Abstract 3771: Capecitabine pharmacokinetics and efficacy in spontaneous tumors occurring in a genetically engineered mouse model (GEMM) of pancreatic cancer
Authors: Courtin Aurelie , Richards Frances M. , Bapiro Tashinga E. , Smith Donna-Michelle , Williams Michael , Bramhall Jo L. , Frese Kristopher , Tuveson David A. , Jodrell Duncan I. 
Published: August 2012

Abstract
Capecitabine (CAP) is an oral fluoropyrimidine, converted sequentially and selectively to 5-FU at the tumour site. It is used in the treatment of a number of cancers as a single agent and in patients with pancreatic cancer, in combination with gemcitabine. However, pre-clinical data in pancreatic cancer models are limited. In this study, we investigated the pharmacokinetics (PK) and efficacy of CAP in a GEMM of spontaneous pancreatic adenocarcinoma (PDA) occurring in KrasG12D; p53R172H; Pdx1-Cre (KPC) mice, compared to an allograft model of a cell line isolated from a PDA arising in the KPC mice. In the PK study, tumour was collected 2 hours after CAP treatment (755 mg/kg by oral gavage), homogenates were analysed using an LC-MS/MS assay developed to simultaneously detect capecitabine and its 3 metabolites DFCR, DFUR and 5-FU (modified from S.M.Guichard, et al., J. Chrom. B. 2005). Data were compared to our previously reported studies in an allograft model (Proc. AACR 2011 a 5446). After a QDx7 treatment, 5-FU concentrations of 27 ± 13 μM were achieved (compared to 23.0 ± 8.1 μM and 22.7 ± 7.7 μM in allograft tumours after 1 and 5 consecutive doses respectively), confirming adequate drug delivery to the in situ tumour following oral administration of CAP. Therefore we proceeded to efficacy studies in this model. In the allograft model we had identified a significant reduction of the tumour doubling time with 755 mg/kg CAP (5 days/week, 3 weeks), compared to control (7.5 ± 3.0 vs 3.5 ± 0.5 days; P&lt;0.001). In in situ tumours, a short term study over 7 days showed a reduction in tumour growth in CAP-treated KPC PDA tumours compared to control (199% ± 22% vs 121% ± 10%; P&lt;0.01). In a survival study in KPC mice, CAP (755 mg/kg, 5 days/week) was compared to the standard treatment for advanced pancreatic cancer, gemcitabine (GEM, 100 mg/kg, Q3D), and there was no difference in the median survival of mice with spontaneous PDA tumours (P=0.61) suggesting a similar efficacy of CAP to GEM. There is conflicting evidence regarding the utility of the combination of GEM and CAP in this disease, so we also investigated the combination in mice bearing allograft PDA tumours. Full doses of both drugs were not tolerated, but the combination of GEM (75 mg/kg Q3D, 2 weeks) plus CAP (539 mg/kg, 5 days/week, 2 weeks) was feasible. This regimen was associated with significant growth inhibition, but this was not superior to GEM alone (75 mg/kg) at the same dose (tumour doubling time: 8.6 ± 10.8 vs 7.2 ± 2.8 days respectively). In summary, orally administered CAP achieves active concentrations of 5-FU in PDA tumours. Similar effects on survival compared to GEM are seen in PDA tumours. Growth inhibition data in allograft tumours did not show any additional benefit for the GEMCAP combination, when compared to GEM alone. CAP could be considered as an alternative to GEM in future, rationally designed, combination treatment strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3771. doi:1538-7445.AM2012-3771