Pharmacology and Drug Development Group, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom.
PLoS One. 2013 Jun 28;8(6):e67330. doi: 10.1371/journal.pone.0067330. Print 2013.
Capecitabine (CAP) is a 5-FU pro-drug approved for the treatment of several cancers and it is used in combination with gemcitabine (GEM) in the treatment of patients with pancreatic adenocarcinoma (PDAC). However, limited pre-clinical data of the effects of CAP in PDAC are available to support the use of the GEMCAP combination in clinic. Therefore, we investigated the pharmacokinetics and the efficacy of CAP as a single agent first and then in combination with GEM to assess the utility of the GEMCAP therapy in clinic. Using a model of spontaneous PDAC occurring in Kras(G12D); p53(R172H); Pdx1-Cre (KPC) mice and subcutaneous allografts of a KPC PDAC-derived cell line (K8484), we showed that CAP achieved tumour concentrations (∼25 µM) of 5-FU in both models, as a single agent, and induced survival similar to GEM in KPC mice, suggesting similar efficacy. In vitro studies performed in K8484 cells as well as in human pancreatic cell lines showed an additive effect of the GEMCAP combination however, it increased toxicity in vivo and no benefit of a tolerable GEMCAP combination was identified in the allograft model when compared to GEM alone. Our work provides pre-clinical evidence of 5-FU delivery to tumours and anti-tumour efficacy following oral CAP administration that was similar to effects of GEM. Nevertheless, the GEMCAP combination does not improve the therapeutic index compared to GEM alone. These data suggest that CAP could be considered as an alternative to GEM in future, rationally designed, combination treatment strategies for advanced pancreatic cancer.
卡培他滨 (CAP) 是一种 5-FU 前体药物，已被批准用于治疗多种癌症，并且与吉西他滨 (GEM) 联合用于治疗胰腺腺癌 (PDAC) 患者。然而，目前仅有有限的临床前数据支持 CAP 在 PDAC 中的应用，以支持 GEMCAP 联合治疗在临床中的应用。因此，我们首先研究了 CAP 作为单一药物的药代动力学和疗效，然后研究了与 GEM 的联合疗效，以评估 GEMCAP 治疗在临床中的应用。我们使用自发发生在 Kras(G12D); p53(R172H); Pdx1-Cre (KPC) 小鼠中的 PDAC 模型和 KPC PDAC 衍生细胞系 (K8484) 的皮下同种异体移植模型，表明 CAP 在两种模型中均能达到肿瘤浓度 (∼25 µM) 的 5-FU，作为单一药物，并且在 KPC 小鼠中诱导的存活率与 GEM 相似，表明疗效相似。在 K8484 细胞以及人胰腺细胞系中进行的体外研究表明，GEMCAP 联合具有相加作用，然而，它在体内增加了毒性，并且在同种异体移植模型中，与单独使用 GEM 相比，没有发现可耐受的 GEMCAP 联合的益处。我们的工作提供了临床前证据，表明口服 CAP 给药后可向肿瘤输送 5-FU 并发挥抗肿瘤疗效，其效果与 GEM 相似。然而，与单独使用 GEM 相比，GEMCAP 联合并没有改善治疗指数。这些数据表明，在未来，CAP 可被视为治疗晚期胰腺癌的合理设计联合治疗策略中替代 GEM 的一种选择。
