*Department of Surgery and Transplantation, Swiss Hepato-pancreato-biliary (HPB) and Transplantation Laboratory, University Hospital Zurich, Zurich, Switzerland †Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA ‡Institute of Supramolecular Science and Engineering, University of Strasbourg, Strasbourg, France.
Ann Surg. 2017 Nov;266(5):746-753. doi: 10.1097/SLA.0000000000002431.
To test the effects of enhanced intracellular oxygen contents on the metastatic potential of colon cancer.
Colorectal cancer is the commonest gastrointestinal carcinoma. Distant metastases occur in half of patients and are responsible for most cancer-related deaths. Tumor hypoxia is central to the pathogenesis of metastases. Myo-Inositoltrispyrophosphate (ITPP), a nontoxic, antihypoxic compound, has recently shown significant benefits in experimental cancer, particularly when combined with standard chemotherapy. Whether ITPP protects from distant metastases in primary colon cancer is unknown.
ITPP alone or combined with FOLFOX was tested in a mouse model with cecal implantation of green fluorescent protein-labeled syngeneic colorectal cancer cells. Tumor development was monitored through longitudinal magnetic resonance imaging-based morphometric analysis and survival. Established serum markers of tumor spread were measured serially and circulating tumor cells were detected via fluorescence measurements.
ITPP significantly reduced the occurrence of metastases as well as other indicators of tumor aggressiveness. Less circulating tumor cells along with reduction in malignant serum markers (osteopontin, Cxcl12) were noted. The ITPP benefits also affected the primary cancer site. Importantly, animals treated with ITPP had a significant survival benefit compared with respective controls, while a combination of FOLFOX with ITPP conferred the maximum benefits, including dramatic improvements in survival (mean 86 vs 188 d).
Restoring oxygen in metastatic colon cancer through ITPP inhibits tumor spread and markedly improves animal survival; an effect that is enhanced through the application of subsequent chemotherapy. These promising novel findings call for a clinical trial on ITPP in patients with colorectal cancer, which is under way.
检测增强细胞内氧含量对结肠癌转移潜能的影响。
结直肠癌是最常见的胃肠道癌。半数患者发生远处转移，且大多数癌症相关死亡与之相关。肿瘤缺氧是转移发生的关键。肌醇三磷酸（ITPP）是一种无毒、抗缺氧的化合物，最近在实验性癌症中显示出显著的益处，尤其是与标准化疗联合使用时。ITPP 是否能预防原发性结肠癌的远处转移尚不清楚。
在通过 Cecal 植入绿色荧光蛋白标记的同源结直肠癌细胞的小鼠模型中，单独使用 ITPP 或与 FOLFOX 联合使用。通过基于纵向磁共振成像的形态计量学分析和生存监测肿瘤的发展。连续测量已建立的肿瘤扩散血清标志物，并通过荧光测量检测循环肿瘤细胞。
ITPP 显著降低了转移的发生以及其他肿瘤侵袭性指标。循环肿瘤细胞数量减少，恶性血清标志物（骨桥蛋白、Cxcl12）减少。ITPP 的益处也影响了原发性癌症部位。重要的是，与相应对照组相比，接受 ITPP 治疗的动物具有显著的生存获益，而 FOLFOX 与 ITPP 的联合治疗则带来了最大的获益，包括显著提高了生存（平均 86 天 vs 188 天）。
通过 ITPP 恢复转移性结肠癌中的氧气含量可抑制肿瘤扩散，并显著提高动物的生存率；后续化疗的应用可增强这种效果。这些有前途的新发现呼吁在结直肠癌患者中进行 ITPP 的临床试验，目前该试验正在进行中。
