Combination chemotherapy regimens that include fluoropyrimidine (FP) drugs, e.g., 5-fluorouracil (5-FU), are central to the treatment of colorectal cancer liver metastases (CRLMs), a major cause of cancer mortality. We tested a second-generation FP polymer, CF10, in a CC531/WAGRij syngeneic orthotopic rat model of liver metastasis to determine if CF10 improved response relative to 5-FU. CF10 displayed increased potency relative to 5-FU in CC531 rat colorectal cancer cells based on clonogenic assay results and caused increased apoptosis, as shown using a live/dead assay. The increased potency of CF10 to CC531 cells was associated with increased replication stress, as assessed by Western blot for biomarkers of ATR/Chk1 and ATM/Chk2 pathway activation. CF10 dosed to deliver equivalent FP content as an established dose of 5-FU in rats (50 mg/kg) did not cause weight loss in WAGRij rats even when combined with ethynyl uracil (EU), an inhibitor of dihydropyrimidine dehydrogenase, the enzyme primarily responsible for 5-FU degradation in the liver. In contrast, 5-FU caused significant weight loss that was exacerbated in combination with EU. Importantly, CF10 was significantly more effective than 5-FU at inhibiting tumor progression (~90% reduction) in the CC531/WAG/Rij CRLM model. Our results reveal strong potential for CF10 to be used for CRLM treatment.
包含氟嘧啶类药物（如5-氟尿嘧啶）的联合化疗方案是治疗结直肠癌肝转移（癌症死亡的主要原因）的核心。我们在CC531/WAG/Rij同基因原位大鼠肝转移模型中测试了第二代氟嘧啶聚合物CF10，以确定CF10是否比5-氟尿嘧啶具有更好的疗效。根据克隆形成实验结果显示，CF10在CC531大鼠结直肠癌细胞中表现出比5-氟尿嘧啶更强的效力，并通过活/死细胞检测证实其诱导了更多的细胞凋亡。通过Western blot检测ATR/Chk1和ATM/Chk2通路激活的生物标志物，发现CF10对CC531细胞效力的增强与复制应激增加相关。在大鼠中，CF10以与既定5-氟尿嘧啶剂量（50 mg/kg）等效的氟嘧啶含量给药时，即使与乙炔尿嘧啶（一种二氢嘧啶脱氢酶抑制剂，该酶主要负责肝脏中5-氟尿嘧啶的降解）联合使用，也未引起WAG/Rij大鼠体重下降。相比之下，5-氟尿嘧啶会导致显著的体重下降，且与乙炔尿嘧啶联合使用时更为严重。重要的是，在CC531/WAG/Rij结直肠癌肝转移模型中，CF10抑制肿瘤进展的效果显著优于5-氟尿嘧啶（约减少90%）。我们的研究结果表明，CF10在结直肠癌肝转移治疗中具有巨大潜力。
肿瘤(癌症)患者之家