AVE8062, a derivative of
combretastatin A-4, has a strong stanching effect on tumour blood flow (TBF), which leads to complete blockage of nutrient supply to solid tumours and their
necrosis. Previously, we reported that TBF stasis is due to increased arteriolar resistance caused by
AVE8062 and a lasting decrease in perfusion pressure in tumour-feeding vessels. Here, we measured changes in TBF in rat solid tumour LY80 during continuous administration of AVE8062-like
epinephrine or four
catecholamines that are unlike
AVE8062 (
norepinephrine,
dopamine,
methoxamine, and
metaraminol) to the region of increased vascular resistance. Venous administration of 0.3 mg ml(-1)
epinephrine caused TBF to fall immediately to near zero, where it remained throughout the administration period. With a 30-min
drug administration, TBF began to recover immediately when
drug administration halted. With a 60-min
epinephrine administration, TBF recovered somewhat, but not to the previous level. With
drug administration of 120 min, TBF did not recover during the subsequent 8 h. Likewise, 0.1 mg ml(-1)
epinephrine produced irreversible occlusion after 120 min of administration. In contrast, 120 min of administration of the four other
catecholamines resulted in no occlusion. Only the group given 0.3 mg ml(-1)
epinephrine (not that given
methoxamine) showed significantly greater
necrosis than the control. We conclude that, for
epinephrine to cause irreversible occlusion of these vessels, a marked decrease in perfusion pressure in tumour-feeding blood vessels is necessary and should be maintained for 2 h. This conclusion is consistent with the previously demonstrated mechanism of irreversible arteriole occlusion caused by
AVE8062.
AVE8062 and
epinephrine appear to have the same mechanism of action regarding induction of tumour blood flow stasis.