Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The syndrome of cachexia associated with malignant diseases can be in part attributed to the effects of tumour necrosis factor alpha (TNFalpha) which itself is produced by a variety of tumour cells. We have recently reported that the human hepatoma cell line HepG2 expresses the TNFalpha gene and releases biologically active TNFalpha protein after stimulation with interleukin-1beta (IL-1beta). Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein necessary for the proliferation and differentiation of neutrophil progenitor cells in the bone marrow. In addition G-CSF has been reported to exert anti-inflammatory effects. In our study we tested the effect of recombinant human G-CSF (rhG-CSF) on TNFalpha production in HepG2 cells. It could be shown that rhG-CSF (250 U/ml) significantly reduced IL-1beta-induced (300 pg/ml) TNFalpha gene expression after 1-h and 3-h incubation periods (TNFalpha mRNA concentrations were: 8.8+/-2.1 amol/ microg total RNA after a 1-h incubation with IL-1beta versus 3.8+/-1.3 amol/ microg total RNA after a 1-h incubation with IL-1beta + rhG-CSF and 13.8+/-2.2 amol/ microg total RNA after a 3-h incubation with IL-1beta versus 8.8+/-2. 1 amol/ microg total RNA after a 3-h incubation with IL-1beta + rhG-CSF). From these data we conclude that rhG-CSF is a potent inhibitor of cytokine-induced TNFalpha production by tumour cells. Therefore, treatment of patients with malignant diseases with rhG-CSF might represent a useful tool to improve the tumour-associated cachexia.
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PMID:Granulocyte-colony stimulating factor inhibits TNFalpha production in a human hepatoma cell line. 959 23

Previous studies have shown that alteration of the dietary arginine-methionine balance by use of synthetic L-amino acids inhibits tumor growth of a subcutaneously transplanted Morris hepatoma at the expense of maintaining body weight. However, L-methionine is susceptible to degradation and, therefore, may contribute to a deficiency state. The present studies were performed to determine whether growth of subcutaneous hepatoma transplants is inhibited, and body growth maintained, when rats are fed diets containing L-methionine in replacement of N-acetyl-L-methionine (NALM) for 28 days. Tumor-free and tumor-bearing rats fed a control diet, with amino acids replacing protein, had gains in body weight: 31.3 +/- 1.0 and 19.1 +/- 0.5 g (12% and 7%), respectively. Rats fed six experimental diets, with varying L-arginine-NALM balances, had body weight gains ranging from 18.4 +/- 0.3 to 26.7 +/- 0.9 g (7-10%). Tumor weight of control rats was 10.65 +/- 0.24% of body weight. Diets supplemented with L-arginine in combination with normal and deficient NALM decreased tumor weights by 35% and 38%, respectively, It is concluded that dietary replacement of L-methionine with NALM and supplementation with L-arginine inhibits growth of a subcutaneously transplanted Morris hepatoma in the absence of cachexia.
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PMID:Growth inhibition of subcutaneously transplanted hepatomas without cachexia by alteration of the dietary arginine-methionine balance. 968 48

Primary hepatocellular carcinoma (HCC) is a common malignancy with a dismal prognosis; new modalities of treatment as alternatives to surgery have been developed for unresectable patients. The authors obtain baseline data for the natural history of HCC so that the efficacy of new treatments may be evaluated. A retrospective study of 157 untreated patients with tissue-proven or serodiagnosed HCC was conducted. Clinical characteristics including laboratory investigation, treatment received, survival from the time of diagnosis, and prognostic factors were evaluated. There were 129 men and 28 women (ratio, 4.6:1). Median age was 50.9 years (range, 14.1-85.3 years). The most common symptoms and signs were weight loss (68.2%), abdominal fullness (62.5%), abdominal pain (51.6%), hepatomegaly (73.7%), ascites (45.2%), and jaundice (40.6%). Eighteen percent had extrahepatic metastases of which the lungs were the most common site. Seventy percent were hepatitis B virus related. Overall median survival was 8.7 weeks after the time of diagnosis. Survivals by stages were: TNM II, 16.6 weeks; TNM III, 7.3 weeks; TNM IVA, 9.7 weeks; TNM IVB, 7.6 weeks; Okuda II, 10.7 weeks; and Okuda III, 7.3 weeks. Multivariate analysis revealed serum total bilirubin and albumin as independent prognostic factors of survival. Common causes of death were upper gastrointestinal hemorrhage (34.1%), cancer-related causes (cachexia, HCC rupture, metastatic disease, 31.8%), and hepatic failure (25.0%). Patients with HCC were diagnosed at late stages of their disease and the advanced nature of the tumor precluded effective therapy. Earlier tumor detection at a time when patients are better candidates for treatment may be aided by an active surveillance program of high risk groups.
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PMID:Natural history of untreated primary hepatocellular carcinoma: a retrospective study of 157 patients. 970 39

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.
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PMID:Suppression of hepatoma growth and angiogenesis by a fumagillin derivative TNP470: possible involvement of nitric oxide synthase. 972 89

Rats bearing the Yoshida AH-130 ascites hepatoma showed an increased expression of both uncoupling protein-2 (UCP2) (194%) and UCP3 (189%) mRNA levels in skeletal muscle 7 days after tumour inoculation. Interestingly, an even greater increase was observed in mRNA for both UCP2 (278%) and UCP3 (797%) in the pair-fed animals, suggesting that the increase in gene expression was the result of the anorexia associated with tumour burden. The results constitute the first report of UCP2 and UCP3 gene expression during cancer cachexia and agree to their possible role in the increase of energy expenditure associated with tumour growth.
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PMID:Skeletal muscle UCP2 and UCP3 gene expression in a rat cancer cachexia model. 980 Nov 60

The ascites hepatoma Yoshida AH130 causes in the host a rapid and progressive body weight loss, associated with reduced food intake, and protein and lipid hypercatabolism. Because insulin regulates glucose as well as lipid and protein metabolism, we suggest that the observed alterations are at least in part secondary to hypoinsulinemia and/or to the increase of counterregulatory hormones in AH130-bearing rats. To verify this hypothesis, controls with free access to food (n = 4), controls with free access to food plus insulin (107 micromol. kg body wt-1. d-1) (n = 4), controls pair-fed to the tumor-bearing rats (n = 4), pair-fed controls treated with insulin (n= 4), tumor hosts (n = 9), and tumor hosts treated with insulin (n = 6) were used. The Yoshida ascites hepatoma cells ( approximately 10(8) cells/rat) were inoculated intraperitoneally. Daily food intake and body weight were measured; insulin was injected starting the day of tumor implantation for 6 d. The metabolism of both cholesterol and lipids was investigated in tumor cells, and ascitic fluid and blood serum were investigated at the end of treatment. Insulin prevented the reduction of food intake (19 +/- 0.6 vs. 13 +/- 0.4 g/d, P < 0.01; AH130 hosts treated and not treated with insulin, respectively), the loss of body weight (202 +/- 12 vs. 135 +/- 9 g, P < 0.01), lowered the circulating triglycerides (48.3 +/- 4.9 vs. 84.5 +/- 7.1 mmol/L, P < 0.01), and free fatty acids (561 +/- 47 vs. 989 +/- 54 mmol/L (P < 0.01), while corrected the decrease of adipose lipoprotein lipase activity (1,240 +/- vs. 300 +/- pmol FA, P < 0.01) observed in AH130 hosts. Moreover, insulin prevented the decrease in HDL cholesterol (13.2 +/- 0.8 vs. 9.3. +/- 0.7 mmol/L, P < 0.01) and significantly increased hepatic cholesterol synthesis as evaluated by 14C-acetate incorporation into cholesterol, in both liver (3,337 +/- 245 vs. 830 +/- 115 Bq/g, P < 0.01) and AH130 cells (11,676 +/- 1,693 vs. 4,196 +/- 527 Bq/10(6) cells, P < 0.01). Thus insulin treatment ameliorated many metabolic derangements, with a lengthening of rats survival time (7 +/- 1 vs. 11 +/- 1 d, P < 0.05) without significantly stimulating tumor growth. These data, together with our previous observations on the effectiveness of insulin on protein turnover perturbations, suggest that many metabolic alterations occurring during cancer cachexia can be avoided by the administration of this hormone.
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PMID:Alterations of lipid and cholesterol metabolism in cachectic tumor-bearing rats are prevented by insulin. 1008 77

TNF alpha and IL-1 alpha are thought to contribute to impaired anabolism in a variety of clinical states, including sepsis, cancer cachexia and the AIDS wasting syndrome. We asked whether cytokines exert direct effects on hepatic production of IGFBP-1, an important modulator of IGF bioavailability. C57BL/6 mice were treated with 100 micrograms/kg of recombinant IL-1 alpha or TNF alpha by intraperitoneal injection. Western ligand blotting and immunoprecipitation with specific antisera revealed that serum levels of IGFBP-1 (but not IGFBP-2, -3, -4, -5 or -6) are increased approximately 4 fold 2 h after treatment and then decline. Northern blotting confirms that hepatic IGFBP-1 mRNA abundance also is increased acutely in both IL-1 alpha- and TNF alpha-treated animals. Similar results obtained in adrenalectomized mice indicate that adrenal activation is not required for this effect. Cell culture studies show that cytokines exert direct effects on the production of IGFBP-1 by HepG2 hepatoma cells, increasing IGFBP-1 levels in conditioned medium and the abundance of IGFBP-1 mRNA approximately 3-fold. In contrast, transient transfection studies with IGFBP-1 promoter/luciferase reporter gene constructs show that IGFBP-1 promoter activity is reduced after 18 hr cytokine treatment. We conclude that IL-1 alpha and TNF alpha increase circulating levels of IGFBP-1, reflecting direct effects on hepatic IGFBP-1 mRNA abundance. Stimulation of hepatic IGFBP-1 production may contribute to alterations in IGF bioactivity and impaired anabolism in clinical conditions where cytokine production is high. Additional studies are required to identify specific mechanisms mediating effects of cytokines on hepatic production of IGFBP-1.
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PMID:Interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha) regulate insulin-like growth factor binding protein-1 (IGFBP-1) levels and mRNA abundance in vivo and in vitro. 1022 4

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.
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PMID:Inhibitors of prostaglandin synthesis do not improve food intake or body weight of tumor-bearing rats. 1052 Jan 90

In two different experimental models of cancer cachexia, the rat Yoshida AH-130 ascites hepatoma and the mouse Lewis lung carcinoma, the implantation of the tumor caused a loss of body weight which was associated with a reduction in the weight of different skeletal muscles, as well as with their protein content. The decrease in protein content was accompanied by a reduction in DNA content. Interestingly, the protein/DNA ratio was unchanged in the skeletal muscle of the tumor-bearing animals as compared with the non-tumor-bearing controls. Analysis of DNA fragmentation in skeletal muscle clearly showed enhanced laddering in the skeletal muscle of tumor-bearing animals, suggesting an apoptotic phenomenon. Interestingly, the degree of laddering (total DNA fragmented) increased with tumor burden. These results suggest that DNA fragmentation may be a primary event in cancer-associated cachexia.
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PMID:DNA fragmentation occurs in skeletal muscle during tumor growth: A link with cancer cachexia? 1075 59

The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the protein hypercatabolism associated with cancer cachexia. The present study was aimed at investigating if the calpain-3 gene expression in skeletal muscle was affected by tumor growth. The results presented clearly show that calpain-3 gene expression is considerably reduced in experimental cancer cachexia, while there is a reciprocal change in the expression of the ubiquitin-dependent proteolytic system and in the ubiquitous m-calpain. The results, observed during cancer cachexia, suggest a potential counterregulatory role of calpain-3 in muscle proteolysis.
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PMID:Calpain-3 gene expression is decreased during experimental cancer cachexia. 1080 31


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