Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
Department of Internal Medicine, Research Unit, University Hospital Zurich, Zurich, Switzerland.
Clin Cancer Res. 2016 Dec 1;22(23):5887-5897. doi: 10.1158/1078-0432.CCR-15-3112. Epub 2016 Aug 3.
Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.
We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.
ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.
Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. ©2016 AACR.
肿瘤缺氧会激活缺氧诱导因子（Hifs），从而诱导包括血管异常在内的一系列恶性变化。在这里，我们通过使用具有抗缺氧特性的肌醇三磷酸（ITPP）抑制缺氧肿瘤反应，来确定是否能够导致血管持续正常化，从而可以利用这种方法来改善标准治疗。
我们在两种同源的、原位的、致命的结直肠癌肝转移的小鼠模型中测试了 ITPP。通过 MRI 监测肿瘤，并分析缺氧反应及其恶性潜能。使用 Hif 激活剂和体外测定来确定 ITPP 的工作模式。治疗 4 周后重新评估缺氧反应和血管。最后，我们确定了 ITPP 单药治疗、FOLFOX 单药治疗、FOLFOX 加 Vegf 抗体治疗以及 FOLFOX 加 ITPP 治疗（重叠和序贯）后的生存情况。
ITPP 减少了肿瘤负荷，有效地抑制了缺氧反应，并提高了生存率。当小鼠用 Hif 激活剂预处理时，这些效果就会消失。它对缺氧反应的即时影响，包括肿瘤血管的明显正常化，在治疗停止后至少持续 4 周。与 FOLFOX 单独使用相比，Vegf 抗体与 FOLFOX 联合使用将生存率延长了<30%，而 ITPP 与 FOLFOX 联合使用将生存率延长了>140%，无论 FOLFOX 是在 ITPP 暴露前还是暴露后使用。
我们的研究结果揭示了 ITPP 真正的抗缺氧机制，并证明了这种无毒化合物的能力，以增强现有抗癌治疗的疗效，这种方法适合临床转化。临床癌症研究；22(23)；5887-97. ©2016AACR。
