Abstract
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 KrasG12D; p53R172H; 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in industrialised countries
To investigate the pharmacokinetics of CAP and its metabolites, we analysed by mass spectrometry the homogenates of plasma, tumour and liver from mice bearing K8484 allograft tumour collected at different time points after a single dose of CAP given orally at 755 mg/kg (2.1 mmol/kg/day)
As our in vitro experiments on K8484 cells showed an IC50 for 5FU of 2.5660.55 mM, these in vivo results suggest that an oral CAP dosing delivers a therapeutically effective dose to the allograft tumours. 5-FU levels were more than 30 fold lower in plasma (1.960.5 mM at 40 min and 0.360.2 mM after 4 h) than in tumour and were below the limit of quantification in the liver from 2 h (Figure 1C)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in industrialised countries. Overall 5 year survival rate is less than 5% [1]. The high degree of mortality of PDAC is attributable to the lack of early detection methods and the poor efficacy of existing therapies. Gemcitabine (GEM) is the standard therapy, but the median survival time remains only 5–7 months in patients with advanced disease [2]. Capecitabine (XelodaH; Hoffmann La Roche) is an orally administered fluoropyrimidine carbamate, metabolised in liver and tumour by carboxylesterases and cytidine deaminase to 59deoxy-5-fluorocytidine (59-DFCR) and 59-deoxy-5-fluorouridine (59-DFUR) respectively. The final step of the activation of capecitabine (CAP), conversion of 59-DFUR to cytotoxic 5fluorouracil (5-FU), is mediated by thymidine phosphorylase [3–
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