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PubMed1988

An overview of megestrol acetate for the treatment of advanced breast cancer.

Megestrol acetate was one of the first progestational agents to be evaluated for use in the hormonal therapy of advanced breast cancer. Since that time, megestrol acetate has become a standard for progestin antitumor research because of its progestational potency and excellent safety profile. As single-agent therapy, the average overall response rate to megestrol acetate therapy is 30%. This response rate is equivalent to that reported for tamoxifen, another hormonal agent widely used in treatment of breast cancer. Furthermore, although the side-effect profiles of these two agents are similar, the weight gain associated with megestrol acetate use may be beneficial in breast cancer patients who also have cancer cachexia. Because megestrol acetate and tamoxifen have been shown to be somewhat non-cross-resistant, megestrol acetate may prove useful as first-line treatment for disease that progresses during adjuvant tamoxifen therapy. Other focuses of research, including treatment of estrogen- and progestogen-receptor negative disease and moderation of weight loss for cancer cachexia, may offer hope to many cancer patients, even those with a currently unfavorable prognosis.

Breast Neoplasms↗
PubMed1988

Glucocorticoid receptor-mediated effects on rat fibrosarcoma growth.

Glucocorticoid receptors are present in most normal and malignant mammalian cells. To examine the hypothesis that the growth of methylcholanthrene-induced malignant sarcoma is glucocorticoid dependent, we evaluated the behavior of malignant fibrosarcoma (MCA) in adrenalectomized rats treated with either normal saline or deoxycorticosterone acetate and in intact rats treated with placebo or with the glucocorticoid receptor antagonist RU 486. Survival, tumor weight, and loss of body weight (an index of cachexia) were measured. In MCA-bearing rats, neither survival nor loss of body weight was affected by bilateral adrenalectomy or by treatment with RU 486. Tumor weight and time-integrated tumor volume, however, were significantly less in bilaterally adrenalectomized rats without deoxycorticosterone acetate replacement than in animals treated with deoxycorticosterone acetate. Similarly, tumor weight and time-integrated tumor volume were less in intact animals treated with RU 486 than in intact animals treated with placebo. The glucocorticoid receptors in the tumor cells had similar binding capacity (Ro) and equilibrium dissociation constant (Kd) as in control rat fibroblasts. These results suggest that the growth of MCA sarcoma cells is partially dependent upon glucocorticoids. This effect of glucocorticoids, however, was not of sufficient magnitude to improve survival and prevent cachexia. We conclude that glucocorticoids appear to influence MCA sarcoma growth in the rat, and that glucocorticoid receptor blockade, perhaps in combination with other antitumor agents, merits future study in the treatment of malignant tumors.

Adrenalectomy↗
PubMed1982

Production of human alpha 1-antichymotrypsin-like protein by a human malignant melanoma transplanted into nude mice.

A tissue culture line of a human malignant melanoma, SEKI, induced cachexia in nude mice (BALB/c-nu/nu) (Kondo et al., Cancer Res., 41: 2912-2916, 1981). During the investigation of the cause of the cachexia, the melanoma was found to produce a protein immunologically identical to human alpha 1-antichymotrypsin (alpha 1-Ach). Tissues of the SEKI melanoma contained the protein immunologically equivalent to 0.29 +/- 0.11 (S.D.) mg of human alpha 1-Ach per g of wet tissue, while the other six human malignant tumors transplanted into nude mice did not contain a detectable amount of it. In the serum of nude mice bearing the melanoma, this protein appeared soon after the tumor growth occurred and gradually increased up to the level equivalent to 5 mg of human alpha 1-Ach per dl. Removal of the tumor resulted in a rapid decrease of the protein in the serum to an undetectable level within 1 day. This problem was never detected in the serum of nude mice bearing the other 27 human malignant tumors or controls. Purification of this protein was carried out by the column chromatography using DE-52, Blue-Sepharose, and SP-Sephadex. The elution patterns were the same as those of alpha 1-Ach in human serum, and the molecular weight of the protein was estimated as 69,000 by Sephadex G-100 column chromatography and 65,000 by polyacrylamide gel electrophoresis with sodium dodecyl sulfate. This purified protein, however, did not exhibit inhibitory activity against chymotrypsin. These results show that this melanoma produced a protein immunologically identical and physicochemically very similar to human alpha 1-Ach. This melanoma-nude mouse system may provide a useful model for investigating the synthesis of human alpha 1-Ach and analysis of its physiological roles.

Animals↗
PubMedDate not supplied

Prominent white matter cavitation in an infant with Alexander's disease.

The clinical history and autopsy findings are reported on a case of infantile Alexander's disease (AD). The patient, a white baby girl, developed seizures at age 4 months accompanied by internal hydrocephalus. She died at age 11 months following a progressive, downhill course of profound psychomotor retardation, recurrent seizures and cachexia. The general autopsy was remarkable for cachexia. The formalin fixed brain and spinal cord were studied by light and electron microscopy (EM). The brain was normal in weight for age but showed diffuse pallor of white matter and marked cavitation involving the cerebral and cerebellar subcortical white matter, most profound in the frontal lobes. Microscopically the CNS showed classic features of AD with diffuse paucity of myelin and massive proliferation of astrocytes bearing Rosenthal fibers (RF). The latter appeared as granular osmiophilic deposits associated with 8-10 nm filaments within astrocytic processes and cell bodies by EM. This case of AD is remarkable for the extreme degree of cavitation. Cavitary changes affect up to one third of typical cases of AD and are invariably present in the frontal white matter. Affected patients are generally much younger and have a shorter clinical course than AD patients without brain cavitation. The dysmyelination of AD inversely parallels the temporal sequence of normal myelination and suggests a relative resistance of early myelinated structures to the presumed astrocytic defect causing AD. Adults with de novo formation of RF's in the CNS have a varied clinical and pathological appearance, rarely show brain cavitation and should probably be distinguished from classic AD in children.

Astrocytes↗
PubMed1993

A temporal study of the lesions induced by MoMuSV-349.

We used time point studies to document the progression of neoplasms, haematologic abnormalities and associated lesions induced by Moloney murine sarcoma virus-349 (MoMuSV-349). BALB/c mice inoculated intraperitoneally with MoMuSV-349 first developed histologically discernible lesions at 14 days post-inoculation (d.p.i.). The initial neoplasms were characterized by whorls of fusiform or spindle-shaped cells enmeshing dense infiltrates of neutrophils and macrophages. By 21 d.p.i., clinical signs associated with MoMuSV-349 infection were evident. The distribution of the neoplasms was more widespread, although the histologic appearance of the tumours was very similar to that found at 14 d.p.i. All mice sacrificed at 28 d.p.i. exhibited characteristic clinical signs associated with MoMuSV-349, including moderate cachexia. Histologically, neoplasms observed at 28 d.p.i. contained a significant vascular component. By 35 d.p.i., all mice exhibited severe clinical signs (e.g. cachexia, dull hair coat, uneven gait). Histologically, all the neoplasms had a predominant vascular component. Non-neoplastic lesions, such as severe thymic atrophy and multifocal pulmonary haemorrhage, were commonly present. Mice sacrificed 42 d.p.i. were clinically, grossly and histologically similar to those sacrificed at 35 d.p.i. However, one difference found in the 42 d.p.i. group was the presence of rare rhabdomyosarcomas infiltrating the skeletal muscles. Mice inoculated with MoMuSV-349 developed severe neutrophilia and lymphopenia, and moderate anaemia. This study demonstrates that MoMuSV-349 induced angiosarcomatous neoplasms are characterized by stage development and severe haematologic and non-neoplastic abnormalities.

Animals↗
PubMed1996

Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development.

With the advent of gene targeting in pluripotent mouse embryonic stem cells, it is now possible to modify the mammalian genome to generate mutant strains of mice with precise genetic mutations. The major goal of my laboratory is to generate transgenic mice to use as physiologic models to study mammalian reproduction and development. The initial focus of our research has been to generate mice deficient in inhibins, activins, activin binding proteins (i.e., follistatin), and activin receptors (i.e., activin receptor type II) to understand their interactions and roles in the hypothalamic-pituitary-gonadal axis and mammalian development. Inhibins and activins, dimeric members of the TGF-beta superfamily, were discovered due to their role in pituitary follicle stimulating hormone homeostasis. However, these proteins have later been shown to have diverse endocrine, paracrine, and autocrine functions. Activins have been shown to mediate their signals through type I and type II serine/threonine kinase receptors. The high interspecies conservation of activins, inhibins, and activin receptors and the universal presence of activins in mammals, birds, amphibians, and fish suggest an evolutionarily conserved role of these proteins in animal development. Our initial studies have demonstrated a tumor suppressor role of inhibin in the gonads and adrenals and have also suggested a role of activins in cancer cachexia-like syndrome. To further study the gonadal tumor development and the cancer cachexia-like syndrome in these mice, we have begun to generate mice with multiple genetic alterations (e.g., mice deficient in both inhibin and Mullerian inhibiting substance). We have also generated mice deficient in other components of this complex system (e.g., activin beta A, activin receptor type II, follistatin). Analysis of these transgenic mutant models has aided our overall understanding of the critical roles these proteins play in the development of the reproductive system, in the modulation of the endocrine milieu that regulates reproductive function, and in mammalian development.

Activins↗
PubMed1996

Survival of diabetic patients on peritoneal dialysis or hemodialysis.

Our objective was to analyze the survival of diabetic patients on renal replacement therapy and to compare their survival on extracorporeal and on peritoneal dialysis. All data regarding diabetic patients admitted to dialysis between 1 January 1983 and 31 December 1993 were collected by means of individual patient questionnaires sent to all of the 44 regional Renal Units (100% answers) of Lombardy, Italy. Cox proportional hazards model, stepwise procedure, was applied in order to select the covariates significantly associated with survival. Age (at baseline), sex, type of diabetes, initial modality of treatment (hemodialysis or peritoneal dialysis), and initial clinical risk factors (malignancies, serious heart disease, vascular disease, cirrhosis of the liver, cachexia) were considered. Descriptive analysis of survival was performed using the Kaplan-Meier technique. The survival of all diabetic patients (895) was 86.5% at one year, 52% at three years, and 34% at five years. The main causes of the 488 deaths of diabetic patients were cardiovascular diseases (56%), cachexia (18%), and infections (11%). The relative death risk of patients on peritoneal dialysis versus those on hemodialysis, after taking into account the main comorbid conditions, did not significantly differ from 1, as estimated by the Cox proportional hazards regression model. Five-year survival of diabetic patients was 34%, and no differences were found between peritoneal dialysis and hemodialysis as far as mortality is concerned.

Adult↗
PubMed1998

[Nutrition and cancer patients].

Nutritional therapy for cancer patients includes various objectives such as improvement of cachexia, elucidation of the mechanism of malnutrition, development of therapy for anorexia, nutrition support during chemotherapy or radiotherapy, and inhibition of tumor growth under controlled caloric intake. This review describes recent remarkable developments in nutritional therapy for cancer patients. Cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor which induce proteolysis and lipolysis are involved in the cause of malnutrition and cachexia in cancer patients. IL-1 also plays a significant role in the development of cancer anorexia via direct action in the brain. For anorexia therapy, progestogens have been shown to improve appetite and food intake in cancer patients. Moreover, glutamine supplementation improves the host protein metabolism without enhancement of tumor growth during chemotherapy. Among the effects of caloric intake on anticancer therapy, AO-90, a methionine-free intravenous amino acid solution, has been shown to increase the antitumor effect of 5-fluorouracil in clinical studies. From these observations, recent progress in nutritional therapy for cancer patients has been remarkable. Further study of nutritional therapy is required in order to maintain or improve the quality of life of cancer patients in the future.

Humans↗
PubMed1998

Suppression of hepatoma growth and angiogenesis by a fumagillin derivative TNP470: possible involvement of nitric oxide synthase.

TNP470, a derivative of fumagillin, suppressed in vivo growth of human PLC/PRF/5 hepatoma and ameliorated cachexia of hepatoma-bearing mice. These in vivo effects were associated with reductions in microvessel and macrophage counts. In in vitro experiments, TNP470 inhibited the growth and migration of human hepatoma and bovine vascular endothelial (VE) cells. TNP470 did not inhibit the production of VE growth factor by the hepatoma, which suggests that this compound acts directly on VE cells in vivo. In contrast, TNP470 inhibited the production of leukemia inhibitory factor, which may be related to the amelioration of cancer cachexia. TNP470 induced apoptosis and enhanced the expression of beta-galactosidase, a biomarker of senescence, which was partly mimicked by a nitric oxide (NO) donor S-nitroso-N-acetyl penicillamin. TNP470 inhibited myristoylation and membrane translocation of NO synthase and increased the cellular content of NO synthase and production of NO. Therefore, it is suggested that the actions of TNP470 are mediated, at least in part, through the inhibition of membrane translocation of biologically active proteins.

Animals↗
PubMed2005

Compliance with nutrition prescription improves outcomes in patients with unresectable pancreatic cancer.

BACKGROUND & AIMS: There are few well-designed studies evaluating the effect of oral nutrition supplements in patients with cancer cachexia. The aim of this study, in a posthoc analysis, was to examine the effect of dietary compliance on intake and body composition in patients with unresectable pancreatic cancer. METHODS: Two hundred patients were randomised to receive 2 cans/day of a protein and energy dense, oral nutrition supplement+/-n-3 fatty acids in an international, multi-centre randomised trial over 8 weeks. Dietary compliance was defined a priori as consumption of a minimum of 1.5 cans/day of either supplement. Body composition, dietary intake and quality of life were measured at baseline, 4 and 8 weeks. RESULTS: On average, there were significant differences in energy intake (501 kcal), protein intake (25.4 g) and weight (1.7 kg) between patients who were compliant with the nutrition prescription compared to noncompliant patients controlling for n-3 fatty acid randomisation, baseline weight and quality of life. Over the 8-week period, there was significant improvement in weight only. There was no significant difference in the energy intake from meals of the total group over the 8 weeks. CONCLUSIONS: Compliance with the prescription of 1.5 cans of a protein and energy dense, oral nutrition supplement +/-n-3 fatty acids improved nutrition related outcomes in untreated pancreatic cancer patients. This level of supplement intake does not inhibit meal intake.

Aged↗
PubMed1965

THE ACUTE TOXICITY OF TANNIC ACID ADMINISTERED INTRAGASTRICALLY.

The LD(50) +/- S.E. of tannic acid given orally to albino rats was found to be 2.26+/-0.083 g. per kg. body weight, which is higher than its apparent LD(50) when given per rectum. The immediate cause of death was respiratory failure preceded by convulsions when death occurred early and by hypothermic cachexia when death was delayed. Death was associated with a progressively developing hepatic necrosis and nephritis and a temporary acute gastroenteritis. It was accompanied by loss of weight and edema in many organs, evidence of stimulation of the spleen, adrenal cortex and testes, and atrophy of the thymus. Recovery in survivors was associated with a temporary increase in weight of the spleen and testes and persistence of loss of weight in the adrenal, pyloric stomach, and skin.

Cachexia↗
PubMed1989

Elevated serum levels of tumor necrosis factor are associated with progressive encephalopathy in children with acquired immunodeficiency syndrome.

The cytokine tumor necrosis factor (TNF) was assayed in the sera (n = 31) and cerebrospinal fluid (n = 26) of children with acquired immunodeficiency syndrome, using a competitive radioimmunoassay. Elevated serum levels of TNF were found in 15 (79%) of 19 patients with progressive encephalopathy (PE), compared with 1 (8%) of 12 patients without neurologic involvement. There was a significant association of PE with elevated serum TNF levels. Conversely, of 16 patients with elevated serum TNF levels, 15 (94%) were found to have PE, and of 8 patients with serum TNF levels greater than 100 pg/ml, all 8 (100%) had PE. No association was found between cerebrospinal fluid levels of TNF and PE. Neither serum nor cerebrospinal fluid TNF levels correlated with the degree of cachexia. These data suggest that circulating TNF may be responsible for the myelin damage that occurs in human immunodeficiency virus type 1-associated PE.

Acquired Immunodeficiency Syndrome↗
PubMed1987

The acute metabolic effects of tumor necrosis factor administration in humans.

It has been suggested that the monokine tumor necrosis factor (TNF) (cachectin) is responsible for metabolic abnormalities frequently accompanying malignant neoplasms. The acute metabolic effects of TNF in patients with cancer were studied. Subcutaneous administration of recombinant human TNF led to a rise in the C-reactive protein level (4.4 +/- 1.2 mg/dL vs 11.6 +/- 1.8 mg/dL) and a reduction in the serum zinc level (12.9 +/- 0.8 mumol/L vs 7.3 +/- 0.8 mumol/L [79 +/- 5 mg/dL vs 48 +/- 5 mg/dL]) (values are the mean +/- SEM). Forearm efflux of total amino acids more than doubled after intravenous TNF injection, principally because of increases in release of the gluconeogenic amino acids alanine and glutamine. Concomitantly, the arterial levels of alanine, glutamine, and total amino acids fell, indicating that TNF also stimulated the uptake of amino acids by other tissues. The observed amino acid pattern cannot be explained solely on the basis of measured changes in cortisol, glucagon, or insulin levels. These findings are discussed in relation to known alterations of amino acid metabolism in cancer-associated cachexia.

Adult↗
PubMed1999

Inhibitors of prostaglandin synthesis do not improve food intake or body weight of tumor-bearing rats.

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are immunoregulatory cytokines that mediate many aspects of the acute phase response to infection and injury. It has been hypothesized that these cytokines mediate the onset of the cachexia-anorexia syndrome with tumor growth. The anorexigenic effects of IL-1 are mediated in part by prostaglandins (PG). Therefore, the purpose of the present study was to determine if administration of ibuprofen (ibu) or indomethacin (indo), which inhibit PG synthesis, would affect the food intake and body weight of tumor-bearing rats. Rats were implanted with the Morris 7777 hepatoma, a tumor known to induce anorexia and weight loss in rats, and weight loss and leukocyte synthesis of IL-1 and TNF in mice. Treatment with indo or ibu did not improve food intake or body weight in the tumor-bearing rats. However, administration of ibu coincident with tumor implantation did result in smaller tumor mass compared to placebo-treated controls. The results of the present study suggest that PG synthesis is not a major factor in the onset of anorexia in this animal model of tumor-induced anorexia. However, further studies of the effects of inhibitors of PG synthesis on the kinetics of tumor growth are clearly indicated.

Analysis of Variance↗
PubMed1998

The effect of Walker-256 tumour development upon Kupffer cell metabolism.

The liver plays a central role in the establishment and maintenance of the cachectic state in rats bearing extra-hepatic tumours. Kupffer cells, which as macrophages, show a strong relationship between metabolism and function could be involved in the alterations observed in the disruption of many functions of the organ as a whole. To assess whether the metabolic/functional pattern of Kupffer cells was altered by cachexia we have investigated the utilization of glucose, glutamine and palmitate by the cells from tumour-bearing and control rats. We have found an enhanced utilization of the three substrates by the cells from tumour-bearing rats as compared with controls, which was related to greater energy production through the Krebs cycle and enhanced production of precursors for the synthesis of the many substances the cells secrete when activated. The use of palmitate as substrate was also augmented in these cells, in the opposition to the observation in stimulated peritoneal macrophages. The availability of palmitate however, was not associated with a reduction of glucose or glutamine consumption. The cycle of interconversion, free fatty acids/triacyglycerol in Kupffer cells from tumour-bearing rats was also found to be increased, as was hydrogen peroxide production. Taken together the results suggest an increased utilization of substrates for both energy production and for synthetic processes (e.g. NADPH for hydrogen peroxide production).

Amino Acids, Dicarboxylic↗
PubMedDate not supplied

The uses of psychotropics in symptom management in advanced cancer.

Approximately 50% of patients diagnosed with cancer die because of progressive disease. Psychotropic drugs are frequently used for the management of physical and psychosocial symptoms in these patients. Thalidomide, cannabinoids and melatonin are emerging agents for the management of cachexia. Psychostimulants have a defined role in the management of opioid-induced sedation. Haloperidol, tricyclic anti-depressants and newer anti-depressants also have an established role in the management of neuropsychiatric symptoms such as delirium or depression. Cancer patients present unique challenges for successful psychotropic therapy including older age, malnutrition, autonomic failure, borderline cognition, opioid and psychotropic therapy. A practical clinical approach which defines a specific target symptom, an outcome latency period, expected side effects, and reviews possible drug interactions, and frequent monitoring is outlined. Continued research is needed to further define the role of psychotropics in the management of the different physical and psychosocial symptoms in advanced cancer patients.

Cachexia↗
PubMed1978

A comparative study of the influence of malignant tumor on host metabolism in mice and man: evaluation of an experimental model.

Metabolic alterations in skeletal muscles and liver tissue from cancer patients were compared with corresponding alterations in mice (C-57) with sarcoma (MCG-101). In tumor-bearing man and mice similar changes in enzyme activities and in protein turnover were found. Glycolytic and oxidative enzyme activities were decreased in skeletal muscle tissue. Tumor-associated increase in lysosomal enzyme activities was found in both species. Leucine was incorporated into skeletal muscle proteins at a lower rate and into hepatic proteins at a higher rate in both species with malignant tumor. In tumor-bearing mice ribosome profiles from skeletal muscle, heart muscle and liver showed a preponderance of slowly sedimenting units of polyribosomes suggesting that initiation of protein synthesis may be a rate limiting step. The metabolic host reactions in tumor-bearing mice were similar to those in cancer patients implying that experimental tumors are relevant to use for analysis of mechanisms behind the development of cancer cachexia in man.

Adult↗
PubMed1982

Theoretical aspects of weight loss in patients with cancer. Possible importance of pyruvate dehydrogenase.

In the analysis of weight loss in cancer patients, consideration must be given to decreased caloric intake, increased caloric expenditure and abnormal losses of calories. When these factors do not adequately explain the degree of weight loss, this may be due to a specific loss of lean body mass, as the caloric density of muscle is much less than that of fat. The key enzyme for the protection of lean body mass in hypocaloric states is pyruvate dehydrogenase (PDH). During fasting, fast oxidation in host tissues leads to inactivation of PDH, preventing irreversible loss of pyruvate precursors which would have to be replaced by protein breakdown. A tumor in which PDH activity remains high in the fasting state would cause loss of lean body mass in the host. This report suggests that this phenomenon may be important in certain patients with cancer cachexia.

Amino Acids↗