Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer.
Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer.
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DOI：
10.1158/1078-0432.ccr-16-0725
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发表时间：
2017-01-15
期刊：
影响因子：
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通讯作者：
Geschwind JF
中科院分区：
文献类型：
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作者：
Duran R;Mirpour S;Pekurovsky V;Ganapathy-Kanniappan S;Brayton CF;Cornish TC;Gorodetski B;Reyes J;Chapiro J;Schernthaner RE;Frangakis C;Lin M;Sun JD;Hart CP;Geschwind JF
目的：评价依福福胺肝低氧激活动脉内治疗(HIAAT)的安全性和抗癌效果。荷瘤兔随机分为4组(每组7只)：生理盐水组(对照组)，伊福福胺组(Evo)，阿霉素碘油乳剂+1 0 0~30 0μm微球栓塞组(常规组)，cTACE+伊福福胺组(对照组+evo)。分别于IAT前和IAT后1/2/7/14天采集血样。半定量评分系统评估肝细胞损伤。在多层螺旋CT上分割肿瘤体积(基线，IAT后7/14天)。对整个切片图像进行手动分割，对病理性肿瘤坏死进行量化。用吡曼硝唑染色测定低氧分数(HF)和脑室(HC)。定量检测肿瘤细胞的γ-H_2AX、Annexin V、Caspase-3、Ki-67、HIF1α、血管内皮生长因子、GAPDH、MCT4和乳酸脱氢酶等指标。与cTACE相比，cTACE+Evo显示出相似的肝酶升高和病理评分。未观察到血液学和肾脏毒性。与cTACE相比，接受cTACE+Evo治疗的动物显示出较小的肿瘤体积、较低的肿瘤生长率和较高的坏死率。CTACE+EVO组的HF和HC明显降低。观察到HF或HC的降低与肿瘤坏死的相关性。CTACE+EVO可促进肿瘤细胞的抗肿瘤作用，表现为γ-H_2A.X表达增加，细胞凋亡生物标志物表达增加，细胞增殖抑制。HIF1α/血管内皮生长因子表达增加和肿瘤糖酵解支持HAAT。HAIAT朝着肿瘤缺氧的局部区域靶向迈出了有希望的一步。依福福胺与cTACE联合应用的良好毒性和增强的抗癌效果为肝癌患者的临床试验铺平了道路。
To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intraarterial therapy (HAIAT) with evofosfamide in a rabbit model. VX2-tumor-bearing rabbits were assigned to 4 intraarterial therapy (IAT) groups (n=7/group): 1) saline (control); 2) evofosfamide (Evo); 3) doxorubicin-Lipiodol emulsion followed by embolization with 100-300μm beads (conventional, cTACE); or 4) cTACE and evofosfamide (cTACE+Evo). Blood samples were collected pre-IAT and 1/2/7/14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia and metabolism were quantified (γ-H2AX, annexin V, caspase-3, Ki-67, HIF1α, VEGF, GAPDH, MCT4 and LDH). cTACE+Evo showed a similar profile of liver enzymes elevation and pathologic scores compared to cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE+Evo demonstrated smaller tumor volumes, lower tumor growth rates and higher necrotic fractions compared to cTACE. cTACE+Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE+Evo promoted antitumor effects as evidenced by increased expression of γ-H2A.X, apoptotic biomarkers and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT. HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer.