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 therapeutic modalities used in cancer treatment. Ischemia reperfusion insult 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 reperfusion injury and the role that oxygen radicals and nitric oxide may play in this phenomenon. Our results show that little or no cell kill is detected in tumors exposed to up to 3 h of ischemia if the tumors are excised immediately before reperfusion. However, if reperfusion is permitted, then extensive cell kill is evident 24 h later. i.v. administration of superoxide dismutase or catalase, at the time when vascular reperfusion occurred, resulted in a significant protection against tumor cell kill, suggesting that the damage was mediated by oxygen radicals. Conversely, administration of an inhibitor of nitric oxide synthase, N omega-nitro-L-arginine, resulted in potentiation of tumor cell damage. Administration of a nitric oxide (NO) donor, diethylamine NO, at the time when vascular reperfusion occurred resulted in significant 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 tumors was investigated by measuring the accumulation of nitrate in the medium of tumor explants cultured in vitro in two tumors with differing sensitivity to ischemia reperfusion damage. The clamp-insensitive tumor SaS showed a greater nitrate accumulation than the clamp-sensitive tumor CaNT, which may confer a greater capacity for preventing tumor and endothelial cell damage after oxidative stress.
CRC Tumor Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
C S
CS
Parkins
M F
MF
Dennis
M R
MR
Stratford
S A
SA
Hill
D J
DJ
Chaplin
D000230:Adenocarcinoma / Q000098:blood supply; D000818:Animals; D002374:Catalase / Q000097:blood; D002470:Cell Survival; D005260:Female; D051379:Mice; D008808:Mice, Inbred CBA; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009569:Nitric Oxide / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000503:physiopathology*; D012513:Sarcoma, Experimental / Q000098:blood supply; D013482:Superoxide Dismutase / Q000097:blood
D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D002374:Catalase; D013482:Superoxide Dismutase