Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis
Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis
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DOI：
10.1080/15384047.2015.1078025
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发表时间：
2015-12-01
影响因子：
3.6
通讯作者：
Gilmour, Susan K.
中科院分区：
文献类型：
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作者：
Alexander, Eric T.;Minton, Allyson R.;Gilmour, Susan K.
癌症通常与血栓形成事件的风险增加有关，而用环磷酰胺(CP)等化疗药物治疗会加剧血栓形成事件。有证据表明，凝血酶可以通过形成纤维蛋白和激活蛋白酶激活的受体(PARs)和血小板来刺激肿瘤进展。在小鼠原位4T1肿瘤模型上，我们检测了CP和直接凝血酶抑制剂达比卡特兰乙塞酯联合治疗的效果。接受低剂量CP和达比卡特兰乙酯联合治疗的小鼠，与单独使用CP或达比格拉他汀组相比，乳腺肿瘤明显较小，肺转移也较少。达比加特兰与低剂量CP联合治疗后，荷瘤小鼠脾组织中精氨酸酶(+)、Gr-1(+)、CD11b(+)髓系来源抑制细胞的数量及转化生长因子-β水平均显著降低。4T1肿瘤表达促凝血剂组织因子(TF)，并自发释放TF+微粒，是促进凝血酶生成的强有力的促凝血因子。单用达比卡特兰Eexilate治疗可防止肿瘤引起的循环Tf+微粒的增加，也可使肿瘤引起的活化血小板数量减少40%。这些结果表明，达比卡特兰和环磷酰胺联合治疗可协同抑制乳腺肿瘤的生长和转移，提示口服凝血酶抑制剂达比卡特兰不仅有益于预防癌症患者的血栓事件，而且对治疗恶性肿瘤本身也有好处。
Cancer is often associated with an increased risk of thrombotic events which are exacerbated by treatment with chemotherapeutics such as cyclosphosphamide (CP). Evidence suggests that thrombin can stimulate tumor progression via formation of fibrin and activation of protease-activated receptors (PARs) and platelets. We examined the effect of co-treatment with CP and dabigatran etexilate, a direct inhibitor of thrombin, using the murine orthotopic 4T1 tumor model. Mice receiving co-treatment with both low dose CP and dabigatran etexilate had significantly smaller mammary tumors and fewer lung metastases than mice treated with CP or dabigratran etexilate alone. Co-treatment with dabigatran etexilate and low dose CP also significantly decreased the number of arginase(+)Gr-1(+)CD11b(+) myeloid derived suppressor cells as well as levels of TGF-beta in spleens from tumor bearing mice. 4T1 tumors express procoagulant tissue factor (TF) and spontaneously release TF+ microparticles which are potent procoagulant factors that promote thrombin generation. Treatment with dabigatran etexilate alone prevented tumor-induced increases in circulating TF+ microparticles and also decreased the numbers of tumor-induced activated platelets by 40%. These results show that co-treatment with dabigatran etexilate and CP synergistically inhibits growth and metastasis of mammary tumors, suggesting that oral administration of the thrombin inhibitor dabigatran etexilate may be beneficial in not only preventing thrombotic events in cancer patients but also in treating malignant tumors themselves.