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

Autor: Bapiro TE; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Frese KK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Courtin A; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Bramhall JL; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Madhu B; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Cook N; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Neesse A; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Griffiths JR; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Tuveson DA; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA., Jodrell DI; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK., Richards FM; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2014 Jul 15; Vol. 111 (2), pp. 318-25. Date of Electronic Publication: 2014 May 29.
DOI: 10.1038/bjc.2014.288
Abstrakt: 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: KRAS(G12D); p53(R172H); 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.
Databáze: MEDLINE
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