Abstract
Flavone Acetic Acid (FAA) exerts much of its effect by reducing tumour blood flow. Previous studies on FAA-induced changes in blood flow have used established tumours with a functional microvasculature. Using radioactive Xenon(133Xe) clearance to monitor local blood flow we show that the effects of FAA are dependent on the presence of this functional microvasculature with no evidence that FAA inhibits the actual development of tumour microcirculation. Thus, administration of multiple doses of FAA around the time of tumour cell injection failed to diminish t1/2 values of 133Xe (e.g. t1/2 16 min for FAA vs 14 min for saline controls at 10 days) or to affect tumour volumes (5.55 +/- 0.06 cm3 in FAA-treated animals vs 5.7 +/- 1.3 cm3 in controls at 25 days). In marked contrast a single dose of FAA (200 mg kg-1 body weight) 2 weeks after tumour cell injection dramatically extended t1/2 times (47 min for FAA vs 7 min for controls; P less than 0.001) and significantly reduced tumour burden. This effect is specific for tumour microvasculature and is not directed simply at new vessels since a similar treatment of animals with implanted-sponge-induced granulation tissue had no effect on t1/2 times (6.8 +/- 1.1 min for FAA at 200 mg kg-1 vs 7.2 +/- 1.0 min for saline-treated controls.
Highlights
We show here that the inhibition of tumour blood flow achieved by Flavone Acetic Acid (FAA) administration depends on an established tumour microvasculature with no evidence that the drug inhibits new vessel formation
In contrast to the lack of effect manifested by multiple injections of FAA early in tumour growth Protamine given at the same points in time caused a signficant extension of T1 times
We previously have used the '33Xe clearance technique as the basis for developing a dynamic assessment of blood flow (Mahadevan et al, 1989) and have shown, using this assay, that FAA acts to shut down tumour vascularity via the effects of TNFx (Mahadevan et al, 1990)
Summary
Young adult male Balb/c mice (weighing 24-28 g), used in all experiments, were obtained from the Imperial Cancer Research Fund animal breeding unit, Clare Hall Laboratories, South Mimms, Herts, UK. Animals were housed individually in plastic cages in an air-conditioned room; food and water were available ad libitum and a 12 h light/dark schedule was maintained. All animal procedures were carried out under a Project Licence approved by the Home Office, London, UK. Radioactive Xenon ('33Xe) in sterile physiologic saline (specific activity 370 MBq in 3 ml) was purchased from Amersham International, Aylesbury, UK. Formulated FAA (LIPHA, Lyons, France), supplied as a lyophilised powder, was a generous gift from Dr J.A. Double, Clinical Oncology Unit, University of Bradford, UK
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