Heterogeneous response of adipose tissue to cancer cachexia

Cancer cachexia causes disruption of lipid metabolism. Since it has been well established that the various adipose tissue depots demonstrate different responses to stimuli, we assessed the effect of cachexia on some biochemical and morphological parameters of adipocytes obtained from the mesenteric (MES), retroperitoneal (RPAT), and epididymal (EAT) adipose tissues of rats bearing Walker 256 carcinosarcoma, compared with controls. Relative weight and total fat content of tissues did not differ between tumor-bearing rats and controls, but fatty acid composition was modified by cachexia. Adipocyte dimensions were increased in MES and RPAT from tumor-bearing rats, but not in EAT, in relation to control. Ultrastructural alterations were observed in the adipocytes of tumor-bearing rat RPAT (membrane projections) and EAT (nuclear bodies)

Incorporation of dietary trans monounsaturated fatty acids into tissues of Walker 256 tumor-bearing rats

The correlation between dietary trans fatty acids and neoplasia was examined in the present study. Walker 256 tumor-bearing and control rats were fed a trans monounsaturated fatty acid (MUFA)-rich diet for 8 weeks and the incorporation of trans fatty acids by tumor tissue was examined. Also, the effect of tumor growth on trans fatty acid composition of plasma and liver, and the content of thiobarbituric acid-reactive substances (TBARS) was determined. Walker 256 tumor cells presented both trans and cis MUFAs given in the diet. The equivalent diet proportions were 0.66 for trans and 1.14 for cis. Taking into consideration the proportion of trans MUFAs in plasma (11.47 percent), the tumor incorporated these fatty acids in a more efficient manner (18.27 percent) than the liver (9.34 percent). Therefore, the dietary trans fatty acids present in the diet are actively incorporated by the tumor. Tumor growth itself caused marked changes in the proportion of polyunsaturated fatty acids in the plasma and liver but provoked only slight modifications in both trans and cis MUFAs. Tumor growth also reduced the unsaturation index in both plasma and liver, from 97.79 to 86.83 and from 77.51 to 69.64, respectively. This effect was partially related to an increase in the occurrence of the lipid oxidation/peroxidation process of TBARS content which was increased in both plasma (from 0.428 to 0.505) and liver (from 9.425 to 127.792) due to tumor growth

Effect of a leucine-supplemented diet on body composition changes in pregnant rats bearing Walker 256 tumor

Cancer patients present high mobilization of host protein, with a decrease in lean body mass and body fat depletion occurring in parallel to neoplastic growth. Since leucine is one of the principal amino acids used by skeletal muscle for energy, we investigated the changes in body composition of pregnant tumor-bearing rats after a leucine-supplemented diet. Sixty pregnant Wistar rats divided into six groups were fed a normal protein diet (18 percent, N) or a leucine-supplemented diet (3 percent L-leucine, L). The pregnant groups were: control (CN), Walker 256 carcinoma-bearing rats (WN), control rats pair-fed with tumor-bearing rats (pfN), leucine-supplemented (CL), leucine-supplemented tumor-bearing (WL), and leucine-supplemented rats pair-fed with tumor-bearing rats (pfL). At the end of pregnancy, all animals were sacrificed and body weight and tumor and fetal weight were determined. The carcasses were then analyzed for water, fat and total, collagen and non-collagen nitrogen content. Carcass weight was reduced in the WN, WL, pfN and pfL groups compared to control. The lean body mass and total carcass nitrogen were reduced in both tumor-bearing groups. Despite tumor growth and a decrease in fetal weight, there was a slight decrease in collagen (7 percent) and non-collagen nitrogen (8 percent) in the WL group compared with the WN group which showed a decrease of 8 and 12 percent, respectively. Although the WL group presented severe tumor growth effects, total carcass nitrogen and non-collagen nitrogen were particularly higher in this leucine-supplemented group compared to the WN group. These data suggest that the leucine-supplemented diet had a beneficial effect, probably attenuating body wasting

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

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 percent 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 (~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 percent 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 37§C), 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.

The influence of septal lesions on sodium and water retention induced by Walker 256 tumor

In the course of studies on the effects of septal area lesions on neuroimmunomodulation and Walker 256 tumor development, it was observed that tumor-induced sodium and water retention was less marked in lesioned than in non-lesioned rats. In the present study possible mechanisms involved in this phenomenon were investigated. The experiments were performed in septal-lesioned (LW; N = 15) and sham-operated (SW; N = 7) 8-week-old male Wistar rats, which received multifocal simultaneous subcutaneous (sc) inoculations of Walker 256 tumor cells about 30 days after the stereotaxic surgery. Control groups (no tumor, sham-operated food-restricted (SFR), N = 7) and lesioned food-restricted (LFR, N = 10) were subjected to a feeding pattern similar to that observed in tumor-bearing animals. Multifocal inoculation of Walker 256 tumor rapidly induces anorexia, which is paradoxically accompanied by an increase in body weight, as a result of renal Na+ and fluid retention. These effects of the tumor were also seen in LW rats, although the rise in fractional sodium balance during the early clinical period was significantly smaller than in SW rats (day 4: SW = 47.6 = 6.4 percent and LW = 13.8 = 5.2 percent; day 5: SW = 57.5 = 3.5 percent and LW = 25.7 = 4.8 percent; day 6: SW = 54.4 = 3.8 percent and LW = 32.1 = 4.4 percent; P<0.05), suggesting a temporary reduction in tumor-induced sodium retention. In contrast, urine output was significantly reduced in SW rats and increased in LW rats (LW up to -0.85 and SW up to 4.5 ml/100 g body weight), with no change in osmolar excretion. These temporary changes in the tumor's effects on LW rats may reflect a "reversal" of the secondary central antidiuretic response induced by the tumor (from antidiuretic to diuretic)

Effect of Walker 256 tumor growth on intestinal absorption of leucine, methionine and glucose in newly weaned and mature rats

In tumor-bearing rats, most of the serum amino acids are used for synthesis and oxidation processes by the neoplastic tissue. In the present study, the effect of Walker 256 carcinoma growth on the intestinal absorption of leucine, methionine and glucose was investigated in newly weaned and mature rats. Food intake and carcass weight were decreased in newly weaned (NT) and mature (MT) rats bearing Walker 256 tumor in comparison with control animals (NC and MC). The tumor/carcass weight ratio was higher in NT than in MT rats, whereas nitrogen balance was significantly decreased in both as compared to control animals. Glucose absorption was significantly reduced in MT rats (MT = 47.3 ñ 4.9 vs MC = 99.8 ñ 5.3 nmol min-1 cm-1, Kruskal-Wallis test, P<0.05) but this fact did not hamper the evolution of cancer. There was a significant increase in methionine absorption in both groups (NT = 4.2 ñ 0.3 and MT = 2.0 ñ 0.1 vs NC = 3.7 ñ 0.1 and MC = 1.2 ñ 0.2 nmol min-1 cm-1, Kruskal-Wallis test, P<0.05), whereas leucine absorption was increased only in young tumor-bearing rats (NT = 8.6 ñ 0.2 vs NC = 7.7 ñ 0.4 nmol min-1 cm-1, Kruskal-Wallis test, P<0.05), suggesting that these metabolites are being used for synthesis and oxidation processes by the neoplastic cells, which might ensure their rapid proliferation especially in NT rats.

Reduced renal sodium excretion in walker-256 tumor-bearing rats

Subcutaneous inoculation of Walker-256 tumor is followes by an asymptomatic period which is widely variable in duration, after which, paraneoplastic effects appear suddenly in the form of progressive and rapidy changing homeostatic alterations. Multifocal inoculation of tumor cells in each animal, was carried out with data averaging in each (sub-clinical [SubC], moderate [mCP] and grave [gCP] clinical phases and compared to foodrestrieted FR. The renal sites involved were studied in awake unrestrained animals by measure of sodium, cratinine and lithium clearance. Results indicated an initial increase of both absolute proximal (mCP:21.4+1.7 vs FR: 16.0+1.1 mmol/min/100 g.b.w., p<0.05) and postproximal (mCP:11.1+0.4 vs FR:6.6+0.4 mmol/min/100g g.b.w., p<0.001) Na+ reabsorption, which were partially compensated by a rise in glomerular filtration rate (mCP:213+11.4 vs FR: 162+10.2p1/min/100 g.b.w., p<0.01) and by fell of fractional proximal Na+ reabsorption (mCP:62.8+ vs FR: 70.1+1.7 per cent, p<0.05), despite this a significant Na+ and fluid retention was observed. Additionally, this study shows that terminal phase of the illness (gCP) culminated with a marked decrease in the creatinine clearance suggesting a significant fall of the renal function.

Metabolism of glucose, glutamine and pyruvate in lymphocytes from Walker 256 tumor bearing rats

This study examined the effect of Walker 256 tumor growth in vivo on the metabolism of glucose, glutamine and pyruvate in lymphocytes. A comparison between the metabolism of Walker 256 tumor cells obtained in vivo with that of lymphocytes was also carried out. Lymphocytes and tumor cells were isolated and incubated for 1 h for the following measurements: lactate production from glucose (5.6 mM) and pyruvate (3 mM), glutamate and aspartate formation from glutamine (3 mM) and decarboxylation of [U-14C]-glucose, [U-14C]-glutamine, [1-14C]-pyruvate and [3-14C]-pyruvate. The presence of the tumor increased lactate production (2.7-fold from glucose and 2-fold from pyruvate), decarboxylation of [U-14C]-glucose (3.7-fold) and [1-14C]-pyruvate (4.4-fold) and the formation of aspartate (6.3-fold) and glutamate (4.6-fold) from glutamine. The conversion of glucose to lactate and CO2 was higher in tumor cells as compared to lymphocytes. Tumor cells also showed a higher production of glutamate and an 8-fold increased decarboxylation rate of [U-14C]-glutamine in tumor cells, which was more active than that of lymphocytes even from tumor-bearing rats. Tumor growth stimulated glucose and glutamine metabolism in lymphocytes; however, the importance of this fact for the function of these cells remains to be elucidated

Estudo experimental da excreçäo fecal de nitrogênio em diferentes condiçöes nutricionais / Experimental study of fecal excretion of nitrogen in different nutritional conditions

Os autores estudaram experimentalmente o comportamento da excreçäo fecal de nitrogênio em diferentes condiçöes nutricionais, utilizando 32 ratos Wistar machos, adultos. Os animais foram distribuídos aleatoriamente em 4 conjuntos: o grupo A(12 ratos), formado por ratos normais, que serviam de controle para os demais grupos do experimento; o grupo B com 6 ratos, em que se fez o implante de células de carcinossarcoma de walker 256 no sub-cutâneo da regiäo do flanco do animal no início do experimento; grupo C, com 8 ratos em que se fez o implante de células do tumor de Walker no subcutâneo do flanco 8 dias antes do início do acompanhamento; p grupo D (16 ratos), nos quais foi feita no 15§ dia do experimento ferida cutânea padronizada. Os animais foram mantidos em gaiolas metabólicas individuais, que permitem a colheita diária em separado de urina e fezes, além de determinaçäo diária da ingestäo de dieta padronizada, contendo 25 por cento de caseína; o valor calórico dessa dieta era 4,61 Kcal/g e seu conteúdo em nitrogênio era de 35,25 mg por grama de substrato. Os parâmetros de análise utilizados foram: ingestäo de nitrogênio, excreçäo urinária, fecal e total de nitrogênio, relaçöes de nitrogênio fecal com ingestäo, com excreçäo urinária e excreçäo total; relaçöes de excreçäo urinária com ingestäo e excreçäo total. A dosagem de nitrogênio urinário e fecal foi feita pelo método de micro Kjedhal. Os resultados foram submetidos a análise estatística, aceitando-se como significativas as diferenças quando p < 0,05. Os resultados obtidos permitem concluir que a excreçäo fecal de nitrogênio corresponde a 5,7 por cento da ingestäo em ratos normais, submetidos a uma dieta à base de caseína; em animais normais, a excreçäo corresponde a 12,0 por cento da excreçäo urinária e a 10,8 por cento da excreçäo total de nitrogênio, em condiçöes de desenvolvimento da massa tumoral maligna, a excreçäo fecal de nitrogênio corresponde a 79 por cento daquela observada em animais normais; em animais submetidos a ferida cutânea em cicatrizaçäo, a excreçäo fecal corresponde a 70,5 por cento da eliminaçäo fecal de nitrogênio observada nos animais normais

Acao da 3,5,3'-triiodotironina ('T IND.3') sobre a evolucao do carcinossarcoma 256 de Walker / Action of 3,5,3'- triiodothyronine('T IND.3') on Walkers 256 carcinosarcoma development

Com o objetivo de verificar os efeitos da inoculacao de triiodotironina('T IND. 3') em animais portadores de tumor de Walker, os autores propuseram este estudo experimental utilizando ratos Wistar portadores da forma ascitica e da forma solida do referido tumor e camundongos Balb/c isogenicos para estudo da ativacao macrofagica. Os animais foram tratados com 'T IND. 3'20 *g/100g de peso e os resultados obtidos submetidos aos testes estatisticos do Chi-quadrado de Mann-Whitney. Os autores concluem que este hormonio aumenta a sobrevida de ratos portadores do tumor de Walker, porem, sem interferir no peso da massa tumoral. Quanto ao espraiamento de macrofagos, o 'T IND. 3' promoveu aumento significativo quando injetado na cavidade peritonal de camundongos. Tais resultados talvez possam ser explicados pela propria ativacao macrofagica e pela sintese do Fator de Necrose Tumoral(FNT), entre outros fatores.

Metabolismo energetico e desenvolvimento de tumor maligno experimental / Energy metabolism in experimental malignant tumor development

A causa mais frequente de mortalidade no cancer e a caquexia, cuja interpretacao mais comum e um balanco negativo entre a ingestao e o gasto calorico. Os autores utilizaram 48 ratos Wistar, adultos, machos, com peso corporeo em torno de 200 gramas. Os animais eram submetidos a periodo de adaptacao ao calorimetro durante seis dias, sendo mantidos em gaiolas metabolicas individuais, recebendo racao balanceada normal. A seguir, os animais foram aleatoriamente divididos em quatro grupos, cada qual com 12 ratos: grupo C, em que os animais eram mantidos com racao balanceada normoproteica ao longo de todo o experimento; grupo D, em que os animais recebiam dieta com baixo teor (1 por cento) proteico, durante toda a experiencia; grupo T, em que os animais eram alimentados com racao balanceada normoproteica ao longo de todo o experimento, recebendo subcutaneo do flanco o implante de celulas do tumor de Walker 256: grupo PF, em que cada animal era alimentado com racao balanceada normoproteica em quantidade diaria igual a ingerida na vespera por seu parceiro do grupo T, em esquema de alimentacao pareada (pair-feeding). A partir do 6. dia, cada animal tinha determinado seu peso corporeo e a quantidade de racao ingerida, bem como eram recolhidas fezes e urina, para determinacao do seu teor nitrogenado. ...

4-Epidoxorubicin activity in experimental malignant tumors

A literatura tem indicado a atividade positiva da doxorrubicina sobre adenocarcinomas gastrointestinais, seja isoladamente, seja em associacao com outros quimioterapicos. Permanece, porem, a critica representada pela toxicidade da droga, o que tem levado a pesquisa de derivados mais toleraveis e igualmente atuantes; e o caso da 4-epidoxorrubicina (4-EPI). E estudada a atividade da 4-EPI sobre o tumor maligno experimental denominado carcinossarcoma de Walker 256. Para tanto, foi observado o comportamento de 48 ratos Wistar adultos dividos aleatoriamente em cinco grupos: grupo T (seis ratos), com animais que receberam implante subcutaneo de celulas do tumor de Walker na regiao do flanco; grupo TE (11 ratos), em que os animais recebiam o implante tumoral, tal como descrito e simultaneamente a injecao endovenosa de 1 mg de 4-EPI na veia caudal; grupo T6E (oito ratos), em que os animais recebiam a 4-EPI, na dose referida, 6 dias apos o implante tumoral; grupo E (11 ratos) apenas injetados com a 4-EPI, sempre por via endovenosa; grupo C (12 ratos), que servia de controle para o comportamento dos demais grupos. Os animais de todos os grupos eram mantidos em gaiolas metabolicas individuais, recebendo dieta padronizada. Diariamente eram registrados: quantidade de dieta ingerida; peso corporeo;...

Effects of Walker 256 carcinoma on metabolic alterations during the evolution of pregnancy

The control of pregnant cancer patients is difficult because it involvers both mother and fetus, and the metabolic alterations in the cancer host induce a massive mobiliztion of nutrients diverted to the neoplastic cells. The purpose of the present study was to determine the evolution of the Walker 256 carcinoma in pregnant rats and its consequences on fetal development. The results showed tha t the tumors displayed a very rapid rate of growth and induced a reduction in fetal weights in the pregnant tumor-bearing rats. The tumor-bearing and pregnant tumor-bearing groups showed a decrease in blood glucose and total serum protein, suggesting an increase in energy utilization of these substrates and synthetic activity by the tumoral cells. An imbalance between protein synthesis and catabolism may occur in the tumor-bearing rats whic may be related to the degree of nutritional depletion

Alteraçöes da composiçäo corpórea no câncer: estudo experimental / Body composition changes in cancer: experimental study

Com o objetivo de estudar as alteraçöes de composiçäo corpórea frente ao câncer em diferentes condiçöes nutricionais, ratos Wistar foram distribuidos de acordo com alimentaçäo por raçäo de biotério, dieta aprotéica ou raçäo de biotério após três semanas iniciais de dieta aprotéica. A seguir os ratos foram subdivididos em subgrupos inoculados com carcinoma 256 de Walker e subgrupos controle sem tumor. Medidas de composiçäo corpórea foram realizadas por ocasiäo do sacrifício. Observou-se significativa perda de gordura total corpórea, massa celular corpórea e expansäo de razäo Na/K nos subgrupos portadores de tumor independentemente da situaçäo nutricional a que os animais estavam submetidos, indicando ser este tumor causa de desnutriçäo protéico-calórica, mesmo em animais já depletados. De outro lado verificou-se ser possível a recuperaçäo de composiçäo corpórea em animais previamente desnutridos, mas convenientemente realimentados, mesmo na presença do tumor maligno

Efeitos do trauma e desenvolvimento tumoral sobre o processo de cicatrizaçäo e estado nutricional do hospedeiro: estudo experimental / Effects of trauma and tumor development on wound healing and nutritional status of the host: experimental study

Os autores examinam aspectos metabólicos do desenvolvimento de tumor maligno e da cicatrizaçäo da ferida cutânea aberta, em modelo experimental que permite analisar as conseqüências do trauma cirúrgico, do processo de cicatrizaçäo e da expansäo da massa tumoral: para tanto utilizam grupos de ratos Wistar em que tais situaçöes desenvolvem-se isolada ou simultaneamente. Os resultados indicam que a cicatrizaçäo näo é alterada pelo crescimento do tumor, nem este sofre reduçäo pela concorrência da cicatrizaçäo; na verdade, é o hospedeiro que sofre prejuízo com cada um dos processos, em particular, quando ambos se desenvolvem simultaneamente