Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia
Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia
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DOI：
10.1158/0008-5472.can-05-3295
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Kerbel, RS
中科院分区：
文献类型：
--
作者：
Franco, M;Man, S;Kerbel, RS
由于抗血管生成疗法抑制新的肿瘤相关血管的生长以及新形成的脉管系统的生长，因此预计它们会减少氧气的供应，从而增加肿瘤缺氧。然而，尚不清楚抗血管生成治疗是否仅导致缺氧持续且持续的增加，或肿瘤缺氧的短暂减少以及缺氧增加的时期。我们使用 DC101（一种抗血管内皮生长因子受体 2 抗体）对原位移植的人乳腺癌 (MDA-MB-231) 在 3 周的治疗期内进行了详细分析。我们观察到微血管密度、血流量（通过高频微超声测量）、抗灌注持续降低。这些效应导致缺氧肿瘤分数增加（用外源标记物哌莫硝唑测量），同时缺氧诱导因子批次表达（一种内源标记物）升高。肿瘤缺氧的增加在 5 天内就很明显，并且在整个治疗过程中一直如此。第一次注射后第 2、5、7、8、14 和 21 天的血管灌注和血流受损，但 4 小时则没有。 3周治疗期后，检测到血管成熟指数适度增加，但这并没有伴随着血管功能的改善。这些结果表明，持续缺氧和血管功能受损可能是抗血管生成药物治疗的两个一致后果。讨论了这些结果的含义，特别是关于它们如何与抗血管生成药物的反直觉化学增敏作用的不同理论相关，即使缺氧增加也是如此。
Because antiangiogenic therapies inhibit the growth of new tumor-associated blood vessels, as well as prime newly formed vasculature, they would be expected to reduce the supply of oxygen and thus increase tumor hypoxia. However, it is not clear if antiangiogenic treatments lead only to consistent and sustained increases in hypoxia, or transient decreases in tumor hypoxia along with periods of increased hypoxia. We undertook a detailed analysis of an orthotopically transplanted human breast carcinoma (MDA-MB-231) over a 3-week treatment period using DC101, an anti-vascular endothelial growth factor receptor 2 antibody. We observed consistent reductions in microvascular density, blood flow (measured by high-frequency micro-ultrasound), anti perfusion. These effects resulted in an increase in the hypoxic tumor fraction, measured with an exogenous marker, pimonidazole, concurrent with an elevation in hypoxia-inducible factor-lot expression, an endogenous marker. The increase in tumor hypoxia was evident within 5 days and remained so throughout the entire course of treatment. Vascular perfusion and flow were impaired at days 2, 5, 7, 8, 14, and 21 after the first injection, but not at 4 hours. A modest increase in the vessel maturation index was detected after the 3-week treatment period, but this was not accompanied by an improvement in vascular function. These results suggest that sustained hypoxia and impairment of vascular function can be two consistent consequences of antiangiogenic drug treatment. The implications of the results are discussed, particularly with respect to how they relate to different theories for the counterintuitive chemosensitizing effects of antiangiogenic drugs, even when hypoxia is increased.