Orally Available Selective Melanocortin-4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice 英文参考文献.docVIP

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Orally Available Selective Melanocortin-4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice 英文参考文献.doc

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Orally Available Selective Melanocortin-4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice 英文参考文献

OrallyAvailableSelectiveMelanocortin-4Receptor AntagonistsStimulateFoodIntakeandReduceCancer- InducedCachexiainMice PhilippWeyermann*,RobertDallmann,JosefMagyar,CorinneAnklin,MartinaHufschmid,Judith Dubach-Powell,IsabelleCourdier-Fruh,MarcoHennebo¨hle,SonjaNordhoff,CesareMondadori SantheraPharmaceuticals(Switzerland)Ltd.,Liestal,Switzerland Abstract Background: Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndromeaffectingessentialfunctionalcircuitsinvolvedintheregulationofhomeostasis,andincludesanorexia,fatand muscletissuewasting.Theanorexigenicpeptidea-MSHisbelievedtobecruciallyinvolvedinthenormalandpathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC)-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmarkfeaturesofcachexia,i.e.toincreasefoodintakeandtoreduceenergyexpenditure. Methodology/Principal Findings: SNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctlyincreasefoodintakeinhealthymice.Moreover,inmicesubcutaneouslyimplantedwithC26adenocarcinomacells, repeatedoraladministration(startingthedayaftertumorimplantation)ofeachofthetwocompoundsalmostcompletely preventedtumorinducedweightloss,anddiminishedlossofleanbodymassandfatmass. Conclusions/Significance: In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantageforthetreatmentofcachexiapatients. Citation:WeyermannP,DallmannR,MagyarJ,AnklinC,HufschmidM,etal.(2009)OrallyAvailableSelectiv