Use of thymidine analogues to indicate vascular perfusion in tumours

Temporary reduction in blood-flow within tumour blood vessels can reduce ox ygen supply leading to transient perfusion-limited hypoxia. Consequent sele ction of cells with mutations and reduced radiosensitivity can lead to dise ase progression and treatment-resistance. In the present study, we investig ated whether heterogeneity of labelling after thymidine analogue administra tion is related to perfusion variations, and ii so, could it be quantified and used as a perfusion indicator. Perfusion in murine RIF1 tumours was red uced by hydralazine or increased by nicotinamide and the mice subsequently injected with IdUrd. Tumours were halved for analysis by both flow cytometr y and immunohistochemistry. Tumour sections were stained for vasculature an d IdUrd. Each blood vessel was scored for the density of IdUrd-labelled cel ls surrounding it, using a semi-quantitative scoring system. Flow cytometry showed that the IdUrd labelling index and intensity decreased by approxima tely 50% after hydralazine. In tumour sections of control animals, 2.9% of vessels showed no IdUrd label. In contrast, after hydralazine almost 50% of vessels had no surrounding IdUrd labelling, whereas after nicotinamide the re were fewer vessels with low labelling and a higher median score. In conc lusion, changes of tumour perfusion by pharmacological agents is reflected in changes in tumour-cell labelling by the thymidine analogue IdUrd, sugges ting that IdUrd labelling could be used to indicate perfusion in individual vessels in human tumours. (C) 2000 Cancer Research Campaign.