Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo

Bapiro, T. E., Frese, K. K., Courtin, A., Bramhall, J. L., Madhu, B., Cook, N., Neesse, A., Griffiths, J. R., Tuveson, D. A., Jodrell, D. I., Richards, F. M. (2014) Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo. British Journal of Cancer, 111 (2). pp. 318-325. ISSN 0007-0920

URL: http://www.ncbi.nlm.nih.gov/pubmed/24874484
DOI: 10.1038/bjc.2014.288

Abstract

Background:The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRASG12D; p53R172H; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism.Methods:LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay.Results:In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition.Conclusions:GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo.British Journal of Cancer advance online publication, 29 May 2014; doi:10.1038/bjc.2014.288 www.bjcancer.com.

Item Type: Paper
Subjects: organism description > model organism
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 09 Jun 2014 19:45
Last Modified: 08 Aug 2014 18:45
PMCID: PMC4102943
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30291

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