Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis.
Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis.
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DOI：
10.1038/sj.bjc.6601261
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发表时间：
2003-10-06
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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我们以前报道，一种新的combretastatin A-4衍生物，AC 7700，具有显着的抗肿瘤作用，因为不可逆的停滞肿瘤血流（TBF）和随后的损失的营养供应的肿瘤组织。自2002年初以来，AC 7700以新名称AVE 8062在欧洲和美国进行了临床试验。然而，关于AC 7700如何阻断TBF以及为什么TBF停滞不能恢复的问题仍然存在。在这项研究中，使用大鼠肿瘤LY 80，吉田肉瘤的一种变体，我们研究了AC 7700给药后TBF停止是否是由于该药物对肿瘤血管的直接作用。我们构建了电极，可以将少量的药物溶液直接滴在血流测量部位，并将其插入皮下和肿瘤中。我们比较了给予10 μl不同浓度（0.2、1、10和50 mg ml−1）的AC 7700溶液后正常血管和肿瘤血管的血流反应。此外，我们评估了LY 80诱导的肾脏肿瘤静脉和动脉内给予10 mg kg-1 AC 7700后的TBF停滞。为了确定为什么TBF停滞是不可逆的，我们观察了AC 7700诱导的变化，在宿主小动脉和肿瘤血管网络的佐藤肺癌使用一个重要的显微镜大鼠透明室。由于肿瘤间质液压力的增加导致TBF降低，我们还测量了10 mg kg−1 AC 7700诱导的该压力变化。肿瘤内应用AC 7700后，正常血管的血流反应灵敏度明显高于肿瘤血管。AC 7700动脉内给药对TBF淤滞的影响并不强于静脉内给药。活体显微镜检查显示，AC 7700诱导宿主小动脉的强大而持久的收缩，使得下游血管中的血流完全停滞，从而为肿瘤提供血液。由于这种停滞，许多肿瘤血管的管腔变窄或完全消失，许多红细胞停滞在肿瘤血管网的引流血管中。这些红细胞在2-3小时后发生溶血，导致完全血栓形成。在显示溶血的血管中没有再灌注迹象。这种溶血被认为是TBF停滞不可逆的主要原因。由于AC 7700静脉给药后肿瘤间质液压力降低，因此排除了肿瘤血管压迫导致TBF停滞的可能性。所有这些结果强烈表明，AC 7700的主要靶点是宿主小动脉，并且AC 7700诱导的TBF停滞不是由药物对肿瘤血管的直接作用触发的。
We previously reported that a novel combretastatin A-4 derivative, AC7700, has remarkable antitumour effects because of an irreversible stasis of tumour blood flow (TBF) and subsequent loss of nutrient supply to tumour tissue. Since early 2002, under the new designation AVE8062, AC7700 has undergone clinical trials in Europe and the US. Questions remain, however, concerning how AC7700 blocks TBF and why the TBF stasis does not recover. In this study, using a rat tumour LY80, a variant of Yoshida sarcoma, we examined whether TBF cessation after AC7700 administration is due to a direct action of the agent on tumour blood vessels. We constructed electrodes that can drop a small quantity of the drug solution directly at the site of blood flow measurement and inserted them subcutaneously and into the tumour. We compared the blood flow responses of normal vessels and tumour vessels after administration of 10-μl doses of various concentrations (0.2, 1, 10, and 50 mg ml−1) of the AC7700 solution. In addition, we assessed TBF stasis after i.v. and intra-arterial 10 mg kg−1 AC7700 administration in an LY80-induced kidney tumour. To determine why the TBF stasis is irreversible, we observed AC7700-induced changes in host arterioles and the tumour vascular network of the Sato lung carcinoma using a vital microscopic rat transparent chamber. Since an increase in tumour interstitial fluid pressure brings about a decrease in TBF, we also measured 10 mg kg−1 AC7700-induced changes in this pressure. The sensitivity of the blood flow response after intratumoral application of AC7700 was markedly higher in normal vessels relative to tumour vessels. Intra-arterial administration of AC7700 did not have stronger effects on TBF stasis than did i.v. administration. Intravital microscopy showed that AC7700 induced a powerful and long-lasting constriction of host arterioles, so that complete stasis of blood flow occurred in downstream vessels, which supplied blood to tumours. Owing to this stasis, the lumens of numerous tumour vessels narrowed or completely disappeared, and numerous erythrocytes stagnated in drainage vessels of the tumour vascular network. Haemolysis of these erythrocytes occurred after 2–3 h, resulting in complete thrombosis. There was no indication of reperfusion in vessels showing haemolysis. This haemolysis is thought to be the main cause for the irreversibility of TBF stasis. Since the tumour interstitial fluid pressure decreased after i.v. AC7700 administration, the possibility of stasis of TBF being caused by tumour vascular compression was excluded. All these results strongly suggest that the main target of AC7700 is host arterioles and that the stasis of TBF induced by AC7700 is not triggered by a direct action of the drug on tumour vessels.
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DOI：
10.1111/j.1349-7006.1999.tb00850.x
发表时间：
1999-09-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Nihei, Y;Suga, Y;Tsuruo, T
通讯作者：
Tsuruo, T
影响因子：
9.7
作者：
Eikesdal, HP;Landuyt, W;Dahl, O
通讯作者：
Dahl, O
DOI：
10.1111/j.1349-7006.1991.tb01797.x
发表时间：
1991-11
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Hori K;Suzuki M;Tanda S;Saito S;Shinozaki M;Zhang QH
通讯作者：
Zhang QH
DOI：
10.1111/j.1349-7006.1999.tb00724.x
发表时间：
1999-12
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Nihei Y;Suzuki M;Okano A;Tsuji T;Akiyama Y;Tsuruo T;Saito S;Hori K;Sato Y
通讯作者：
Sato Y
影响因子：
7.3
作者：
Ohsumi, K;Nakagawa, R;Tsuji, T
通讯作者：
Tsuji, T