ISCHEMIA-REPERFUSION INJURY IN TUMORS - THE ROLE OF OXYGEN RADICALS AND NITRIC-OXIDE

Oxidative stress is a key process involved in the action of several th erapeutic modalities used in cancer treatment, Ischemia reperfusion in sult provides a model system for investigating the processes involved in determining the sensitivity of tumor tissue to oxidative stress, We have investigated the response of the murine CaNT tumor to ischemia r eperfusion injury and the role that oxygen radicals and nitric oxide m ay play in this phenomenon, Our results show that little or no cell ki ll is detected in tumors exposed to up to 3 h of ischemia if the tumor s are excised immediately before reperfusion, However, if reperfusion is permitted, then extensive cell kill is evident 24 h later, i,v, adm inistration of superoxide dismutase or catalase, at the time when vasc ular reperfusion occurred, resulted in a significant protection agains t tumor cell kill, suggesting that the damage was mediated by oxygen r adicals, Conversely, administration of an inhibitor of nitric oxide sy nthase, N-omega-nitro-L-arginine, resulted in potentiation of tumor ce ll damage, Administration of a nitric oxide (NO) donor, diethylamine N O, at the time when vascular reperfusion occurred resulted in signific ant protection against tumor damage, These results suggest that nitric oxide is a potent mediator in determining tumor damage after ischemia reperfusion injury, The role of intrinsic NO production by murine tum ors was investigated by measuring the accumulation of nitrate in the m edium of tumor explants cultured in vitro in two tumors with differing sensitivity to ischemia reperfusion damage. The clamp-insensitive tum or SaS showed a greater nitrate accumulation than the clamp-sensitive tumor CaNT, which may confer a greater capacity for preventing tumor a nd endothelial cell damage after oxidative stress.