Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer cachexia, characterized by anorexia, weight loss and progressive tissue wasting, has been postulated to be mediated by various cytokines. However, the precise mechanism of cachexia induction is not fully explained. We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis-elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation in vivo as well as in vitro. This novel molecular strategy could be useful for treating a broad range of human diseases including cancer. In this study, we injected decoy ODN targeting the transcriptional factor, NF-kappa B (NF kappa B) binding cis-elements, which are essential for transactivation of gene expression of cytokines, directly into tumors of adenocarcinoma colon26 in mice, in order to examine whether or not cachexia is alleviated by inhibiting the action of cytokines. Tumor growth was not affected by transfection of NF kappa B decoy ODN as compared with scrambled decoy ODN. Nevertheless, transfection of NF kappa B decoy, but not scrambled decoy, ODN resulted in attenuation of the reductions in body weight, epididymal fat, gastrocnemius muscle mass and food intake, which were induced by the tumor presence. Interleukin 6 mRNA in the tumor was also markedly decreased by the transfection of NF kappa B decoy ODN. It is known that the transcriptional factor E2F plays a pivotal role in the coordinated transactivation of cell cycle regulatory genes. Therefore, we hypothesized that the introduction of synthetic double-stranded DNA with high affinity for E2F in vivo as 'decoy' cis-elements might inhibit the tumor growth of colon26, resulting in turn in inhibition of cachexia induction. However, injection of E2F decoy ODN failed to inhibit tumor growth and cachexia induction, as compared with mismatched decoy ODN. Overall, the present study demonstrated that cachexia induced by adenocarcinoma colon26 was inhibited by blocking of NF kappa B, using a novel molecular decoy strategy, without an effect on tumor growth, and also that tumor growth and cachexia induction in the colon26 model were not affected by E2F decoy ODN. These results suggest that cytokines regulated by NF kappa B may play a pivotal role in the induction of cachexia by colon26, providing a new therapeutic strategy for cancer cachexia.
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PMID:Intratumoral injection of oligonucleotides to the NF kappa B binding site inhibits cachexia in a mouse tumor model. 1034 80

With progression of tumor growth, rats demonstrate anorexia and reduced food intake, a function of meal number and meal size. Tumor necrosis factor-alpha (TNF-alpha), a recognized anorectic agent, reacts with two different receptors (type I: 55 kDa; type II: 75 kDa). We used a dimeric, pegylated 55-kDa TNF receptor construct to test its effects on food intake, meal number, and meal size, which were continuously measured with a rat eater meter in 16 Fischer 344 male rats injected with 10(6) viable methylcholanthrene cells. When anorexia developed, rats received a subcutaneous injection of either 0.25 mg/kg body wt of soluble TNF receptor construct (study) or vehicle (tumor-bearing control). Before TNF inhibitor injection, no differences were observed in food intake, meal number, or meal size between the two groups. After the TNF inhibitor injection, study vs. control rats significantly improved food intake as a result of an increase in meal number and meal size. Rats also showed a significant improvement in body weight. These data suggest that TNF-alpha, in addition to other cytokines, contributes to the anorexia of tumor growth, probably mediated via the hypothalamus.
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PMID:Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats. 1048 3

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

Increased plasma free tryptophan levels have been reported in cancer patients and causally associated to the presence of anorexia. The pathogenesis of this occurrence is yet to be completely understood. Kynurenine is a metabolite of tryptophan, and has been reported increased in plasma during tumor growth. Because of the similarities between tryptophan and kynurenine we speculate that their rise in the presence of a tumor might be causally related. To test this hypothesis, we performed a series of in-vitro studies, showing that kynurenine supplementation reduces the amount of tryptophan bound to albumin, and thus, by competition, increases free tryptophan levels. The likely clinical consequences of these findings are discussed.
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PMID:Effect of kynurenine on tryptophan-albumin binding in human plasma. 1072 Oct 66

Cancer anemia is classified as an anemia of chronic diseases, although it is sometimes the first symptom of cancer. Cancer anemia includes a hemolytic component, important in the terminal stage when even transfused cells are rapidly destroyed. The presence of a chronic component and the terminal complications of the illness limit studies of the hemolytic component. A multifocal model of tumor growth was used here to simulate the terminal metastatic dissemination stage (several simultaneous inoculations of Walker 256 cells). The hemolytic component of anemia began 3-4 days after inoculation in 100% of the rats and progressed rapidly thereafter: Hb levels dropped from 14.9 +/- 0.02 to 8.7 +/- 0.06 from days 7 to 11 ( approximately 5 times the physiologically normal rate in rats) in the absence of bleeding. The development of anemia was correlated (r2 = 0.86) with the development of other systemic effects such as anorexia. There was a significant decrease in the osmotic fragility of circulating erythrocytes: the NaCl concentration causing 50% lysis was reduced from 4.52 +/- 0.06 to 4.10 +/- 0.01 (P<0.01) on day 7, indicating a reduction in erythrocyte volume. However, with mild metabolic stress (4-h incubation at 37oC), the erythrocytes showed a greater increase in osmotic fragility than the controls, suggesting marked alteration of erythrocyte homeostasis. These effects may be due to primary plasma membrane alterations (transport and/or permeability) and/or may be secondary to metabolic changes. This multifocal model is adequate for studying the hemolytic component of cancer anemia since it is rapid, highly reproducible and causes minimal animal suffering.
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PMID:The hemolytic component of cancer anemia: effects of osmotic and metabolic stress on the erythrocytes of rats bearing multifocal inoculations of the Walker 256 tumor. 1088 Oct 57

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

Individuals affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. Stimulation of the hypothalamic melanocortin 4 receptor (MC4-R) produces relative anorexia and increased metabolic rate, even in a relatively starved state. Here we demonstrate that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated by central MC4-R blockade. MC4-R knock-out mice or mice administered the MC3-R/MC4-R antagonist, agouti-related peptide, resist tumor-induced loss of lean body mass, and maintain normal circadian activity patterns during tumor growth. The final tumor mass is not affected in these animals, providing further support for the potential role of MC4-R antagonism in the treatment of cachexia in disease states.
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PMID:Role of the central melanocortin system in cachexia. 1124 47

Gender differences of feeding pattern in normal male and female rats are well recognized. Differences in gender-related feeding patterns have also been established following a variety of experimental manipulations, such as hypothalamic lesions, nicotine infusion, and total parenteral nutrition administration. Anorexia is a common feature during tumor growth. The present study examined whether the feeding indices constituting the feeding patterns differed with the development of cancer anorexia in male and female rats. Sixteen male and 15 female Fischer-344 rats had their food intake (FI) and feeding indices, meal number (MN) and meal size (MZ), continuously measured by a computerized rat eater meter. Viable methylcholanthrene (MCA) sarcoma cells (10(6)) were inoculated subcutaneously in 10 male (M-TB) and 8 female (F-TB) Fischer rats, while the rest were controls and received an equal volume of vehicle. Tumor-bearing (TB) rats became anorectic by Day 18, when the weight of the tumor was approximately 8% of the total body weight (BW). A notable decrease in BW was observed in both M-TB and F-TB. A decrease in FI resulted from different feeding indices between male and female rats. In male rats, lower FI was due to a decrease in both MN and MZ. In female rats, lower FI was solely due to a decrease in MN. The data show that gender differences in feeding patterns, which are an external manifestation of biochemical changes in the brain, occur following development of cancer-related anorexia suggesting that besides other factors, cancer anorexia is also influenced by sex-related hormones.
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PMID:Gender differences in tumor-induced anorectic feeding pattern in Fischer-344 rats. 1156 48

Thalidomide is an immunomodulator, anti-angiogenic agent, anti-cytokine, and anti-integrin. Alone or in combination with other drugs, thalidomide has also demonstrated anti-cachexin and anti-neoplastic properties. Anorexia and cachexia are common symptoms of advanced cancer. Since certain cytokines also promote tumor growth, we may have a class of agents with palliative and anti-tumor benefits in combination with anti-neoplastics and anti-cytokines, such as thalidomide.
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PMID:Thalidomide: dual benefits in palliative medicine and oncology. 1156 89

Fatigue is prominent in cancer patients and probably multifactorial in origin. Factors contributing to fatigue include anemia, weight loss, fever, pain, medication, and infection. In cancer patients, many of these factors are influenced by a frequently disrupted balance between endogenous cytokine levels and their natural antagonists. Indeed, cancer cells and the immune system appear to overexpress a range of cytokines in patients with malignancies. Some of these cytokines act as autocrine or paracrine growth factors for the neoplastic tissue while simultaneously causing secondary symptoms related to fatigue. For instance, cancer-associated anemia may be due to a blunted erythropoietin response and/or cytokines (interleukin-1 [IL-1], IL-6, tumor necrosis factor-alpha [TNF-alpha]), which suppress erythropoiesis. Cancerous cachexia, a wasting syndrome and a hallmark of cancer, can be attributed to loss of appetite or enhanced energy expenditure. Several different interleukins, as well as TNF, interferon-gamma, and leukemia inhibitory factor, act as cachectins in animal models. Similarly, fever and night sweats are influenced by pyrogenic cytokines. Recently, molecules that function as cytokine antagonists have been identified. These molecules may be exploitable in combating the components of cancer-related fatigue, and may inhibit tumor growth as well.
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PMID:The role of cytokines in cancer-related fatigue. 1159 87


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