title: Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia.
abstract: Cachexia is a common co-morbidity in cancer occurring in up to 80% of patients depending on the type of cancer. Uric acid (UA), the end-product of the purine metabolism, is elevated in cachexia due to tissue wasting and upregulated xanthine oxidase (XO) activity. High serum UA levels indicate increased XO-dependent production of oxygen free radicals (reactive oxygen species; ROS) and correlate with metabolic illness and poor survival. We hypothesized that XO-inhibition might reduce inflammatory signals accounting for tissue wasting and improve survival in experimental cancer cachexia. Animals were inoculated intraperitoneally with AH-130 hepatoma cells and treated with two XO-inhibitors: allopurinol [Allo, low (LD) and high dose (HD) 4 and 40 mg/kg/d] and its more effective active metabolite oxypurinol (Oxy, 4 and 40 mg/kg/d) or placebo for 15 days. Weight loss and tissue wasting of both fat and lean tissue (assessed by NMR-scanning) was reduced by both LD and HD Allo and LD-Oxy, but not by HD-Oxy. A robust induction of XO-activity for generation of reactive oxygen species was seen in the placebo group (assessed by electron paramagnetic spectroscopy), which was reduced by XO-inhibition. Increased ROS induced cytokine signaling, proteolytic activity and tissue degradation were all attenuated by XO inhibition. Survival was significantly and dose dependently improved. Food intake and spontaneous locomotor activity were higher, indicating a higher quality of life. Inhibition of XO can reduce tissue wasting and improve survival in cancer cachexia and clearly clinical studies are needed.
authors.affiliation: Department of Cardiology, Applied Cachexia Research, Charité Medical School, Berlin, Germany. jochen.springer@charite.de
authors.forename: Jochen
authors.initials: J
authors.lastname: Springer
authors.forename: Anika
authors.initials: A
authors.lastname: Tschirner
authors.forename: Kai
authors.initials: K
authors.lastname: Hartman
authors.forename: Sandra
authors.initials: S
authors.lastname: Palus
authors.forename: Eva K
authors.initials: EK
authors.lastname: Wirth
authors.forename: Silvia Busquets
authors.initials: SB
authors.lastname: Ruis
authors.forename: Nadine
authors.initials: N
authors.lastname: Möller
authors.forename: Stephan
authors.initials: S
authors.lastname: von Haehling
authors.forename: Josep M
authors.initials: JM
authors.lastname: Argiles
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.forename: Volker
authors.initials: V
authors.lastname: Adams
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.forename: Wolfram
authors.initials: W
authors.lastname: Doehner
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010117:Oxypurinol / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014527:Uric Acid; D000493:Allopurinol; D014969:Xanthine Oxidase; D053148:Caspase 3; D010117:Oxypurinol