TY - JOUR
T1 - Induction of tumour blood flow stasis and necrosis
T2 - A new function for epinephrine similar to that of combretastatin A-4 derivative AVE8062 (AC7700)
AU - Hori, K.
AU - Saito, S.
N1 - Funding Information:
We thank Ms H Oikawa for expert technical assistance. This study was supported in part by a Grant-in-Aid (2000-Designated Research-1) for Cancer Research from the Ministry of Health, Labour and Welfare, Japan; by a Grant-in-Aid (No. 14030005) for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan; and by the Haruo Sato Fund for Yoshida Sarcoma and Ascites Hepatoma Memorial.
PY - 2004/1/26
Y1 - 2004/1/26
N2 - 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.
AB - 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.
KW - Combretastatin A-4
KW - Epinephrine
KW - Necrosis
KW - Tumour blood flow
KW - Tumour vessel
UR - http://www.scopus.com/inward/record.url?scp=1342280435&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1342280435&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6601582
DO - 10.1038/sj.bjc.6601582
M3 - Article
C2 - 14735207
AN - SCOPUS:1342280435
VL - 90
SP - 549
EP - 553
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 2
ER -