Estudo do sistema neuroimunoendócrino na caquexia neoplásica e da resposta ao tratamento com esteróides

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

The anorexia-cachexia syndrome (ACS), of multifactorial source and complex, is common in chronic diseases, like advanced cancer. Is associated with weight loss and decrease food intake, sometimes causing death. The objective of the present study was to evaluate the influence of neoplastic cachexia over the hypothalamus-pituitary-adrenal axis and immune system, as well as to analyze the drug effects with steroid action utilized on the clinical therapeutics over the tumoral development and ACS. For Walker-256 tumor induction, 8x107 LLC WRC-256 cells were subcutaneously inoculated in Wistar male rats. The control group animals were inoculated with PBS 0,5mL, instead of the tumoral cells received by the tumor group. Starting from 5th day until de 10th day (sacrifice) from the cell inoculation, the rats received the following treatments: anti-inflammatory dexamethasone doses (50 μg/Kg/day subcutaneous, Dex-AI), immunosuppressor dexamethasone doses (1 mg/Kg/day subcutaneous, Dex-IS), megestrol (100 mg/Kg/day oral, Meg) or vehicle (PBS or corn oil). The body weight and food intake of animals were evaluated daily; the tumoral mass measurement was done starting from the 4th day. At the sacrifice day was assessed the body weight loss and blood was collected for basal corticosterone dosage, as well as performance of stimuli test with ACTH, corticosterone after-stimuli dosage, cholesterol dosage and leucocytes differential count. The tumor, spleen, thymus, adrenal and pituitary were removed and weighted for morphological study and right adrenal for molecular study. The animals bearing tumor presented weight loss starting from 6th day as well as decreased food intake at the last 5 days (p<0,01) and development of cachexia, confirming the presence of ACS. The Dex-AI and Dex-IS groups presented decreased weight starting from 7th day, that was not due to decreased food intake (p>0,05). Only Dex-IS treatment caused cachexia in rats non-bearing tumor. Animals bearing tumor presented structural modification of thymus, increased neutrophils count (p<0,05), decreased lymphocytes count (p<0,05) and increased spleen weight (p<0,001), while only Dex-AI and Dex-IS prevented (p<0,05 and p<0,001) the spleen growth; Meg did not influence on spleen size. Also, the tumor presence caused increased adrenal weight (p<0,01), probably due to, hyperplasia, and metastasis presence. There was decreased of plasmatic corticosterone levels after-stimuli by ACTH, result of adrenal exhaustion because chronic stress; plasmatic cholesterol was not changed (p>0,05). Genic expression reduction of MC2R (melanocortin receptor 2) (p<0,05) and 3βHSDI (3β dehydrogenase I) (p<0,01) occurred in rats bearing tumor, confirming adrenal exhaustion, while the Tspo (translocator protein) expression was not significant (p=0,052), in spite of fall tendency; the StAR genic expression was not significant. Only Dex-AI and Dex-IS prevented the adrenal growth (p<0,01), suggesting the inhibitory effect of glucocorticoids over adrenal cortex and causing inhibition of adrenal function by diminishing of basal (p<0,05) and after-stimuli (p<0,01) plasmatic corticosterone levels; Meg did not influence on adrenal size. Meg did not present basal cortical-adrenal disfunction, however there was loss of response after stimuli test with ACTH, indicating response against stress failure. The pituitary weight was non-significant between the groups (p>0,05), but the tumor group presented reduction of somatotropic cells (p<0,01) and increased thyrotropic cells (p<0,01) percentage. Additionally, only Dex-IS was effective in preventing the tumoral development, that did not occur with Meg. These results show the harmful influence of ACS over the HPA axis and immune system. The knowledgement of pathophysiology and consequences of steroids drugs use allow to extrapolate our data for clinical context in advanced cancer patients.

ASSUNTO(S)

patologia experimental caquexia - câncer câncer - tratamento experimental pathology cachexy - cancer cancer treatment

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