AraC-FdUMP\[10\] (CF10) is a second-generation polymeric fluoropyrimidine that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOLFIRNOX, a standard-of-care regimen for pancreatic ductal adenocarcinoma (PDAC). We demonstrated that F10 and CF10 are potent inhibitors of PDAC cell survival (in multiple cell lines including patient-derived lines) with IC50s in the nanomolar range and are nearly 1,000-fold more potent than 5-FU. The increased potency of CF10 relative to 5-FU correlated with enhanced TS inhibition and strong Top1 cleavage complex formation. Furthermore, CF10 displayed single-agent activity in PDAC murine xenografts without inducing weight loss. Through a focused drug synergy screen, we identified that combining CF10 with targeting the DNA repair enzyme, poly (ADP-ribose) glycohydrolase, induces substantial DNA damage and apoptosis. This work moves CF10 closer to a clinical trial for the treatment of PDAC. Implications: CF10 is a promising polymeric fluoropyrimidine with dual mechanisms of action (i.e., TS and Top1 inhibition) for the treatment of PDAC and synergizes with targeting of DNA repair. Visual Overview: . This article is featured in Highlights of This Issue, [p. 541][1] [1]: /lookup/volpage/19/541?iss=4

中文翻译：

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AraC-FdUMP[10] 是下一代氟嘧啶，在 PDAC 中具有有效的抗肿瘤活性并与 PARG 抑制有协同作用

AraC-FdUMP\[10\] (CF10) 是第二代聚合氟嘧啶，它同时靶向 5-氟尿嘧啶 (5-FU) 的靶标胸苷酸合酶 (TS) 和靶向 DNA 拓扑异构酶 1 (Top1)伊立替康，这两种药物是 FOLFIRNOX 的关键成分，这是一种胰腺导管腺癌 (PDAC) 的标准护理方案。我们证明 F10 和 CF10 是 PDAC 细胞存活的有效抑制剂（在多个细胞系中，包括患者来源的细胞系），IC50 在纳摩尔范围内，比 5-FU 强近 1,000 倍。CF10 相对于 5-FU 的效力增加与增强的 TS 抑制和强烈的 Top1 切割复合物形成相关。此外，CF10 在 PDAC 小鼠异种移植物中显示出单剂活性，而不会导致体重减轻。通过集中的药物协同筛选，我们发现，将 CF10 与靶向 DNA 修复酶聚（ADP-核糖）糖水解酶结合，可诱导大量 DNA 损伤和细胞凋亡。这项工作使 CF10 更接近于治疗 PDAC 的临床试验。启示：CF10 是一种很有前途的聚合氟嘧啶，具有双重作用机制（即 TS 和 Top1 抑制），用于治疗 PDAC 并与靶向 DNA 修复协同作用。视觉概览：. 这篇文章被收录在本期的亮点中，[p. 541][1][1]：/lookup/volpage/19/541?iss=4