Abstract:
:Tumour cell survival is intimately related to blood vessel function and so the tumour vasculature represents a novel target for cancer therapy. We have investigated a murine tumour model in which a metal clamp was used to occlude the vascular supply temporarily and then removed to allow reperfusion. This allows the study of ischaemia-reperfusion as a model system for investigating tumour response to metabolic and oxidative stress. Recent studies have shown that prolonged reduction of tumour blood flow results in a deterioration of the hypoxic and acidic microenvironment found within tumours which leads to cytotoxicity. This cytotoxicity is dramatically enhanced if these cells are subsequently reperfused. It was the aim of the present study to determine the relative contribution of cytotoxicity occurring during the ischaemic period and that occurring during reperfusion. Although significant reductions in tumour energy status were induced during the clamping period itself, these were poorly correlated with the degree of tumour cytotoxicity. Relative vascular perfusion, measured using a radiolabelled tracer, remained significantly depressed below the control value following clamp removal. The degree of recovery of perfusion was also dependent upon the clamp duration. Relative tumour perfusion at 1 h after clamp removal was 70.1 +/- 14.6 and 50.5 +/- 6.3% of control values after a 1 or 3 h clamp, respectively, and showed no significant further increase when measured at 24 h after clamp removal. Tumour cytotoxicity following ischaemia reperfusion insult was modulated by administering the anti-oxidant enzymes superoxide dismutase or catalase intravenously just before clamp removal. These enzymes are restricted to the vascular compartment, where it is proposed that they modulate the concentration of oxygen free radicals released during reperfusion and by neutrophil oxidative burst. Reperfusion injury to the tumour was enhanced by administration of an inhibitor of nitric oxide synthase, nitro-L-arginine, probably owing to enhanced neutrophil adhesion and oxidative burst. Conversely, reperfusion injury to the tumour was reduced by administration of a nitric oxide donor, diethylamine nitric oxide. The murine model reported in this paper shows that ischaemia-reperfusion damage mediated by oxygen free radical formation provides a model system for investigating tumour response to oxidative stress at the level of the vascular endothelium.
journal_name
Exp Physioljournal_title
Experimental physiologyauthors
Parkins CS,Hill SA,Stratford MR,Dennis MF,Chaplin DJdoi
10.1113/expphysiol.1997.sp004031subject
Has Abstractpub_date
1997-03-01 00:00:00pages
361-8issue
2eissn
0958-0670issn
1469-445Xjournal_volume
82pub_type
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