Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006625 (cachexia)
 5,650 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the mouse NC tumour, a subcutaneously transplanted adenocarcinoma originally of mammary origin. Measurements per g tissue were made of 17 fatty acids (FAs), the combined amounts of n-3, n-6, saturated, unsaturated, and total FAs, and of various FA ratios in the tumour, mammary tissue, spleen, liver and plasma. Compared with mammary tissue from normal mice, tumours of vehicle-treated controls had less of seven of the FAs and more of two FAs. Mice bearing the NC tumour often had changed (usually decreased) amounts of FAs in the 'normal' spleen, liver and plasma, but not in mammary tissue. Treatment with methotrexate (MTX) was studied alone and with indomethacin which can potentiate MTX cytotoxicity. Indomethacin 1.25 mg kg-1 (INDO) increased the amounts of 3/17 tumours FAs and the unsaturated FAs, but reduced 9/17 FAs, the saturated and the unsaturated FAs in 'normal' mammary tissue, and usually had no effect on the FAs of other tissues. MTX 2 or 4 mg kg-1 (MTX 2 or 4 mg) +/- INDO in general partly restored (increased) the amounts of tumour FAs, and reduced the saturated/unsaturated FA ratio. In the 'normal' spleen and plasma also, but not in the liver, MTX 2 mg generally somewhat restored the FA composition. However, as in the liver, the spleen 20:4 and 22:6 (which form prostaglandins and lipid peroxides) did not increase in the presence of INDO. With MTX 4 mg, some of the plasma and liver FAs decreased, in contrast to the tumour. There was generally no evidence of MTX potentiation by INDO. These results are discussed in relation to carcinogenesis, cachexia, and the response to treatment.
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PMID:Changes in tissue fatty acid composition in murine malignancy and following anticancer therapy. 173 11

Several studies have shown the relationship between prostaglandins (PGs) and cell proliferation. Some PGs may trigger cell division or are involved in this process. This study analyzes the effect of PG biosynthesis inhibitors on tumor growth in vivo and cachexia in Walker 256 tumor-bearing rats. Indomethacin markedly inhibited tumor growth (95.5%) while ibuprofen and aspirin reduced tumor growth by 73.9% and 59.4%, respectively. In addition, all drug-treated rats partially recovered body weight and food intake as compared to the saline-treated group. These findings suggest that PG synthesis inhibitors improve cancer cachexia.
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PMID:Effects of aspirin-like drugs on Walker 256 tumor growth and cachexia in rats. 263 46

Eicosanoids may be important factors for tumor cell proliferation, metastatic formation, and development of cancer cachexia. The present study has evaluated the effect of anti-inflammatory treatment on tumor progression in clinical cancer. Patients (n = 135) with insidious or overt malnutrition due to generalized malignancy (various kinds of solid tumors) and an expected survival of more than 6 months were randomized by a computer-based algorithm to receive placebo, prednisolone (10 mg twice daily), or indomethacin (50 mg twice daily) p.o. until death. Patient groups were stratified in the randomization procedure for sex, tumor type, stage, nutritional state, and previous tumor treatment, and biochemical, physiological, and some functional variables (Karnowsky index, fatigue and pain score). A majority of these variables was then registered during the follow-up. Indomethacin and prednisolone treatment maintained Karnowsky index, while placebo-treated patients experienced a decreased index. Indomethacin-treated patients suffered less pain and consumed less additional analgetics compared to the other patient groups. Indomethacin prolonged mean survival compared to placebo-treated patients from 250 +/- 28 days to 510 +/- 28 days (P < 0.05). Survival analysis on observations from all patients treated with either indomethacin or prednisolone demonstrated a significantly prolonged survival by anti-inflammatory treatment compared to placebo treatment (log rank, P < 0.03). The results suggest that not only may prostaglandin synthesis inhibition offer palliative support to patients with solid advanced cancer, but it may also impact on pathways that ultimately determine outcome.
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PMID:Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors. 792 4

We have previously demonstrated that experimentally induced T-cell leukemia in the rat results in a rapid and severe cachexia. This weight loss is largely due to a reduction in food intake, but is also accompanied by inappropriately high rates of energy expenditure. Increases in resting oxygen consumption (VO2) of 25% to 35% above the levels of pair-fed animals were observed over the period of weight loss. The present study investigated the possible involvement of prostaglandins in the cachexia induced by T-cell leukemia in the rat. Acute systemic injection of the cyclo-oxygenase inhibitors (indomethacin 1 mg/kg or flurbiprofen 1 mg/kg intraperitoneally [IP]) significantly reduced (by 14% and 10%, respectively) the increase in metabolic rate and also reversed the elevated body temperature of leukemic animals. Intracerebroventricular (ICV) injection of indomethacin (0.2 mg/kg) had only modest effects on the increase in temperature or hypermetabolism of leukemic animals. Long-term daily injection of indomethacin or flurbiprofen (1 mg/kg/d IP) had no significant effect on food intake or body weight of leukemic animals, and neither treatment significantly affected disease status. Indomethacin significantly reduced the decline in epididymal fat pad weight of leukemic animals. These data indicate that prostaglandins, produced peripherally, are involved in the acute hypermetabolism associated with T-cell leukemia, but have little or no effect on the hypophagia or body weight loss of leukemic rats.
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PMID:Involvement of prostaglandins in cachexia induced by T-cell leukemia in the rat. 910 35

We tested the hypothesis that increased dietary fish oil levels (via modulation of the production of inflammatory mediators) modulate sickness symptoms (i.e., anorexia, cachexia, fever, lethargy) of systemic and local inflammation. Swiss Webster mice were implanted with biotelemeters to measure body temperature and motor activity and were fed a diet high in n-3 fatty acids (17% wt/wt menhaden oil) or a reference diet (17% wt/wt hydrogenated coconut oil or normal rodent chow) for 6 wk. Local inflammation was induced by subcutaneous injection of turpentine (100 microl/mouse). Systemic inflammation was elicited by intraperitoneal injection of lipopolysaccharide (LPS; 2.5 mg/kg). Fever, lethargy, anorexia, and weight decrease during turpentine abscess were all inhibited (P < 0.05) in mice fed the fish oil diet. Indomethacin, similar to the fish oil diet, attenuated the turpentine-induced symptoms in mice fed a normal diet. Dietary n-3 fatty acids prevented fever and attenuated the decrease in body weight caused by LPS but did not affect the LPS-induced lethargy and anorexia. Within 90 min of LPS injection, the bioactivity of plasma tumor necrosis factor-alpha (TNF-alpha) increased to 98.2 +/- 5.1 ng/ml in mice fed fish oil compared with 32.6 +/- 3.6 ng/ml in those fed the reference diet (P < 0.05). Plasma prostaglandin E2 (PGE2) levels after LPS injection of mice fed the control diet increased within 90 min to 16.4 +/- 5.1 pg/ml. Mice fed the fish oil diet did not show any elevation in plasma PGE2 levels at that time (P < 0.05). We speculate that dietary n-3 fatty acids suppressed PGE2-related responses, including a PGE2-dependent negative feedback on TNF-alpha production, which resulted in differential modulation of sickness behavior depending on the locus of inflammation.
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PMID:Dietary n-3 fatty acids differentially affect sickness behavior in mice during local and systemic inflammation. 914 33

The syndrome of cancer cachexia is accompanied by several alterations of lipid metabolism, especially that in the liver. In this study we have investigated a possible mechanism whereby the presence of the Walker 256 carcinosarcoma affects hepatic fatty acid oxidative capacity in tumour-bearing rats. Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I), generally accepted as the main site of regulation of fatty acid oxidation, was unaffected by the presence of the extra-hepatic tumour. However, mitochondrial inner-membrane carnitine palmitoyltransferase II (CPT II) activity was markedly decreased in mitochondria isolated from the liver of tumour-bearing rats. Immuno-detection by Western blotting using a CPT II-specific antibody identified two bands (corresponding to M(r) 69,000 and 54,000) in tumour-bearing rats whereas only the normal-sized CPT II was present (at the expected M(r) 69,000) in mitochondria from control rats. It is suggested that the emergence of the second, smaller protein may represent a catalytically less active protein that arises in vivo, since its appearance was not affected by the inclusion of proteolysis inhibitors in the mitochondrial preparation buffers. Treatment of the tumour-bearing rats with indomethacin, a prostaglandin (including PGE2) synthesis inhibitor, increased CPT II activity to levels even higher than those found in the control animals. It is suggested that PGE2 may play a role in the control of CPT II expression in the liver of tumour-bearing rats. Indomethacin treatment did not affect either of the two CPT activities of the mitochondria isolated from tumour tissue.
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PMID:Carnitine palmitoyltransferase II activity is decreased in liver mitochondria of cachectic rats bearing the Walker 256 carcinosarcoma: effect of indomethacin treatment. 950 62

The potential interaction between cyclooxygenase (Cox) and NO metabolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57B1; MCG 101) or a malignant melanoma (C3H/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and low production of prostanoids, respectively. Cox inhibitors (Cox-1 and Cox-2) decreased tumor growth by 35-40% in MCG 101-bearing mice but had no such effect on melanoma-bearing mice, despite the expression of the Cox-2 protein in melanoma cells. Indomethacin reduced prostanoid production in both tumor (MCG 101) and host tissues and reduced tumor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibitors (N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine) reduced tumor growth in vivo by approximately 50% in both tumor models. Tumor growth reduction, related to NOS inhibition, was unrelated to prostanoid production and was an in vivo phenomenon in both tumor models. Specific inhibitors of inducible NOS activity, unexpectedly, had no effect in any tumor model, although inducible NOS protein was present in tumor tissues in large amounts. A combination of Cox and NOS inhibitors had no additive effect on tumor growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expression of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic fibroblast growth factor. NOS inhibition increased tumor tissue content of cNOS mRNA but showed as well a trend to increase mRNA content of the transferrin receptor and vascular endothelial growth factor. Our results suggest that NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cox inhibition. This effect may reflect cross-talk between Cox and NOS pathways within or among tumor cells, or it may represent unrelated effects on tumor and host cells. Whether NO inhibition may be used therapeutically in clinical tumors that are unresponsive to eicosanoid intervention remains to be evaluated.
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PMID:Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids. 1074 48

MCG 101 tumors were implanted sc. on wild-type C57 Bl and gene knockout mice to evaluate the role of host-produced cytokines [interleukin (IL)-6, IL-12, IFNgamma, tumor necrosis factor (TNF) receptor 1, and TNF receptor 2] to explain local tumor growth, anorexia, and carcass weight loss in a well-defined model with experimental cachexia. Indomethacin was provided in the drinking water to explore interactions between host and tumor-derived prostaglandins and proinflammatory cytokines for tumor growth. Wild-type tumor-bearing mice developed cachexia because of rapid tumor growth, which were both attenuated in IL-6 gene knockouts. Similar findings were observed after provision of anti-IL-6 to wild-type tumor-bearing mice. Alterations in food intake were not directly related to systemic IL-6 but rather secondarily to IL-6-dependent tumor growth. The absence of host-derived IL-12, IFN-gamma, or the TNF receptor 1 or receptor 2 gene did not attenuate tumor growth or improve subsequent cachexia. Thus, carcass weight loss was not improved by the omission of host cytokine (TNF-alpha, IL-12, or IFN-gamma) except for IL-6. Systemic indomethacin provision decreased plasma prostaglandin E2 in five of six groups of gene knockout tumor-bearing mice, which was associated with improved carcass weight in these groups. Indomethacin seemed to improve food intake to a similar extent in both wild-type and gene knockouts, which agree with the speculation that eicosanoids are more important to explain anorexia than host cytokines. Our results demonstrate that host- and tumor-derived cytokines and prostaglandins interact with tumor growth and promote cachexia in a more complex fashion than usually presented based on previous information in studies on either anti-cytokine experiments in vivo or on gene knockouts with respect to a "single cytokine model." Overall, host cytokines were quantitatively less important than tumor-derived cytokines to explain net tumor growth, which indirectly explains subsequent cachexia and anorexia.
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PMID:Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia. 1103 92

Chronic arthritis induces cachexia associated with an inhibition of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) system and an activation of the E3 ubiquitin-ligating enzymes muscle atrophy F-box (MAFbx) and muscle Ring finger 1 (MuRF1) in the skeletal muscle. The aim of this work was to study the role of cyclooxygenase (COX)-2 in chronic arthritis-induced cachexia. Arthritis was induced in rats by Freund's adjuvant injection, and the effects of two COX inhibitors (indomethacin, a nonspecific inhibitor, and meloxicam, a selective COX-2 inhibitor on pituitary GH and on liver and serum IGF-I levels) were tested. Arthritis decreased body weight gain and GH and liver IGF-I gene expression. In the arthritic rats, both inhibitors, indomethacin and meloxicam, prevented the inhibitory effect of arthritis on body weight gain. Indomethacin and meloxicam administration to arthritic rats increased pituitary GH and liver IGF-I mRNA as well as serum levels of IGF-I. These data suggest that induction of COX-2 during chronic inflammation is involved in the inhibition of the GH-IGF-I axis and in the body weight loss. In the gastrocnemius muscle, arthritis increased the gene expression of tumor necrosis factor (TNF)-alpha, the E3 ubiquitin-ligating enzymes MAFbx and MuRF1, as well as of IGF-I and IGF-binding protein-5 (IGFBP-5). Inhibition of COX-2 by meloxicam administration increased gastrocnemius weight and decreased MAFbx, MuRF1, TNF-alpha, and IGFBP-5 gene expression. In summary, our data indicate that chronic arthritis-induced cachexia and muscle wasting are mediated by the COX-2 pathway resulting in a decreased GH-IGF-I secretion and increased expression of MAFbx and MuRF1 mRNA.
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PMID:Experimental arthritis inhibits the insulin-like growth factor-I axis and induces muscle wasting through cyclooxygenase-2 activation. 1728 70

The alterations of enzymatic activities involved in lipid degradation in cancer cachexia have not been fully elucidated. One of the two subclones of colon 26 adenocarcinoma, clone 20, with a potent ability to induce cachexia, or clone 5, without such an activity, was transplanted in to CDF-1 male mice. Murine livers were extirpated for analyses on the 14th day after tumor inoculation. The body weights and food intake of mice bearing clone 20 were all significantly lower than those of non-tumor bearing mice and mice bearing the clone 5 tumor. The decline of body weight was accompanied by a shrinkage of epididymal fat pads. Expression of spermidine/spermine N-1 acetyl transferase (SSAT) assessed by real-time PCR was significantly increased in cachectic mice. Conversely, acetyl-CoA carboxylase (ACC) measured by Western blotting and malonyl-CoA levels determined by malonyl-CoA:acetyl-CoA cycling procedures were decreased in cachectic mice. Indomethacin in drinking water reversed the clone 20 induced decrease in body and fat weight and food intake, and simultaneously negated the clone 20 induced increase of SSAT expressions and decrease of ACC and malonyl-CoA amounts. Because malonyl-CoA inhibits the rate-limiting step in the beta-oxidation of fatty acids, the decreased malonyl-CoA and the background metabolic alterations may contribute to the accelerated lipolysis of cancer cachexia.
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PMID:Decrease in malonyl-CoA and its background metabolic alterations in murine model of cancer cachexia. 1928 15


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