肿瘤通常包含对化学疗法和放射疗法有抗性的缺氧区域。TH-302(T)是一种研究性缺氧激活的前药,在缺氧条件下选择性释放DNA交联剂溴异磷酰胺芥末。这项研究评估了T与吉西他滨(G)和nab-紫杉醇(nP)联合在小鼠胰腺导管腺癌(PDAC)异种移植模型中的疗效和安全性。评估了GnPT三联体的抗肿瘤活性,并将其与Hs766t中的单独T或GnP双联体进行了比较,MIAPaCa-2、PANC-1和BxPC-3PDAC异种移植模型。通过肿瘤生长动力学分析评估功效。体重,血细胞计数,血液化学,和vonFrey神经病变试验进行分析,以评估安全性.通过细胞增殖的免疫组织化学测定治疗后的药效学变化,DNA损伤,凋亡,缺氧,和肿瘤基质密度。与单独的T或G+nP双合相比,G+nP+T三联体表现出增强的功效。与车辆(V)相比,G+nP诱导的体重下降,中性粒细胞和淋巴细胞计数减少,增加肝功能参数的水平,并诱导神经毒性。然而,当将T添加到G+nP时,与G+nP相比,损伤无统计学增加.三联体显著增加了DNA损伤,凋亡,和肿瘤坏死。此外,三联体进一步抑制细胞增殖,降低基质密度和瘤内缺氧。在本研究中,G+nP+T的三重态组合表现出优异的功效,但与G+nP双合相比较,累加毒性不明显。本研究为组合G,nP,和T在临床环境中评估疗效和安全性。目前正在进行三联体组合的I期临床试验(NCT02047500)。
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).