Hypothesis: Inhibition of xanthine oxidase by allopurinol, and chelation of available iron by desferrioxamine can substantially ameliorate the oxidative stress incurred during hyperthermic liver perfusion. Moreover, such protection from oxidative stress and the associated heat induced hepatotoxicity can be accomplished without significant reduction of the tumoricidal effects of hyperthermia. The following specific objectives are designed to test this hypothesis: 1. Demonstrate that iron plays a major role in the lipid peroxidation accompanying hyperthermic perfusion of rat liver, and that chelation of iron will ameliorate such lipid peroxidation. 2. Demonstrate that activity of xanthine oxidase type 0 form results in both the release of iron form the storage molecule ferritin, and an increase in oxidative stress by production of superoxide. 3. Demonstrate that inhibition of xanthine oxidase and chelation of iron will substantially ameliorate oxidative damage accompanying hyperthermic perfusion of rat liver. 4. Demonstrate that protection of the liver form oxidative damage during hyperthermic perfusion of inhibition of xanthine oxidase and iron chelation also prevents the pericentral cell death. 5. Demonstrate that protection of the liver as above does not prevent the cytocidal effects of heat on tumor cells within the heated liver.
| Powers, R H; Stadnicka, A; Kalbfleish, J H et al. (1992) Involvement of xanthine oxidase in oxidative stress and iron release during hyperthermic rat liver perfusion. Cancer Res 52:1699-703 |
| Skibba, J L; Powers, R H; Stadnicka, A et al. (1991) Oxidative stress as a precursor to the irreversible hepatocellular injury caused by hyperthermia. Int J Hyperthermia 7:749-61 |
| Skibba, J L; Powers, R H; Stadnicka, A et al. (1990) Lipid peroxidation caused by hyperthermic perfusion of rat liver. Biochem Pharmacol 40:1411-4 |
| Skibba, J L; Stadnicka, A; Kalbfleisch, J H et al. (1989) Effects of hyperthermia on xanthine oxidase activity and glutathione levels in the perfused rat liver. J Biochem Toxicol 4:119-25 |
| Skibba, J L; Stadnicka, A; Kalbfleisch, J H (1989) Hyperthermic liver toxicity: a role for oxidative stress. J Surg Oncol 42:103-12 |
| Skibba, J L; Sonsalla, J C; Kalbfleisch, J H (1987) Hyperthermic liver perfusion and release of lysosomal enzymes. J Surg Res 43:558-64 |
