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At least 19 recordsLinked to original sources
PubMedDate not supplied

Relationship between tumor growth and cachexia during progressive malignant disease: a new measure of the extent of cachexia, the cachexia index.

The relationship between the dynamics of tumor growth and the development of cachexia in C57b1/6j mice bearing the syngeneic transplantable adenocarcinoma EO 771 has been studied. The tumors grow independently of the inoculum size according to the Gompertzian mode of growth, with a maximum growth rate at a tumor size of about 3 g. As a dynamic measure of the degree of cachexia, the cachexia index "K", i.e. the quotient of the alteration of the carcass weight of the animal divided by the alteration of the tumor weight during the same time interval, is introduced. K is superior to a simple estimation of the alteration of the carcass animal weight because it also considers local weight-reducing effects of the infiltrating tumor growth. With respect to cachexia, three phases of tumor growth can be distinguished; cachexia develops mainly during the 2nd phase, i.e. for tumor sizes between 1.0 to 3.5 g which strongly correlates with the maximum growth rate of the tumor.

Adenocarcinoma↗
PubMed1992

Mechanisms of experimental cancer cachexia. Interaction between mononuclear phagocytes and colon-26 carcinoma and its relevance to IL-6-mediated cancer cachexia.

In a recent report we showed that IL-6 is an important mediator of experimental cancer cachexia in the colon-26 (C-26) tumor system. In culture, on a per cell basis, C-26.IVX cell line (which develops tumors and induces severe cachexia of syngeneic hosts) produces up to 60-fold less IL-6 than single cell suspensions prepared from freshly excised tumors. In this study, the mechanism behind this observation was investigated. Analysis of the cellular composition of progressing C-26 tumors indicated they contained up to 6% of macrophages. T cells, B cells, and granulocytes were not detected in the tumors. Because C-26.IVX line grown in vitro contained no macrophages, the possibility that macrophage products may augment IL-6 synthesis by the tumor cells was tested. Indeed, IL-1 beta in a dose-dependent manner and at picogram amounts could potentiate IL-6 production by the C-26 cell line. The presence of high affinity receptors for IL-1 on the C-26.IVX cell line was established. These cells expressed approximately 1500 IL-1 sites per cell with a dissociation constant of approximately 20 pM. Next, we attempted to mimic the situation in vivo by coculture of C-26.IVX cells with syngeneic peritoneal macrophages and found that this condition gives rise to an augmented IL-6 production similar to that observed with in vivo derived tumor cells or rIL-1 beta-treated C-26.IVX cells. Furthermore, anti-IL-1 type I receptor antibody completely blocked C-26.IVX IL-6 production induced by either rIL-1 beta or by peritoneal macrophages. Taken together, these data suggest a pathway of IL-6 production by C-26 tumors that involves a cellular interaction between IL-1R-expressing tumor cells and host-derived macrophages. The results also suggest that this interaction significantly contributes to cachectic events endured by the tumor-bearing host.

Animals↗
PubMed1991

Mechanisms of cancer cachexia.

It is currently hypothesized that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which in turn orchestrate a series of complex interrelated steps that ultimately lead to a chronic state of wasting, malnourishment, and death (see Fig. 1). The metabolic changes seen in the tumor-bearing host are similar, but not identical, to those seen in sepsis and inflammation and appear to result from a generalized response of the host to the stimulus of invasion--the tumor. Although there are likely to be several humoral factors, of either host or tumor origin (see Fig. 1), involved in cancer cachexia, recombinant DNA methodology has provided sufficient amounts of only a few cytokines to enable careful investigation of their cachectic potential. TNF/cachectin has been most extensively studied and appears to play a clear role, because administration of low-dose continuous or escalating doses simulates changes associated with cancer cachexia. In addition, these cachectic changes have been blocked by a specific antisera. IL-1, IL-6, and interferon-gamma all have potential as mediators of cancer cachexia and more work is clearly indicated. It is possible that, given our current understanding of the mechanisms of cancer cachexia, it can be theorized that TNF, which causes many of the manifestations of cancer cachexia, and IL-1 are released by macrophages in response to tumor (see Fig. 1). Interferon-gamma appears to potentiate these effects and may also be necessary for the complete syndrome of cancer cachexia. IL-6 probably is released as another mediator, principally mediating the acute phase response seen in cancer cachexia. Other factors are certain to be involved. Further study into the mechanisms and possible treatment of cancer cachexia is needed, because a large proportion of cancer patients who are incurable by current therapies continue to suffer from this lethal wasting diathesis. Furthermore, specific strategies to reverse the cachectic changes associated with cancer will likely improve antitumor treatment.

Animals↗
PubMed1990

Amino acid metabolism in human cancer cachexia.

Cancer cachexia is a complex syndrome that occurs with variable incidence in patients with solid tumors and those with hematologic malignancies. It is associated with characteristic physical and laboratory findings, and at a more fundamental level, with significant abnormalities in carbohydrate, lipid, and protein metabolism. These alterations in intermediary metabolism are demonstrable early in the syndrome, even before the onset of weight loss, when the more characteristic features of cancer cachexia are evident. Progressive wasting of peripheral protein stores is a major feature of cancer cachexia and often one of the most graphic realities of malignancy for patients and their families. Unfortunately, significant problems with the animal models of cancer cachexia make conclusions derived from animal studies difficult to extrapolate to humans. Data from human studies indicate that human cancer cachexia is associated with minimal aberrations in circulating free amino acid concentrations; increased whole-body protein turnover, synthesis, and catabolism; reduced rates of skeletal muscle protein synthesis; and increased rates of hepatic protein synthesis. Whether or not these alterations represent pathologic responses or physiologic adaptation by the host to the presence of malignancy remains to be seen. Future investigations must focus on more careful evaluation of interorgan amino acid metabolism, investigation of skeletal muscle protein catabolic rates in cancer cachexia, and definition of the roles of altered hormonal and cytokine regulation of these processes. Such studies will more precisely define the level at which amino acid metabolism is altered significantly and, we hope, permit more specific therapeutic intervention designed to reverse the debilitating effects of cancer cachexia.

Amino Acids↗
PubMed1991

Severe cachexia in mice inoculated with interferon-gamma-producing tumor cells.

Nude mice were inoculated with CHO/IFN-gamma cells, a line of Chinese hamster ovary tumor cells, that had been genetically engineered to produce murine IFN-gamma. Severe cachexia, as evident from body weight loss and reduced food intake, occurred in these mice, but not in those injected with CHO/control cells, i.e. the original, non-IFN-gamma-producing line. The essential role of IFN-gamma in the pathogenesis of cachexia was confirmed by the demonstration that monoclonal antibodies (MAbs) against IFN-gamma, given prior to injection of the tumor cells, prevented cachexia. In addition to IFN-gamma, the presence of the tumor cells was also required for cachexia to develop. As evident from pair-feeding experiments, reduced food intake could only partially account for the rapid and extensive body-weight loss. Cachexia was characterized by a marked reduction in the amount of interscapular fat tissue. Injected tumor cells exclusively invaded intraperitoneal adipose tissue and elicited an inflammatory cell infiltrate, indicating that interscapular fat loss was due to humoral factors. Our data suggest that, among the humoral factors responsible for cancer-associated cachexia, IFN-gamma plays a prominent role.

Adipose Tissue↗
PubMedDate not supplied

Cytokines and their role in the pathophysiology of cancer cachexia.

Cancer cachexia describes a syndrome that consists of weight loss, and abnormalities in carbohydrate, protein, and lipid metabolism, which result in a state of persistent net negative energy balance. Patients suffering from cancer cachexia have a significantly shortened survival after cancer treatment. Recent experimental studies have focused on the belief that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which through broad physiologic actions ultimately lead to a chronic state of wasting, malnourishment, and death. Cytokines that have been thought to play a role in the pathophysiology of cachexia include tumor necrosis factor, interleukin-1, interleukin-6, interferon-gamma and differentiation factor. It has become clear that these cytokines have overlapping physiologic activities, which makes it likely that no single substance is the sole cause of cachexia in most cancer patients. Only further investigation may make it possible to more clearly define the role of cytokines in the pathophysiology of cancer cachexia. Specific strategies to reverse the cachectic effects of these substances may then be developed to ultimately improve cancer treatment.

Animals↗
PubMed1989

Factors affecting postoperative ventilatory support in patients with cardiac cachexia.

Factors affecting early v late weaning from ventilatory support after cardiac surgery were retrospectively compared in 15 patients with cardiac cachexia. These patients were divided into two groups based on the duration of postoperative ventilatory support, group I (n = 7) less than two days (22 +/- 8 hours) and group II (n = 8) over three days (140 +/- 125 hours). Findings in 14 randomly selected patients without cardiac cachexia who underwent cardiac valve replacement were also examined. Comparisons were made between the groups in regards to the following parameters: (1) preoperatively: anthropometric, biochemical, and immunologic parameters of nutritional status, hepatic function, cardiothoracic ratio (CTR) on chest x-ray, and data from cardiac catheterization; (2) intraoperatively and postoperatively: anesthetic drugs, duration of surgery, cardiopulmonary bypass (CPB), aortic cross-clamp, and postoperative use of inotropes. The anthropometric measurements, cell-mediated immunity, and hepatic function were significantly decreased in all patients with cachexia, but with no significant differences between the groups. Serum transferrin levels, which increased in patients with cachexia, showed no significant difference between the groups. The levels of serum albumin were significantly lower in cachectic patients than in patients without cachexia; they were significantly higher in group II than in group I. The durations of surgery and CPB were significantly longer in group II, but there was no significant difference in the duration of aortic clamping between the groups. The postoperative use of inotropes was higher in group II. These results indicate that group II patients were nutritionally as well sustained as group I. However, they had less satisfactory cardiac function, and therefore required a longer duration of postoperative ventilatory support.

Blood Pressure↗
PubMed1991

Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice.

Recently, we have established a human squamous cell carcinoma of the maxilla (called MH-85) associated with hypercalcemia, leukocytosis, and cachexia in culture. MH-85 tumor cells caused the same paraneoplastic syndromes in tumor-bearing nude mice. We found that there was a sixfold increase in splenic size in MH-85 tumor-bearing mice. This increase paralleled tumor growth and was reversed by surgical removal of the tumor. Splenectomy in nude mice 1 wk before or 6 wk after tumor inoculation resulted in a decrease in tumor growth, and impairment of hypercalcemia, leukocytosis, and cachexia. In MH-85 tumor-bearing animals that had been pretreated by splenectomy, intravenous injection of fresh normal spleen cells caused an immediate reversal of leukocytosis, hypercalcemia, and cachexia. Since the presence of cachexia in both the patient and the mice carrying the tumor suggested tumor necrosis factor (TNF) may be overproduced, we injected polyclonal neutralizing antibodies raised against murine TNF into tumor-bearing mice. There was a rapid and reproducible decrease in blood ionized calcium, accompanied by suppression of osteoclast activity. No changes in blood ionized calcium were seen in mice injected with normal immune sera. In addition, there was an increase in body weight and decrease in white cell count. Plasma immunoreactive TNF was increased almost fourfold in tumor-bearing nude mice compared with control nude mice. Although TNF activity was undetectable in MH-85 culture supernatants, cells of the macrophage lineage, including spleen cells, released increased amounts of TNF when cultured with MH-85 tumor-conditioned media. These results suggest that splenic cytokines such as TNF may influence the development of the paraneoplastic syndromes of hypercalcemia, leukocytosis, and cachexia in these animals, as well as tumor growth. They also show that paraneoplastic syndromes may be due to factors produced by normal host cells stimulated by the presence of the tumor.

Animals↗
PubMed1992

Evidence for the involvement of interleukin 6 in experimental cancer cachexia.

In this report we describe an experimental model of cachexia that fulfills the criteria of an early effect with a small tumor mass not related to the growth rate of the tumor, and progressive wasting of muscle and fat without a detectable loss of appetite. C-26.IVX is a cell line derived from murine colon-26 adenocarcinoma which retains the transplantability of the original tumor and induces true cachexia in syngeneic hosts. Evidence is presented to support a role for interleukin (IL-6) as a cachectic factor in the development of cancer cachexia in this model system. Thus, increasing levels of IL-6 in C-26.IVX-bearing mice correlate with the development of cachexia. If the primary tumors were resected, mice gained weight and the levels of IL-6 in the serum were reduced significantly. Moreover, monoclonal antibody to murine IL-6 (but not anti-tumor necrosis factor antibody) was able to significantly suppress the development of key parameters of cachexia in tumor bearing mice.

Animals↗
PubMed1991

Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support.

We have performed intraoperative isotopic infusions of carbon 14-labeled leucine in 65 patients to define the abnormalities in protein metabolism at both the whole-body and tissue level in patients with weight-losing and non-weight-losing cancer. Eighteen patients had benign disease, 26 had non-weight-losing cancer, and 21 had cancer cachexia. Samples of plasma and expired breath were taken to determine rates of whole-body protein synthesis (WBPS), whole-body protein catabolism (WBPC), net protein catabolism, and albumin fractional synthetic rates. Tissue samples were taken to determine the fractional synthetic rates (FSR) of protein in muscle, liver, cancer, and the tissue in which the cancer arose. In addition, in 14 patients the effect of nutritional support on protein metabolism was assessed. In all parameters examined we were unable to detect any significant differences between patients with no cancer and the patients with non-weight-losing cancer. In contrast, patients with cancer cachexia had a significant elevation (p less than 0.005) in WBPC compared with the other two groups. WBPS was also elevated (to a lesser extent) in the patients with cancer cachexia, and the rate of net protein catabolism was increased significantly (p less than 0.05). Patients with cancer cachexia also had significantly higher values of FSR of protein in muscle (p less than 0.05), liver (p less than 0.05), and albumin (p less than 0.01) compared with the other two groups. In addition, the protein FSR in the cancer rose progressively when the values for the primary cancer were compared with those for nodal and systemic metastases. Further, although nutritional support resulted in an increase in host muscle protein synthesis (p less than 0.04), there was no promotion of FSR of protein in cancer. We conclude that patients with cancer cachexia are actively losing protein as a result of an increase in WBPC that is only partially compensated for by an increase in WBPS. There are compensatory increases in protein synthesis in muscle and liver, but these increases in host protein synthesis are insufficient to keep pace with the combined effect of the accelerated rate of protein synthesis in the cancer per se and the accelerated rate of net protein catabolism at the whole-body level. In response to nutritional support, there is a significant increase in the muscle protein synthesis, but we could not demonstrate any increase in cancer protein synthesis.

Adult↗
PubMed1990

Lipolytic factors associated with murine and human cancer cachexia.

We have identified a lipolytic factor in extracts of a cachexia-inducing murine carcinoma (MAC16) that shows characteristics of an acidic peptide and appears to be composed of three fractions of apparent molecular weights corresponding to 3 kd, 1.5 kd, and 0.7 kd, as determined by exclusion chromatography. Material with identical chromatographic and molecular weight characteristics was also present in the serum of patients with clinical cancer cachexia but absent from normal serum, even under conditions of starvation. The MAC16 lipid factor, when injected into animals bearing the non-cachexia-inducing tumor MAC13, was capable of inducing weight loss without a significant reduction in food intake. Similar lipolytic material, although in lower concentration, was also found in the MAC13 tumor extracts. These findings suggest that cachexia may arise from the enhanced expression of a lipolytic factor associated with tumor cells.

Adenocarcinoma↗
PubMed1992

Diabetic neuropathic cachexia associated with malabsorption.

Diabetic neuropathic cachexia is characterized by neuropathic pain and severe weight loss of unknown aetiology. We describe four patients with diabetic neuropathic cachexia who were found to have malabsorption. Four diabetic patients presented with neuropathic pain, anorexia, depression and weight loss of 16 (range 10-21) kg. None complained of diarrhoea. There were three males and one female, median age 54 (46-67) years. A butterfat test showed a serum turbidity difference of 9 (6-10) light scattering units (normal greater than 60 units). The median serum xylose was low and there was delayed urinary xylose excretion. Urinary indicans, small bowel histology, liver function tests, and thyroid and renal function were normal. Ultrasound scans of liver, gall bladder and pancreas, and endoscopic retrograde cholangiopancreatogram were normal. The patients were treated with pancreatic supplements and a high calorie diet. Three have completely recovered and the other patient is improving. Thus these cases of diabetic neuropathic cachexia appeared to be associated with malabsorption which may be due to pancreatic dysfunction. It is suggested that the management of diabetic neuropathic cachexia should include the investigation and treatment of malabsorption.

Aged↗
PubMed1989

Studies of cachexia in parasitic infection.

Cachexia and septic shock, syndromes associated with chronic and acute infection, respectively, are mediated by endogenous factors. The search for humoral mediators of cachexia led to the isolation of the cytokine known as cachectin/TNF. A biologic role for cachectin/TNF in cachexia has been identified: it induces a catabolic state in adipose and skeletal muscle cells in vitro, and animals persistently exposed to it in vivo become cachectic. Cachectin/TNF was also discovered to be a primary, essential mediator of septic shock. The acute administration of the recombinant protein causes shock, tissue injury, and derangements of metabolic homeostasis that mimic endotoxemia and septic shock syndrome. Anti-cachectin antibodies protect against the lethal effects of septic shock and cachexia, suggesting that this mediator has a central role as a trigger to the inflammatory and deleterious host responses to infection. Future investigations will undoubtedly be directed towards the effects of inhibiting cachectin/TNF in the treatment of the complications of infectious disease.

Animals↗
PubMed1992

Clinical management of anorexia and cachexia in patients with advanced cancer.

Cachexia occurs in the majority of cancer patients before death. It is the result of major metabolic changes produced by tumor-released substances as well as by cytokines and some endogenous peptides. The most significant clinical manifestation is profound anorexia. Aggressive parenteral nutrition has not been able to increase patient survival or produce any significant symptomatic improvement. Recent research, therefore, has focused on drugs that might result in symptomatic improvement, even if no significant nutritional changes are detected. Corticosteroids have been shown to increase appetite for a brief period of time, but they do not appear to improve caloric intake or nutritional status. In addition to appetite stimulation, corticosteroids also improve a number of other symptoms transiently. Progestational drugs have been found in a number of studies to increase appetite, caloric intake, and nutritional status. The most effective type and dose of progestational drugs have not been clearly established. Cyproheptadine, hydrazine sulfate, and cannabinoids have all been suggested to have beneficial effects on appetite; their effectiveness, however, needs to be confirmed in prospective, controlled trials. Some of these trials are currently under way. Current data suggest that megestrol acetate or other progestational agents could be useful--because of effects on not only appetite but also overall nutritional status--in patients who have profound anorexia as the main manifestation of cachexia, provided expected survival can be measured in weeks or months. In patients with shorter expected survival or those who have problems tolerating progestational drugs, a brief course of corticosteroids may provide short-term symptomatic effects. Future studies should focus on (1) improving understanding of both the pathophysiology of cancer cachexia and the interaction of some of the major syndromes of terminal cancer--e.g., pain, cachexia, and cognitive failure--and (2) characterizing the symptomatic effects of different drugs more completely.

Anorexia↗
PubMed1990

Tumor necrosis factor-alpha inhibits albumin gene expression in a murine model of cachexia.

The mechanisms responsible for decreased serum albumin levels in patients with cachexia-associated infection, inflammation, and cancer are unknown. Since tumor necrosis factor-alpha (TNF alpha) is elevated in cachexia-associated diseases, and chronic administration of TNF alpha induces cachexia in animal models, we assessed the regulation of albumin gene expression by TNF alpha in vivo. In this animal model of cachexia, Chinese hamster ovary cells transfected with the functional gene for human TNF alpha were inoculated into nude mice (TNF alpha mice). TNF alpha mice became cachectic and manifested decreased serum albumin levels, albumin synthesis, and albumin mRNA levels. However, even before the TNF alpha mice lost weight, their albumin mRNA steady-state levels were decreased approximately 90%, and in situ hybridization revealed a low level of albumin gene expression throughout the hepatic lobule. The mRNA levels of several other genes were unchanged. Hepatic nuclei from TNF alpha mice before the onset of weight loss were markedly less active in transcribing the albumin gene than hepatic nuclei from control mice. Therefore, TNF alpha selectively inhibits the genetic expression of albumin in this model before weight loss.

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↗
PubMed1991

5'-Deoxy-5-fluorouridine improves cachexia by a mechanism independent of its antiproliferative action in colon 26 adenocarcinoma-bearing mice.

The cytostatic agent 5'-deoxy-5-fluorouridine (5'-dFUrd) improves cachexia and prolongs survival, suppressing tumor growth in mice bearing large burdens of colon 26 adenocarcinoma. To investigate the mode of this anticachectic action, we isolated colon 26 variants that were resistant to the anticachectic activity in vivo in tumor-bearing mice that initially responded to 5'-dFUrd in terms of tumor growth and cachexia but again became cachectic and refractory to the drug after prolonged treatment. The original line and variants were equally susceptible to the antiproliferative action of 5'-dFUrd, and their growth was stopped. However, 5'-dFUrd given to cachectic mice exhibiting large burdens of these variants could not reverse wasting and only slightly prolonged the survival period. These results indicate that the anticachectic activity of 5'-dFUrd is independent of its antiproliferative action and that the survival of colon 26-bearing mice is shorter when the size of the tumors is not reduced to levels below those that cause cachexia.

Adenocarcinoma↗
PubMedDate not supplied

Cancer cachexia.

Cancer cachexia has been listed as a major cause of death in cancer patients. In order to investigate the metabolic effects of the tumor on the host, we have evaluated an experimental model of cancer cachexia in the mouse (MAC16 colon adenocarcinoma), in which weight loss can reach 30-40% of initial weight with a tumor burden of only 2.5%, without a reduction in the intake of either food or water. The weight loss appears not to arise from tumor necrosis factor production, which is associated with a marked reduction in both food and water intake, but may be a result of catabolic factors produced by the tumor and present in the circulation. Both insulin and 3-hydroxybutyrate are effective inhibitors of the tumor catabolic factors in vitro and protect, to some extent, weight loss in vivo. However, whereas 3-hydroxybutyrate was associated with a reduction in tumor weight, insulin caused an enhancement, suggesting that the former may be more appropriate than the latter in the clinical treatment of cancer cachexia.

Animals↗