Introduction: Trifluridine/tipiracil hydrochloride (FTD/TPI, Lonsurf®) is an oral antineoplastic agent that has been approved as a late-stage chemotherapy for colorectal cancer. Its major mechanism of action is the dysfunction of tumoral DNA including DNA strand breaks and decreased replication. Fruquintinib (ELUNATE®) is a novel kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-1, -2, and -3. In this study, we evaluated the antitumor activity of combination therapy with FTD/TPI and fruquintinib in vivo. Methods: The enhancement of the antitumor effects with FTD/TPI and fruquintinib combination, compared to the single drugs given alone was evaluated using two human colorectal cancer xenografts in nude mouse models. FTD/TPI (200 mg/kg) was orally administered for 5 consecutive days followed by 2 days of rest in a 7-day period. Fruquintinib (10 mg/kg) was orally administered consecutively for 2 and 3 weeks in SW48 and HCT 116 tumor-bearing models, respectively. After treatment with these agents, the microvessel density was evaluated by CD31 immunohistochemical analyses. Results: In both models, FTD/TPI and fruquintinib significantly inhibited tumor growth, and the activity of the combined treatment was significantly superior to that of either monotherapy. Body weight loss of greater than 20% was not observed in any group. A histochemical analysis showed nuclei enlargement, abnormal mitosis and karyorrhexis in the FTD/TPI treatment group. The microvessel density in the HCT 116 tumors treated with FTD/TPI and fruquintinib was significantly lower than that in the control group. Conclusion: The combination of FTD/TPI and fruquintinib could be a promising treatment option for colorectal cancer.


中文翻译：

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基于曲氟尿苷/tipiracil 和呋喹替尼的结直肠癌新型联合疗法的评价

简介：曲氟尿苷/替吡嘧啶盐酸盐（FTD/TPI，Lonsurf®）是一种口服抗肿瘤药，已被批准用作结直肠癌的晚期化疗药物。其主要作用机制是肿瘤 DNA 的功能障碍，包括 DNA 链断裂和复制减少。呋喹替尼 (ELUNATE®) 是一种新型激酶抑制剂，可选择性抑制血管内皮生长因子受体 -1、-2 和 -3。在这项研究中，我们评估了 FTD/TPI 和呋喹替尼联合治疗的体内抗肿瘤活性。方法：与单独给予的单一药物相比，FTD/TPI 和呋喹替尼组合的抗肿瘤作用增强，在裸鼠模型中使用两种人结直肠癌异种移植物进行评估。连续 5 天口服 FTD/TPI (200 mg/kg)，然后在 7 天内休息 2 天。在 SW48 和 HCT 116 荷瘤模型中分别连续口服呋喹替尼 (10 mg/kg) 2 周和 3 周。用这些药物治疗后，通过 CD31 免疫组织化学分析评估微血管密度。结果：在两种模型中，FTD/TPI 和呋喹替尼均显着抑制肿瘤生长，联合治疗的活性明显优于任一单一疗法。在任何组中均未观察到大于 20% 的体重减轻。组织化学分析显示 FTD/TPI 治疗组出现细胞核增大、异常有丝分裂和核碎裂。用 FTD/TPI 和呋喹替尼治疗的 HCT 116 肿瘤的微血管密度明显低于对照组。结论：FTD/TPI 联合呋喹替尼可能是结直肠癌的一种有前途的治疗选择。