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PubMed2006

BARD1 content correlates with increased DNA fragmentation associated with muscle wasting in tumour-bearing rats.

Apoptotic events have been clearly associated with muscle wasting in different types of experimental cancer cachexia. In these conditions, cell death is triggered by cytokines or tumour-produced factors. BARD1 is a nuclear protein that is also involved in apoptosis both in vitro and in vivo. The results presented here demonstrate that BARD1 content in skeletal muscle correlates with increased DNA fragmentation during experimental cancer cachexia. It is suggested that BARD1 acts as a modulator of muscle apoptosis or, alternatively, that BARD1 participates in the protein degradation by functioning as ubiquitin ligase.

Animals↗

PubMed1990

Prolonged survival of tumor-bearing rats with repetitive low-dose recombinant tumor necrosis factor.

Tumor necrosis factor may be a mediator of the syndrome of cancer cachexia. Tachyphylaxis or tolerance to the cachectic effects of recombinant tumor necrosis factor (rTNF) has been previously described. In this study, we investigate whether repetitive exposure to rTNF can induce similar tolerance in tumor-bearing (TB) rats and ameliorate cachexia induced by the tumor. In experiment 1, non-tumor-bearing (NTB) and TB rats were randomized to either escalating low doses of rTNF or saline i.p. twice daily for 9 consecutive days. NTB rats treated with rTNF demonstrated a significant decline in food intake and weight change (P less than 0.00001) but soon developed tolerance to the cachectic effects of rTNF; they consumed significantly more food than on the first day of treatment and had weight change similar to NTB rats treated with saline. TB rats treated with rTNF showed a similar significant decline in food intake and weight change (P less than 0.0001) and also demonstrated similar tolerance to the cachectic effects of rTNF with continued treatment. Following treatment, TB rats that had been treated with rTNF ate significantly more and lost less weight than TB rats that had been treated with saline (P less than 0.00001). rTNF treatment of TB rats also demonstrated antineoplastic activity, as estimated tumor weight of tumors from rats treated with rTNF were significantly less than controls (P = 0.003). The anticachexia and antineoplastic effects of rTNF resulted in prolonged survival of TB rats treated with rTNF compared to control TB rats (P = 0.015). Experiment 2 utilized two different rTNF treatment regimens in TB rats: one group received 12 days of escalating doses of rTNF, and another group received 15 days of rTNF treatment. TB rats treated with rTNF again had a significantly greater food intake (P less than 0.00001) and delayed weight loss (P = 0.0001) posttreatment that was further augmented by additional doses of rTNF. Antineoplastic activity of rTNF was less clear, and overall tumor growth curves were not affected by rTNF treatment. Survival of TB rats treated with rTNF was again significantly increased in a dose-dependent manner (P = 0.006). Repeated administration of low doses of rTNF to TB rats induces mild reduction in tumor growth, tolerance to the cachectic effects of rTNF that results in tolerance to the cachectic effects of tumor, and prolongation of survival.

Animals↗

PubMed1987

Tumor-host wasting not explained by adrenal hyperfunction in tumor-bearing animals.

This study addressed the question of whether hypercorticism in tumor-bearing animals contributes to the wasting of body fat and lean body mass, particularly that of skeletal muscles. For this purpose, hydrocortisone-substituted nongrowing sarcoma-bearing and control C57BL/6J mice were used that were either adrenalectomized or sham-operated prior to experimentation. Adrenalectomy in itself did not alter food intake or body composition in normal animals. Tumor-bearing mice and pair-weighted control animals had elevated urinary excretion of corticosteroids compared with the urinary excretion in freely fed controls. The malignant tumor induced the well-recognized wasting in tumor-bearing animals, irrespective of the presence of the adrenal glands. Therefore, an elevated corticosteroid production did not account for the wasting of body fat, lean body mass, skeletal muscle proteins, or decreased RNA activity in quadriceps muscles from tumor-bearing animals, although such muscles were sensitive to physiologic doses of injected hydrocortisone (20 micrograms/day). Tyrosine aminotransferase (TAT) activity in liver tissue from tumor-bearing animals was higher than that induced by pharmacologic doses of hydrocortisone in normal animals. Physiologic doses of hydrocortisone induced hepatic TAT activity, but pair-weighed control animals with the same degree of hypercorticism as was found in tumor-bearing animals had normal TAT activity in liver tissue. Although hypercorticism is present in tumor-bearing animals, the results demonstrate that cancer cachexia can start and proceed independently of the adrenal glands. Therefore, adrenal hyperfunction is not the proximate cause for the development of experimental cancer cachexia induced by anorexia.

Adrenal Glands↗

PubMed1988

Weight loss in obese mice persistently infected with lymphocytic choriomeningitis virus is not associated with elevated tumor necrosis factor/cachectin activity in peritoneal macrophages.

C57BL/6 ob/ob (C57 ob/ob) mice infected persistently with lymphocytic choriomeningitis virus (LCMV) show cachexia as judged by a weight loss of greater than 20%. Virus persists in a subset of macrophages. Because a cachexic state occurs in several chronic debilitating diseases of humans, often accompanied by persistent microbial infections with macrophage/monocytic involvement and tumor necrosis factor (TNF) cachectin production, the role of TNF in the weightloss of ob/ob mice infected persistently with LCMV was investigated. TNF mRNA expression was not increased in peritoneal cells from such persistently-infected mice, nor did their serum levels of TNF rise above those in uninfected litter-mates. Furthermore, in vitro LCMV infection of adherent peritoneal cells from these C57 ob/ob mice did not enhance TNF mRNA or protein expression. Therefore, the cachexia-like weight loss observed in C57 ob/ob mice during a persistent LCMV infection is apparently not associated with a measurable increase in TNF.

Animals↗

PubMed1985

Parabiotic transfer of cancer anorexia/cachexia in male rats.

To demonstrate that the anorexia and depletion of cachexia reverses on tumor removal, F344 rats underwent sarcoma resection when their food intake fell to 0 g/day. In survivors of surgery, reversal in food intake was apparent within 3 days postoperatively, followed after 2 days by gain in host weight. To detect whether the transmission of anorexia/cachexia in these tumor-bearing (TB) rats was via the circulation, four groups were studied: single non-tumor bearing (NTB); single TB; parabiotic NTB; and parabiotic TB. The measured blood exchange rate between parabiotic halves was 1.2-1.5%/min. No cachectic effect was detected in either half of the NTB parabionts. There was no evidence of sarcoma metastases in the tumor-free half of the parabiotic TB pair. All the rats associated with the presence of tumor showed cachectic effects but the degree and timing of effect varied among the three conditions, single TB, parabiotic TB half, and parabiotic tumor-free half. In all variables examined (fall in food intake, time of first fall in food intake, host weight loss, elevation of blood urea nitrogen) the severities were always in the same sequence: single TB greater than parabiotic TB half greater than parabiotic tumor-free half greater than NTB. In addition, the TB parabiotic pair had a significantly longer survival time and grew a significantly larger tumor than did the single TB animal. The parabiotic tumor had a slower initial growth rate and a slower deceleration rate than the singlet tumor. These results provide evidence for the humoral mediation of cancer-associated cachexia.

Animals↗

PubMed1985

[Complications and causes of fatal outcomes in prostatic cancer].

An analysis of post-mortem examination data on 600 cases of cancer of the prostate showed that among the most frequent complications were ascending pyelonephritis (51.7%), focal pneumonia (42.8%) and cachexia (36.7%). Deaths were caused mainly by progression of cachexia (24.3%), uremia (24.3%) and focal pneumonia (19.5%). Only a small percentage of patients died from postoperative complications and concomitant pathology.

Adenocarcinoma↗

PubMed1977

Malnutrition: a poorly understood surgical risk factor in aged cardiac patients.

This feasibility report is based on the fact that malnutrition has been recognized but too little understood in connection with surgical risk. Patients with cardiac cachexia are remarkably similar to many patients with cachexia of the aged. Cachectic patients generally go through an operation well, but their condition often deteriorates slowly and they die a few days later; they behave as if they are running out of energy reserves. Malnourished people can be divided into three categories: kwashiorkorlike, marasmic, and marasmic-kwashiorkorlike. Recognition and classification of protein/calorie malnutrition into these categories directs treatment. Recognition is based on the usual physical and laboratory tests, plus triceps skinfold/arm circumference observations; leukocyte counts, with absolute and relative lymphocyte counts; serial transferrin, globulin, and albumin assessments; and, particularly, Candida and mumps skin testing to identify the anergic state. Intravenous and oral hyperalimentation can bring about conspicuous improvement in the appearance, attitude, and ability to withstand stress--including major heart surgery--of malnourished patients. However, astute clinical balance is essential, since either oral or intravenous hyperalimentation may cause renal nitrogen overload; moreover, if intravenous delivery is too rapid, congestive heart failure may be precipitated.

Aged↗

PubMed1980

[The application in cancerology of continuous pump-tube enteric alimentation (author's transl)].

Malnutrition and cachexia are major consequences of neoplastic diseases. When a response to one or more forms of oncologic therapy is expected, simultaneous application of artificial nutrition is often needed. Continuous pump-tube enteric alimentation is an efficient, well tolerated method which is easy to perform in a medical ward. We fed 29 patients with this technique during a mean of 43,6 days and a daily intake of more than 3500 Kcal. We noticed the following observations: -- when out of the impact of any therapy directed against the tumor the 21 patients with advanced cancers demonstrated an ability to gain weight and to achieve a positive nitrogen balance equivalent to that performed by the 8 non tumor-bearing patients; -- radiation therapy, administered to the head, neck and thorax resulted in an increase of energetic expenditure; -- chemotherapy impairs for a few days the benefits of the enteric alimentation. This paper underlines the possibility of nutritional rehabilitation of patients with a cancer cachexia. The metabolic injury produced by chemotherapy and radiation therapy increases the need for an afficient treatment of the malnutrition in cancer.

Body Weight↗

PubMed1981

Effect of total parenteral nutrition on tumor-host responses in rats.

Total parenteral nutrition (TPN) is a clinical adjunct to cancer therapy. But it is difficult to do controlled clinical studies on cancer patients undergoing TPN. We therefore turned to a study of TPN on Buffalo strain rats with and without a Morris 7777 transplantable hepatoma. Our results showed that TPN at higher than normal levels (total parenteral hyperalimentation, abbreviated TPH) supported a gain in body weight of nontumorous rats. In tumorous rats, TPH supported body weight gain and stimulated tumor growth. Detailed analysis showed the TPH of the rats with a large rapidly growing hepatoma did gain body weight associated with fluid retention while the carcass weight decreased. Nor did TPH of tumorous rats significantly reverse the low cell proliferative activity to ear epidermis attributed to the tumor though it did stimulate tumor cell proliferation. Thus TPH by itself did not overcome wasting due to presence of the tumor. Using the hypothesis that uncontrolled gluconeogenesis is linked to cancer cachexia, we combined TPH with inhibition of gluconeogenesis (using hydrazine sulfate) and prevented the carcass weight loss (cachexia) in the tumorous rats. Tumor growth was stimulated by this treatment. Stimulation of cell proliferation in the tumor can, however, benefit chemotherapy using an S phase or cell cycle-specific cytotoxic drug.

Animals↗

PubMed1981

Control of food intake in experimental tumor growth.

The cachectic depletion of cancer is invariably an immediate consequence of progressive deficit of food intake below metabolic cost. The deficit of food intake arises from successive impairment of individual feeding controls. The impairment of some feeding controls well before there is overt hypophagia or cachexia indicates that overt cachexia is preceded by a silent or compensated cachectic process, and behavioral compensation for deteriorating feeding controls can be demonstrated. The hypothalamic components of control of food intake are not affected. In some instances, severe asthenic reduction in motor activity further disables capacity to feed since feeding is a motor activity and motor capability is a necessary condition for feeding. The variability in timing and severity of cachectic decay among different tumors and individuals is a function of the timing and sequencing of breakdown of individual controls, capacity for compensation, and impairment of motor capability, and the extent to which all possible controls are functionally expressed in the normal individual.

Animals↗

PubMed1995

Effect of biological response modifiers on growth and cell proliferation of human tumor xenografts in nude mice.

The effect of biological response modifiers on macroscopic tumor growth and on tumor cell proliferation of a human renal cell carcinoma and a squamous cell carcinoma (hypopharynx) in nude mice has been studied. Tumor necrosis factor alpha (TNF-alpha) and interferon alpha (IFN-alpha) as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) were applied either alone or in combination, and TNF-alpha was also combined with etoposide (ETP). TNF-alpha and IFN-alpha alone or in combination did not substantially affect the course of tumor growth, however, they did influence the pattern of tumor growth. There was also only a marginal effect on tumor cell proliferation. However, IFN-alpha protects the animals from tumor growth associated weight loss. ETP and ETP plus TNF-alpha leads to a deceleration of tumor growth, a decrease of the labeling index and to a significant decrease of the animal weight which indicates that the first two effects may be partly due to the toxicity of the treatment. GM-CSF modifies cell proliferation in a dose-dependent manner, i.e. stimulation at low doses and tendency to inhibition at higher doses. Although there is no substantial direct antineoplastic effect of the agents studied, the results make clear that indirect effects of therapeutic agents due to therapy induced cachexia should always be regarded. It is interesting that IFN-alpha has a protective effect against cachexia.

Animals↗

PubMedDate not supplied

Treatment with tumor necrosis factor alpha and interferon alpha of a human kidney cancer xenograft in nude mice: evidence for an anticachectic effect of interferon alpha.

Unfortunately the efficacy of the treatment of the metastatic or recurrent renal cell carcinoma (RCC) has not improved during the last few years. Recently effort has been put into the experimental and clinical evaluation of so-called "biological response modifiers" (BRM; cytokines and related peptides) as treatment modalities for RCC. The present results are, however, still disappointing. Since BRM, if applied alone, are largely ineffective as antineoplastic agents, more experimental studies are now necessary to test the antineoplastic value of their combinations, which seem to be more promising. In the present study, the in vivo effect of tumor necrosis factor a (TNF a) and/or interferon a (IFN a) on the macroscopic tumor growth (external caliper measurements of tumor size) and on the cell proliferation (in vivo 3H-thymidine labelling index, LI, and mitotic index, MI) of a human RCC xenograft line in nude mice has been investigated. Neither of these substances alone nor their combination was effective in changing the time course of the tumor sizes and the growth patterns of the treated tumors in a statistically significant manner as compared to the untreated controls. Also the cell kinetic parameters were only marginally affected by these treatments, whereby TNF a alone proved to be more effective than IFN a alone. However, compared to the effect of TNF alpha alone, the combination with IFN alpha leads to some amelioration of the cell kinetic perturbations and also to an appreciable shift in the growth patterns of the tumors from distinct Gompertzian (under TNF alpha alone) to near exponential (under the combination treatment; p < 0.05). As a consequence, the tumors grow more slowly under the combined treatment during the observation time, and on the other hand, their growth does not decelerate as much as under TNF alpha alone. Actually, if tumor growth continues in the same way, the extrapolation of the present data predicts smaller and greater tumors than the control tumors in the TNF alpha and in the combination treatment groups respectively. Notably, in the combination the effect of the IFN alpha seems to predominate. This is also seen in the effect of this combination on the cachexia of these tumor-bearing animals: either alone or in combination with TNF alpha, IFN alpha partially protects the animals from tumor-growth associated weight loss. Although the direct antineoplastic in vivo effect of the present cytokine combination against this human RCC xenograft line is rather limited, the potential antagonizing effect of IFN alpha on the development of cachexia should be further explored.

Animals↗

PubMedDate not supplied

Lethal toxicity of cyclophosphamide depends on the tumor stage. Studies on the syngeneic adenocarcinoma EO 771 in C57bl/6j mice.

The effect of tumor size and tumor age on the efficiency, and particularly on the lethal toxicity, of a single application of cyclophosphamide (300 micrograms/g body weight i.p.) to C57bl/6j mice bearing the adenocarcinoma EO 771 has been investigated by treating tumors of the same size but different age on the one hand and tumors of the same age but different size on the other. Treatment of animals bearing larger tumors is consistently associated with increased toxicity: 71/74 animals with tumors > 1.25 g at the time of treatment die of toxicity as opposed to only 1/33 animals with tumors < 1.25 g (relative risk of death of toxicity is 31.7 for animals with tumors > 1.25 g as compared to those bearing tumors < 1.25 g). On the contrary, the age of the tumor does not appreciably influence the toxicity of treatment. The reason for the increased toxicity of the antineoplastic chemotherapy with increasing tumor size is not clear. However, the rather abrupt manifestation of lethal toxicity as a function of tumor size coincides well with the beginning of tumor cachexia in the same animals. Possible mechanisms for this interrelationship of cachexia and potentiation of treatment toxicity are discussed.

Adenocarcinoma↗

PubMed1993

Feeding gastrostomy: a critical review of its indications and mortality rate.

Gastrostomy can be a valuable adjunct to patient care, and percutaneous endoscopic gastrostomy is often considered the method of choice for gastrostomy placement. As with all surgical procedures, however, patient selection is important no matter how the gastrostomy is placed. In a retrospective review of 125 randomly selected patients having gastrostomy tube placement, there were certain groups of patients who received virtually no benefit from gastrostomy and may even have died sooner due to gastrostomy placement. The leading indication for gastrostomy placement was neurologic debilitation; the procedural mortality rate for these patients was 28%. However, patients with pulmonary cachexia or metastatic cachexia had much higher mortality rates: 90% and 37%, respectively. We believe patient selection has been imperfect and that certain patients should not have a gastrostomy tube. These patients suffer the moral indignation of persistent intervention and often die without receiving any real benefit.

Adolescent↗

PubMed1996

Induction of muscle protein degradation and weight loss by a tumor product.

Splenocytes from mice bearing a cachexia-inducing tumor (MAC16) have been fused with mouse myeloma cells to produce hybridomas, which have been cloned to produce antibody reactive to a material which copurified with a lipid-mobilizing factor isolated from the same tumor. The monoclonal antibody has been used to investigate factors potentially involved in the development of cachexia. The major protein detectable by immunoprecipitation of a partially purified lipid-mobilizing factor was M(r) 69,000, whereas Western blotting showed two bands of M(r) 69,000 and M(r) 24,000. Although the monoclonal antibody did not neutralize lipid-mobilizing activity in an in vitro assay, it did neutralize a serum factor capable of protein degradation in isolated gastrocnemius muscle. Affinity purification of MAC16 tumor homogenates using the monoclonal antibody yielded two immunoreactive bands of M(r) 69,000 and M(r) 24,000, which were further fractionated on a hydrophobic column (C8). This material was capable of inducing tyrosine release from isolated gastrocnemius muscle, and the effect could be blocked with the monoclonal antibody. The two immunoreactive bands from the hydrophobic column were capable of inducing weight loss in mice, whereas nonimmunoreactive fractions had no effect on body weight. The M(r) 24,000 species had a unique amino acid sequence, whereas the M(r) 69,000 species gave the same sequence as the M(r) 24,000 material, together with that for albumin. The M(r) 24,000 species contained carbohydrate, and lectin blotting showed a strong reaction with wheat germ and Erythrina crystagalli agglutinins. This suggests that the material is a glycoprotein or proteoglycan that shows strong binding affinity for albumin, possibly through the carbohydrate residues.

Animals↗

PubMed1996

[Survival and changes of clinical laboratory data in phase II study with 5'-DFUR].

With patients registered in a Phase II study of 5'-DFUR, we analyzed the results of survival and laboratory findings. The 50% survival days in patients with gastric cancer included: 371 days in all evaluable patients; 912 days in patients of CR+PR; 484 days in MR+NC; and 158 days in PD. On the other hand, those in patients with colorectal cancer were: 467 days in all evaluable patients; 1,308 days (66.7% survival) in CR+PR; 586 days in MR+NC; and 276 days in PD. The figures in patients with breast cancer were: 1,761 days (58.5% survival) in all evaluable patients; 1,761 days (82.1% survival) in CR+PR; 878 days in MR+NC; and 546 days in PD. These 50% survivals were markedly longer than for other anti-cancer drugs given singly or in combination, although response rates with other drugs were higher than with 5'-DFUR. Laboratory findings in patients with gastric and colorectal cancers given 5'-DFUR disclosed many cases with improved levels of blood cells and liver function. There was a correlation between improved laboratory findings and survival. Furthermore, in animal experiments 5'-DFUR improves cancer cachexia. This is thought to be related to the improved survival and laboratory findings. We concluded that the prolonged survival observed in our study was related to reduction in cancer cachexia and improved laboratory findings.

Administration, Oral↗

PubMed1996

E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastases in an experimental metastasis model.

The molecular mechanisms by which human cancer cells spread to bone are largely unexplored. The process likely involves cell adhesion molecules (CAMs) that are responsible for homophilic and heterophilic cell-cell interactions. One relevant CAM may be the calcium-dependent transmembrane glycoprotein E-cadherin. To investigate the involvement of E-cadherin in breast cancer metastasis to bone, we used an in vivo model in which osteolytic bone metastases preferentially occur after injections of cancer cells directly into the arterial circulation through the left ventricle of the hearts of nude mice. We have found that E-cadherin-negative human breast cancer cells MDA-MB-231 (MDA-231) develop radiographically detectable multiple osteolytic bone metastases and cachexia in this model. However, MDA-231 breast cancer cells that were transfected with E-cadherin cDNA showed a dramatically impaired capacity to form osteolytic metastases and induce cachexia. Histological and histomorphometrical analyses of bones of mice bearing mock-transfected MDA-231 revealed aggressive metastatic tumor, whereas metastatic tumor burden was significantly decreased in the bones of mice bearing E-cadherin-expressing MDA-231. Nude mice bearing E-cadherin-transfected MDA-231 breast cancer cells survived longer than mice bearing mock-transfected MDA-231 breast cancer cells. Anchorage-dependent and -independent growth in culture and tumor enlargement in the mammary fat pad of nude mice were unchanged between mock-transfected and E-cadherin-expressing MDA-231, suggesting that these differences in metastatic behavior are not due to an impairment of cell growth and tumor-igenicity. Our results show the suppressive effects of E-cadherin expression on bone metastasis by circulating breast cancer cells and suggest that the modulation of expression of this CAM may reduce the destructive effects of breast cancer cells on bone.

Animals↗

PubMedDate not supplied

Plasma interleukin-6 is not a mediator of changes in lipoprotein lipase activity in cancer patients.

BACKGROUND/AIMS: Cancer cachexia is characterized by a variety of metabolic disorders. Alterations in fat metabolism have been reported to be associated with suppression of tissue lipoprotein lipase (LPL) activity in tumor-bearing animals. Interleukin-6 (IL- 6) has been documented to reduce tissue LPL activity and may play a role in inducing cancer cachexia. This study was conducted to clarify the changes in LPL activity and the role of IL-6 in patients with either gastrointestinal cancer or breast cancer. METHODOLOGY: Twelve patients with colorectal cancer, 7 patients with gastric cancer, 7 patients with breast cancer and 5 normal volunteers were studied. Serum concentrations of triglycerides (TG), non-esterified fatty acids (NEFA) and IL-6 were measured. LPL activity was measured in plasma post-heparin administration. The relationships of LPL activity to tumor progression, body weight loss and serum IL-6 levels were examined. The effect of tumor resection on LPL activity was also studied. RESULTS: LPL activity was suppressed with tumor progression in patients with either gastrointestinal cancer or breast cancer. Suppression of LPL activity and the degree of weight loss were negatively correlated in patients with either gastric or colorectal cancer (r = -0.5826, p = 0.011) but not in patients with breast cancer. The decrease in LPL activity was not always reversed after resection of the tumor. Circulating IL-6 did not correlate with either plasma LPL activity or tumor progression. CONCLUSIONS: Reduced LPL activity in patients with advanced gastrointestinal or breast cancer may reflect changes in nutritional status. Serum IL-6 is less likely to be a mediator of these alterations.

Adult↗