Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia

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 up-regulated xanthine oxidase (XO) activity. High serum UA levels indicate increased XO dependent production of oxygen free radicals (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 intra-peritoneally with AH-130 hepatoma cells and treated with two XO-inhibitors: allopurinol (Allo, low and high dose 4 and 40mg/kg/d) and its more effective active metabolite oxypurinol (Oxy, 4 and 40mg/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 low (LD) and high dose (HD) Allo and low dose 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.