Browsing by Subject "kaloribegränsning"

Angiogenesis, the formation of new blood vessels from preexisting vascular network, is an essential process during tumor development. Growing tumors secrete different growth factors that induce angiogenesis, of which vascular endothelial growth factor (VEGF) is predominant. Angiogenesis inhibitors act either by blocking the extracellular bindning of growth factor to its receptor by monoclonal antibodies or by blocking the intracellular signalling pathway by small-molecule agents. The small-molecule agent sunitinib is a multitargeted tyrosine kinase inhibitor that has antiangiogenic and antitumor activities due to the selective inhibition of several tyrosine kinase receptors. Sunitinib is approved for treatment of gastrointestinal stromal tumors, renal cell carcinoma and pancreatic neuroendocrine tumors. Known side effects are hypertension, cardiotoxicity and renal damage. These toxic effects are due to sunitinibs "off-target" toxicity, which occurs when a tyrosine kinase inhibitor causes adverse effects via inhibiton of a kinase not intended to be a target of the drug. For example inhibition by sunitinib of AMPK, a kinase that plays key roles in maintaining metabolic homeostasis in the heart, accounts in part for the toxicity seen in cardiomyocytes exposed to sunitinib. By achieving a better understandning of what causes the side effects it could be possible to develop treatments that reduce off-target effects. Caloric restriction is one nonpharmacological approach that has been shown to have beneficial effects on the heart partly by activating sirtuins. Sirtuins regulate a diverse array of cellular functions, including metabolism, gene transcription, cell division and cellular stress response. The aim for this study was to investigate whether caloric restriction improves sunitinib-induced cardiovascular toxicity and renal damage in rats, and to study activated cellular pathways. In this study 40 spontaneously hypertensive rats (SHR) and 10 normotensive Wistar-Kyoto (WKY) rats were used. They were divided into groups depending on treatment; I WKY control, II SHR control, III SHR + caloric restriction 70 %, IV SHR + sunitinib 3 mg/kg and V SHR sunitinib 3 mg/kg + caloric restriction 70 %. The follow-up period was eigth weeks. Blood pressure was messured weekly, metabolic cages were used week 4 and week 8 for urine samples, echocardiography was performed the last week and vascular response was studied at the end. The proteins Sirt1 and AMPK in heart were investigated by Western blot and the amount of the marker of macrofage ED1 in kidney by immunohistochemistry. Based on this study it was observed that the dose 3 mg/kg sunitinib was well tolerated in rats because it did not cause more extensive hypertension, worse hypertrophy or renal damage compared to untreated SHR groups. This study also showed that short-term caloric restriction has beneficial cardiovascular effects.