Relationship between tumour endothelial cell apoptosis and tumour blood flow shutdown following treatment with the antivascular agent DMXAA in mice.
Relationship between tumour endothelial cell apoptosis and tumour blood flow shutdown following treatment with the antivascular agent DMXAA in mice.
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DOI：
10.1038/sj.bjc.6601606
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发表时间：
2004-02-23
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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作者：
5，6-二甲基咕吨酮-4-乙酸（DMXAA）目前正在进行作为用于治疗癌症的抗血管剂的临床评价。我们以前已经证明，DMXAA诱导小鼠肿瘤切片和乳腺癌活检组织中的血管内皮细胞的凋亡，从一个病人在I期试验。我们希望确定这种效应的组织选择性及其与诱导血流变化的关系。用DMXAA处理具有Colon 38肿瘤的小鼠，并通过TdT介导的dUTP缺口末端标记（TUNEL）检查组织的细胞凋亡。Hoechst 33342用于染色功能性血管，染色血管的丢失用作肿瘤血管塌陷的量度。DMXAA以25 mg kg−1（最大耐受剂量（MTD））给药3 h后，肿瘤血管内皮细胞的TUNEL染色增加了12倍。相比之下，来自心脏、脑、肝和脾的组织没有显示出增加。肿瘤组织中的细胞凋亡诱导既具有剂量依赖性（在低至5 mg kg−1的剂量下即可观察到），又具有时间依赖性。与野生型小鼠相比，在TNF基因（TNF-/-）或TNF受体1基因（TNFR-/-）的靶向破坏下，小鼠结肠38肿瘤中的细胞凋亡显著降低。在这些基因敲除小鼠中，将DMXAA剂量增加至50 mg kg−1可使肿瘤细胞凋亡增加至与野生型小鼠中以MTD给予DMXAA诱导的水平相当的水平。对于所有数据，发现凋亡诱导的对数百分比与Hoechst染色血管的对数密度之间存在显著相关性（r=0.94; P<0.001）。这些结果表明，由DMXAA引起的血流抑制是肿瘤组织特异性的，并且是诱导肿瘤血管内皮细胞凋亡的结果。
5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is currently undergoing clinical evaluation as an antivascular agent for the treatment of cancer. We have previously demonstrated that DMXAA induces apoptosis of vascular endothelial cells in murine tumour sections and in a breast carcinoma biopsy from one patient in a Phase I trial. We wished to determine the tissue selectivity of this effect and its relationship to induced blood flow changes. Mice with Colon 38 tumours were treated with DMXAA and tissues were examined for apoptosis by TdT-mediated dUTP nick-end labelling (TUNEL). Hoechst 33342 was used to stain functional vessels, with the loss of stained vessels used as a measure of tumour vascular collapse. Treatment with DMXAA at 25 mg kg−1, its maximum tolerated dose (MTD), showed, after 3 h, a 12-fold increase in TUNEL staining of tumour vascular endothelial cells. In contrast, tissue from the heart, brain, liver and spleen showed no increase. Induction of apoptosis in tumour tissue was both dose-dependent, observable at doses as low as 5 mg kg−1, and time-dependent. Apoptosis was significantly lower in Colon 38 tumours of mice, with a targeted disruption in the TNF gene (TNF−/−), or in the TNF receptor 1 gene (TNFR−/−), as compared with that in wild-type mice. Increasing the DMXAA dose to 50 mg kg−1 in these knockout mice raised tumour apoptosis to a level comparable to that induced in wild-type mice given DMXAA at the MTD. For all the data, a significant correlation (r=0.94; P<0.001) was found between logarithmic percentage apoptosis induction and the logarithmic density of Hoechst-stained vessels. These results suggest that blood flow inhibition caused by DMXAA is tumour tissue-specific and is a consequence of induction of apoptosis in tumour vascular endothelial cells.
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通过与 5-羟色胺和生物还原药物联合使用，增强抗血管剂 5,6-二甲基呫吨酮-4-乙酸 (DMXAA) 的抗肿瘤作用。
影响因子：
8.8
作者：
Lash, C J;Li, A E;Rutland, M;Baguley, B C;Zwi, L J;Wilson, W R
通讯作者：
Wilson, W R
影响因子：
8.4
作者：
WATTS, ME;WOODCOCK, M
通讯作者：
WOODCOCK, M
抗血管剂5,6-二甲基苯乙烯-4-乙酸诱导内皮细胞凋亡。
影响因子：
8.8
作者：
Ching, LM;Cao, Z;Kieda, C;Zwain, S;Jameson, MB;Baguley, BC
通讯作者：
Baguley, BC
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Zhao, L;Ching, LM;Kestell, P;Baguley, BC
通讯作者：
Baguley, BC