Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer.
Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer.
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DOI：
10.1080/15384047.2014.1003005
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发表时间：
2015
影响因子：
3.6
通讯作者：
Hart CP
中科院分区：
文献类型：
--
作者：
Sun JD;Liu Q;Ahluwalia D;Li W;Meng F;Wang Y;Bhupathi D;Ruprell AS;Hart CP
肿瘤通常含有耐化疗和放疗的缺氧区域。TH-302（T）是一种研究中的低氧激活前药，在低氧条件下选择性释放DNA交联剂溴异磷酰胺芥子气。本研究评估了T与吉西他滨（G）和白蛋白结合型紫杉醇（nab-paclitaxel）（NAB）组合在小鼠中的人胰腺导管腺癌（PDAC）异种移植物模型中的功效和安全性特征。在Hs 766 t、MIA PaCa-2、PANC-1和BxPC-3 PDAC异种移植物模型中评估G + β 2 + T三联体的抗肿瘤活性，并与单独的T或G + β 2双联体进行比较。通过肿瘤生长动力学分析评估疗效。分析体重、血细胞计数、血液化学和von Frey神经病变试验，以评价安全性特征。采用免疫组化法检测细胞增殖、DNA损伤、凋亡、缺氧、肿瘤间质密度等指标。与单独的T或G + T三联体相比，G + T + T三联体表现出增强的功效。与溶剂（V）相比，G + β-D诱导体重减轻，中性粒细胞和淋巴细胞计数减少，肝功能参数水平升高，并诱导神经毒性。然而，当T加到G + G时，与G + G相比，没有统计学上增加的损伤。三联体显著增加DNA损伤、凋亡和肿瘤坏死。此外，三联体进一步抑制细胞增殖并降低基质密度和瘤内缺氧。在本研究中，与G + β-内酰胺酶双联体相比，G + β-内酰胺酶+ T三联体组合表现出上级疗效，但相加毒性不明显。本研究提供了在临床环境中联合使用G、T2和T以评估疗效和安全性的翻译依据。三联组合的I期临床试验目前正在进行中（NCT 02047500）。
Tumors often contain hypoxic regions resistant to chemo- and radiotherapy. TH-302 (T) is an investigational hypoxia-activated prodrug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under hypoxic conditions. This study evaluated the efficacy and safety profile of combining T with gemcitabine (G) and nab-paclitaxel (nP) in human pancreatic ductal adenocarcinoma (PDAC) xenograft models in mice. Antitumor activity of the G + nP + T triplet was assessed and compared with T-alone or the G + nP doublet in the Hs766t, MIA PaCa-2, PANC-1, and BxPC-3 PDAC xenograft models. Efficacy was assessed by tumor growth kinetic analysis. Body weight, blood cell counts, blood chemistry, and the von Frey neuropathy assay were analyzed to evaluate safety profiles. Pharmacodynamic changes after the treatment were determined by immunohistochemistry of cell proliferation, DNA damage, apoptosis, hypoxia, and tumor stroma density. The G + nP + T triplet exhibited enhanced efficacy compared with T-alone or the G + nP doublet. Compared with vehicle (V), G + nP induced body weight loss, reduced neutrophil and lymphocyte counts, increased the levels of liver function parameters, and induced neurotoxicity. However, when T was added to G + nP, there was no statistically increased impairment compared to G + nP. The triplet significantly increased DNA damage, apoptosis, and tumor necrosis. Furthermore, the triplet further inhibited cell proliferation and reduced stroma density and intratumoral hypoxia. The triplet combination of G + nP + T exhibited superior efficacy but additive toxicity was not evident compared to the G + nP doublet in this study. This study provides a translational rationale for combining G, nP, and T in the clinical setting to assess efficacy and safety. A Phase I clinical trial of the triplet combination is currently underway (NCT02047500).