Induction of tumour blood flow stasis and necrosis: A new function for epinephrine similar to that of combretastatin A-4 derivative AVE8062 (AC7700)

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 2h. 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.