Involvement of oxygen free radicals in ischaemia-reperfusion injury to murine tumours: role of nitric oxide.
Ischaemia-reperfusion (I/R) injury is a model system of oxidative stress and a potential anti-cancer therapy. Tumour cytotoxicity follows oxygen radical damage to the vasculature which is modulated by tumour production of the vasoactive agent, nitric oxide (NO.). In vivo hydroxylation of salicylate, to 2,3- and 2,5-dihydroxybenzoate (DHBs), was used to measure the generation of hydroxyl radicals (OH.) following temporary vascular occlusion in two murine tumours (with widely differing capacity to produce NO.) and normal skin. Significantly greater OH. generation followed I/R of murine adenocarcinoma CaNT tumours (low NO. production) compared to round cell sarcoma SaS tumours (high NO. production) and normal skin. These data suggest that tumour production of NO. confers resistance to I/R injury, in part by reducing production of oxygen radicals and oxidative stress to the vasculature. Inhibition of NO synthase (NOS), during vascular reperfusion, significantly increased OH. generation in both tumour types, but not skin. This increase in cytotoxicity suggests oxidative injury may be attenuation by tumour production of NO.. Hydroxyl radical generation following I/R injury correlated with vascular damage and response of tumours in vivo, but not skin, which indicates a potential therapeutic benefit from this approach.
Parkins
C S
CS
Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK. parkins@graylab.ac.uk
Holder
A L
AL
Dennis
M F
MF
Stratford
M R
MR
Chaplin
D J
DJ
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism*; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism*; D006900:Hydroxylation; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D015427:Reperfusion Injury / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D020156:Salicylic Acid; D018228:Sarcoma, Small Cell / Q000098:blood supply / Q000378:metabolism*
D016166:Free Radical Scavengers; D012459:Salicylates; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D003676:Deferoxamine; D020156:Salicylic Acid