胰腺导管腺癌（PDAC）代表了未满足的临床需求。大约 90% 的 PDAC 表达高水平的 αvβ6 整合素。我们之前描述过 Ad5NULL-A20，这是一种腺病毒载体，其细胞进入的天然方式被消除，并通过掺入 A20 肽重新靶向 αvβ6 整合素。在这里，我们整合了编码胞嘧啶脱氨酶 (CDase) 的自杀基因 FCY1 和 FCU1 或CDase 和 UPRTase 能够催化无毒前药 5-FC 转化为化疗药物 5-FU 和下游代谢物，转化为复制缺陷的 Ad5 和 Ad5NULL-A20。我们表明 Ad5NULL-A20 能够将自杀基因转移到 αvβ6整合素阳性 PDAC 细胞与 5-FC 结合，导致体外细胞死亡，并由非转导细胞中的旁观者效应进一步介导。 Ad5NULL-A20.FCU1 的肿瘤内递送与 5-FC 的腹膜内递送相结合进一步导致体内细胞系异种移植物中的肿瘤生长抑制。使用临床相关的 3D 类器官模型，我们展示了 FCU1 转基因与 5-FC 组合的选择性转导和治疗功效。综合起来，这些数据为联合 Ad5NULL-A20 提供了临床前基本原理。FCU1 加 5-FC 作为一种有前途的靶向治疗介导“肿瘤内化疗”，值得进一步研究 PDAC 患者的治疗。© 2024。作者。

Pancreatic ductal adenocarcinoma (PDAC) represent an unmet clinical need. Approximately 90% of PDACs express high levels of αvβ6 integrin. We have previously described Ad5NULL-A20, an adenovirus vector with ablated native means of cell entry and retargeted to αvβ6 integrin by incorporation of an A20 peptide.Here, we incorporate suicide genes FCY1 and FCU1 encoding for cytosine deaminase (CDase) or a combination of CDase and UPRTase, capable of catalysing a non-toxic prodrug, 5-FC into the chemotherapeutic 5-FU and downstream metabolites, into replication-deficient Ad5 and Ad5NULL-A20.We show that Ad5NULL-A20 enables the transfer of suicide genes to αvβ6 integrin-positive PDAC cells which, in combination with 5-FC, results in cell death in vitro which is further mediated by a bystander effect in non-transduced cells. Intratumoural delivery of Ad5NULL-A20.FCU1 in combination with intraperitoneal delivery of 5-FC further results in tumour growth inhibition in a cell line xenograft in vivo. Using clinically-relevant 3D organoid models, we show selective transduction and therapeutic efficacy of FCU1 transgenes in combination with 5-FC.Taken together these data provide the preclinical rationale for combined Ad5NULL-A20.FCU1 plus 5-FC as a promising targeted therapy to mediate "in-tumour chemotherapy" and merits further investigation for the treatment of PDAC patients.© 2024. The Author(s).