Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas.
Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas.
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DOI：
10.1038/bjc.2015.186
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发表时间：
2015-06-30
影响因子：
8.8
通讯作者：
Yoon SS
中科院分区：
文献类型：
--
作者：
Yoon C;Lee HJ;Park DJ;Lee YJ;Tap WD;Eisinger-Mathason TS;Hart CP;Choy E;Simon MC;Yoon SS
对血管内皮生长因子-A（VEGF-A）抑制和放射治疗（RT）反应较差的人肉瘤中缺氧诱导因子1α（HIF-1α）及其靶基因表达上调。本研究检查了低氧激活的化疗TH-302对VEGF-A抑制和RT（a.k.a.三联疗法）。在两种异种移植模型和体外肿瘤内皮细胞和肉瘤细胞系中检查了三联疗法。在这两种小鼠模型中，VEGF-A抑制和放射治疗在减缓肉瘤生长方面比单独治疗更有效。当加入TH-302时，这种三模态疗法完全阻断了肿瘤生长，肿瘤在停止治疗后保持休眠超过3个月。三联疗法引起的内皮细胞特异性凋亡是三联疗法的2.6- 6.2倍，微血管密度和HIF-1α活性分别降低至对照组的11-13%和13-20%。当在体外检测三模式治疗时，与肉瘤细胞相比，肿瘤内皮细胞中DNA损伤和凋亡的增加更为明显，尤其是在缺氧条件下。TH-302、VEGF-A抑制和RT的组合在肉瘤的临床前模型中是高度有效的，并且与内皮细胞中DNA损伤和凋亡增加以及HIF-1α活性降低相关。
Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1α (HIF-1α) and HIF-1α target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy). Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines. In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1α activity were reduced to 11–13% and 13–20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia. The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1α activity.