 3.5 x 10(5) U human recombinant IL-2 per rat per day sc for 14 consecutive days (n = 5), or normal saline (n = 5). The activities of both phosphoenolpyruvate carboxykinase (PEPCK) and malic enzyme (ME) were increased slightly in the IL-2 group. Furthermore, LPL activity was significantly increased in the adipose tissue of the TNF group and in the cardiac muscle of the IL-2 group, but not in that of the TNF group. These results show that there is a significant difference between the metabolic alterations seen in the tumor-bearing state and those induced by either TNF-alpha or IL-2 alone. Thus, it is unlikely that IL-2 or TNF-alpha is the sole mediator of cancer cachexia in this tumor and rat model.

Animals↗
PubMed1996

Nutrition in cancer patients.

Many factors can modify nutritional status in cancer patients, including cachexia, nausea and vomiting, decreased caloric intake or oncologic treatments capable of determining malabsorption. Cachexia is a complex disease characterized not only by a poor intake of nutrients or starvation, but also by metabolic derangement. Nausea and vomiting may limit the nutrient intake and are most often the consequences of oncologic treatments or opioid chronic therapy. Decreased caloric intake is considered to be one of the major causes of malnutrition, although the causes of anorexia remain unclear. Malabsorption is generally attributed to the consequences of oncologic treatments reducing the gastrointestinal absorption. Biochemical measurements and immunological tests may be not reliable indicators of nutritional status in cancer patients. Therefore, medical history, physical examination, estimates of daily oral intake, weight changes and an appropriate consideration of the nutritional requirements according to the stage of disease must still be assessed. The therapeutic approaches should be individualized and realistic. Whenever possible, oral nutrition is the method of choice, with due consideration for specific dietary needs. Nausea and anorexia can be reduced by different kinds of drugs. A careful decision based on good clinical judgement is necessary before deciding to start either enteral or parenteral nutrition, to avoid a useless, costly and difficult treatment. In choosing the route for administration of nutrients, availability of and access to a functioning gastrointestinal tract, compliance and comfort of the patient, gastrointestinal toxicity due to chemotherapy or radiotherapy fields, different costs, duration and place of treatment should be considered rather than the different capacity of parenteral versus enteral nutrition. However, postoperative periods after massive intestinal resection often require prolonged parenteral nutrition. The benefits of parenteral nutrition are not often demonstrable in patients with bowel obstruction. Different ethical aspects are presented. Flexibility in attempting to meet the nutrition needs of each patient is probably the most useful guide.

Cachexia↗
PubMed2001

Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites.

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin 6, tumor necrosis factor alpha, and interferon gamma, have been proposed as mediators of cancer cachexia; these data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. We therefore studied the relationship between serum leptin and serum cytokines interleukin 6 and tumor necrosis factor alpha levels in advanced-stage cancer patients. Twenty-nine advanced stage cancer patients (all but one stage IV) with tumors at various sites were included in the study. A direct correlation between body mass index and serum leptin levels was found both in cancer patients and in healthy individuals. The serum levels of interleukin 6 were significantly higher in cancer patients than in healthy individuals. In cancer patients an inverse correlation was found between serum levels of leptin and proinflammatory cytokines. There was an inverse correlation between the Eastern Cooperative Oncology Group performance status scale and serum levels of leptin. Regarding survival, patients with very high serum levels of proinflammatory cytokines and very low levels of leptin had very short survival. Although obtained in a cancer patient population not overtly cachectic, our results provide further evidence that a simple dysregulation of leptin production and/or release cannot be involved in cancer-associated pathophysiological changes leading to cachexia.

Adult↗
PubMed1999

Increase in histidine decarboxylase activity in tissues of mice bearing Colon-26 tumor cells.

The changes in histidine decarboxylase (HDC) activity, histamine and tele-methylhistamine contents were examined in tissues of mice after the inoculation of Colon-26 tumor cells subcutaneously into the lower back. The HDC activity in the spleen of mice increased significantly 14 days after the inoculation of Colon-26 and the increase in HDC activity continued for up to 28 days. However, the histamine content in the spleen of tumor-bearing mice was not changed significantly during the observation period. In the following experiments, two subclones of the Colon-26 cell line, cachexia-inducing clone-20 and non cachexia-inducing clone-5, were used and the induction of HDC activity in mice was examined in four tissues, spleen, lung, liver and kidney. Both clone-20 and clone-5 induced the increase in HDC activity to the same extent in the spleen and lung, but not in the liver and kidney. As observed using the Colon-26 original cell line, the histamine contents in the four tissues of tumor-bearing mice were not different from those in the control mice. In contrast, the levels of tele-methylhistamine, one of the major catabolites of histamine, in the tumor-bearing mice increased significantly compared with the control mice in all four tissues examined. There was a correlation between the increase in tele-methylhistamine level and the increase in HDC activity in the tissues. A histological study indicated that the tissue mast cells were not increased in spleen and lung of tumor-bearing mice. These findings indicated that the increase in HDC activity in the spleen and lung occurred in parallel with the growth of inoculated tumor cells in mice and suggested that the cells other than mast cells may be involved in the increase in HDC activity. The tumor-bearing state produced histamine with a high turnover rate in the mouse tissues, especially in the spleen and lung.

Adenocarcinoma↗
PubMed2001

Combined effects of docetaxel and fluoropyrimidines on tumor growth and expression of interleukin-6 and thymidine phosphorylase in breast cancer xenografts.

PURPOSE: Although several combination treatments with docetaxel and other antitumor agents have been tested in experimental and clinical studies, their synergistic effects are still ill-defined. The degree of synergism between docetaxel and two oral fluoropyrimidines, tegafur and 5'-deoxy-5-fluorouridine (5'-dFUrd), was investigated in the KPL-4 human breast cancer xenograft model. METHODS: Because this KPL-4 cell line secretes interleukin-6 (IL-6) and induces cachexia, the effects of the combined treatment on serum IL-6 levels and cachectic markers were investigated. In addition, the expression levels of thymidine phosphorylase (dThdPase), a key enzyme for converting 5'-dFUrd to 5-fluorouracil, were determined. Female nude mice bearing KPL-4 tumors were treated orally with 5'-dFUrd (60 mg/kg, five times a week) or tegafur (100 mg/ kg, five times a week) and by intraperitoneal injection of docetaxel (5 or 10 mg/kg, once a week). RESULTS: Although docetaxel (5 mg/kg) alone did not decrease either tumor growth or serum IL-6 levels, docetaxel (5 mg/kg) plus 5'-dFUrd or tegafur enhanced tumor growth inhibition and decreased serum IL-6 levels more than 5'-dFUrd or tegafur alone. Docetaxel (5 mg/kg) alone slightly increased the percentage of dThdPase-positive tumor cells, but the combined treatment with docetaxel plus 5'-dFUrd or tegafur significantly decreased the percentage of dThdPase-positive cells in the KPL-4 tumors. CONCLUSION: These findings indicate that docetaxel may stimulate dThdPase expression in tumor tissues and may enhance the antitumor activity of oral fluoropyrimidines. In addition, combined treatment with docetaxel and oral fluoropyrimidines may decrease serum IL-6 levels and may ameliorate IL-6-induced cancer cachexia.

Animals↗
PubMed2004

Outcome research in palliative care: could it represent a new dimension of clinical research or clinical practice?

Outcome research is a new dimension of clinical research, and all fields of clinical medicine are involved in this kind of analysis. Overall survival and quality of life are the main outcomes identified in clinical oncology. The former must be the main outcome whenever possible; the latter has to be the main outcome when an improvement of overall survival cannot be expected. It follows that quality of life is the main outcome of palliative care, in which the patient instead of the disease represents the target of the clinical approach. In our critical paper, we review the meaning of clinical outcomes in palliative care, classifying the outcomes as main and surrogate outcomes, and the results of the trials as indexes of activity and efficacy of a treatment. We also review the main randomized clinical trials on the treatment of cancer cachexia, trying to define the role of the treatments in cachexia-related symptom control and quality of life improvement. Strictly related to outcome analysis is the dimension of pharmacoeconomic evaluation. The models of the different designs of pharmacoeconomic analysis are revisited in an attempt to conjugate the pharmacoeconomic evaluation with the particular dimension of palliative care.

Cachexia↗
PubMed1998

Parenteral versus enteral nutrition in cancer patients: indications and practice.

Prospective randomly controlled trials have failed to demonstrate the clinical efficacy of providing nutritional support to most cancer patients in terms of morbidity, mortality, and duration of hospitalization. Serious shortcomings in study design have limited the possibility of drawing definitive conclusions from the data. Thus, nutritional intervention needs to be seen as a method of support, with the aim of maintaining nutritional and functional status during the stress of the oncology treatment to prevent or attenuate cachexia. There is no disease during which the patient benefits from prolonged wasting. Pretreatment weight loss is quoted as a major indicator of poor survival and response to therapy of cancer patients. As a consequence, an early and serial assessment of nutritional status, perhaps followed by an immediate intervention with nutritional support is strongly recommended. There are other specific reasons for using the gut rather than the intravenous route for nutrient administration besides the often reported disadvantage of significant cost. Local intestinal stimulation prevents the mucosal atrophy and bacterial translocation that can be triggered by several precipitating factors, as frequently seen in oncologic patients. These include endotoxin, radiation therapy, cytotoxic and immunosuppressive drugs, cytokines, bowel and biliary obstruction, broad-spectrum antibiotics, and the tumour itself, as well as parenteral nutrition (PN). As the enteral route of nutritional support has been found to be as good as or preferable to PN in terms of maintenance of nutritional status or immune function, prevention of bacterial translocation, maintenance of normal gut flora, transit and histology, and prevention of hypercatabolic responses to stressful events, it is always preferable in terms of physiological response, local and systemic competence, quality of life and cost, and should be the method of choice for the nutritional support of cancer patients. Although retrospective studies of PN suggest a benefit for patients with cancer who are undergoing surgery, radiation, or chemotherapy, carefully designed, prospective studies report less conclusive findings. The failure of conventional PN to improve clinical outcomes in patients with cancer may be related to the fact that standard formulations do not address or reverse abnormalities of intermediate metabolism that result in cancer cachexia. Supplemental substances have been proposed in an attempt to improve the efficacy of PN, including insulin, growth hormone and branched chain amino acids. The difficult task is to identify those patients who are at risk for malnutrition and at the same time identify the subset of patients who will benefit clinically from parenteral nutritional repletion. Severe malnutrition in patients requiring surgery, bone marrow transplantation in patients unable to tolerate enteral supplementation and postoperative complications necessitating nutritional support are specific indications. Routine use of PN should be discouraged.

Cachexia↗
PubMed2004

[Eating and drinking at the end of life. Nutritional support for cancer patients in palliative care].

Anorexia, malnutrition followed by cachexia is observed in up to 80% of cancer patients with advanced stages of their disease, particularly in head and neck cancer, gastro-intestinal cancer and lung cancer. Malnutrition is associated with an unfavourable prognosis and has been demonstrated to be associated with an increased morbidity and an increased readmission rate. Cachexia itself can be the primary cause of death in cancer patients. Early intervention and nutritional support may be helpful in preventing anorexia and further weight loss. Successful approaches in treating anorexia have been undertaken with corticosteroids and gestagenes.

Aged↗
PubMed1985

Weight loss associated with an endotoxin-induced mediator from peritoneal macrophages: the role of cachectin (tumor necrosis factor).

Endotoxin-induced cells of the reticuloendothelial system were shown to produce mediator(s) that evoke a state of cachexia in recipient animals. The factor(s) responsible were assayed in endotoxin-resistant (C3H/HeJ) mice, which were injected with dialyzed conditioned medium obtained from lipopolysaccharide-induced peritoneal macrophages. The mice exhibited weight loss and anorexia, and they died if sufficient quantities of medium were administered. The syndrome was reversible if injections were discontinued. Endotoxin alone did not produce this effect, and no gross pathologic lesions were discernable in the treated animals. In this model system, cachexia appears to result from the action of soluble macromolecules produced by activated macrophages in vitro. Cachectin (murine tumor necrosis factor) is thought to play a central role in this phenomenon.

Animals↗
PubMed1990

The in vitro and in vivo effects of human growth hormone administration on tumor growth of rats bearing a transplantable rat pituitary tumor (7315b).

The direct effects of human GH and IGF-I on PRL secretion and cell proliferation were studied on PRL secreting rat pituitary tumor 7315b cells in vitro, as well as the effects in vivo of human GH administration on body weight, IGF-I levels and tumor size in rats bearing this transplantable tumor. In the in vitro studies IGF-I levels above 5 nM stimulated PRL release in a dose-dependent manner while GH, in concentrations of 0.23-45 nM, did not affect PRL release. Cell proliferation was stimulated by IGF-I in a dose-dependent manner from 0.5 nM onwards, while GH did not have an effect. The in vivo studies showed that 1 mg GH/rat/day prevented tumor-induced cachexia and normalized the suppressed IGF-I levels without stimulating tumor growth. It is concluded that tumor-induced cachexia can be prevented by exogenous GH administration without an increase in tumor mass, even if a tumor model is used whose cultured tumor cells respond to exposure to IGF-I with a mitotic response.

Animals↗
PubMed1993

Omega-3 fatty acids as coadjuvant treatment in AIDS.

Human immunodeficiency virus (HIV), is able to replicate in many human cells such as helper lymphocytes, monocytes/macrophages and glial cells. Monocytes/macrophages must be considered an important reservoir of HIV in vivo and a producer of cytokines such as Interleukin-1 (IL1) and tumor necrosis factor (TNF). These substances lead to an autocrine feedback loop that produces an increased virus replication and a secondary induction of other cytokines such as Interleukin 6 (IL6) and granulocyte-macrophage colony stimulating factor (GM-CSF). These cytokines all together may be responsible for many clinical aspects of the disease such as headache, fever, anorexia, subtle cognitive changes, motor disfunctions and cachexia. The future strategies in the treatment of AIDS must be a combination of drugs acting on different points of viral replication and with synergistic potential. Omega 3 polyunsaturated fatty acids (omega-3) can be considered a candidate for their pleiotropic effects on immunological and metabolic systems. In particular, their use is considered for their ability to decrease IL1 and TNF production by monocytes/macrophages, as demonstrated by many authors. The decreased induction of these cytokines and consequently of IL6 and acute phase proteins may have beneficial effects on many clinical manifestations of AIDS such as cachexia.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Recent implications of weight loss in lung cancer management.

Successful lung cancer management has been hindered by the limited efficacy of dietary and pharmacologic interventions to prevent or reverse cancer-associated weight loss. The addition of total parenteral nutrition to chemotherapy in early trials was associated with survival detriment. Dietary counseling and enteral supplement use are common strategies that, when evaluated in randomized trials, do not improve anthropometrics or clinical outcome in lung cancer. Pharmacologic agents including corticosteroids, cyproheptadine, growth hormone, hydrazine sulfate, dronabinol, and pentoxyphylline also have failed to improve even anthropometric parameters in this condition. Megestrol acetate use is associated with appetite stimulation and non-fluid weight gain but, when evaluated in small cell lung cancer patients receiving defined chemotherapy, failed to improve global quality of life, and survival and was associated with toxicity. New strategies for nutrition-based interventions in lung cancer cachexia must consider their potential influence on tumor growth as well as on nutritional status. Recent lung cancer prognostic analyses have identified gender differences in outcome and weight loss that suggest potential targets for combined hormonal and nutrition interventions. Emerging information regarding the influence of specific fatty acids on tumor growth and cachexia development have identified additional approaches for future evaluation.

Cachexia↗
PubMed1989

Cachectin/tumor necrosis factor and other cytokines in infectious disease.

The studies reviewed here represent but a fraction of those published in the field last year, but they serve to illustrate two important points: (1) the cytokine network possesses enormous diversity of biological function, and (2) it is redundant, such that overlapping and synergistic effects are observed between many different cytokines. The impact of this system on the host is pervasive and readily amplifiable, and integrates the diverse responses to infectious disease which may be either beneficial, protecting against infection, or deleterious, causing tissue injury and death. The example of cachectin/TNF illustrates this type of scenario: during local infection or inflammation, low levels of cachectin/TNF act to enhance immune responsiveness, stimulate blood-vessel growth, increase energy mobilization, induce the release of other cytokines, and promote wound-healing; when overwhelming infection occurs, as in septicemia, large quantities of cachectin/TNF reach the circulation and cause shock, MSOF, and death; if a persisting infection develops and cachectin/TNF is chronically secreted, it mediates a state of cachexia which may be fatal. Future studies will undoubtedly advance our understanding of these effects, and that of the other cytokines. The development of novel therapies for inflammation, septic shock, and cachexia may be based on such advances.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Coenzymes Q9 and Q10 in skeletal and cardiac muscle in tumour-bearing exercising rats.

Physical exercise increases metabolic rate, and induces both adaptational biogenesis of mitochondria in skeletal muscle and an increase in antioxidant capacity. The onset of experimental anorexia and cachexia can be delayed by voluntary exercise. As skeletal muscle is the main target for cancer cachexia, we determined the levels of coenzymes Q9 and Q10 in skeletal muscle from tumour-bearing exercising rats, and compared them to those of sedentary tumour-bearers and controls. Both tumour-bearing groups had increased levels of coenzymes Q9 and Q10 in the anterior tibial muscle (P < 0.05 for exercised animals). In the soleus muscle, only the tumour-bearing exercising animals demonstrated an increase in the levels of both coenzymes (P < 0.05). In cardiac muscle, the presence of tumour and exercise reduced the levels of coenzymes below that of sedentary controls. Exercise counteracted the anaemia in the tumour-bearing host (P < 0.05). In conclusion, the increase in antioxidant capacity in skeletal muscle indicates a defence mechanism in the tumour-bearing hosts which is augmented by physical exercise.

Animals↗