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

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 recapitula...

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Published in:British journal of cancer 2014-07, Vol.111 (2), p.318-325
Main Authors: BAPIRO, T. E, FRESE, K. K, RICHARDS, F. M, COURTIN, A, BRAMHALL, J. L, MADHU, B, COOK, N, NEESSE, A, GRIFFITHS, J. R, TUVESON, D. A, JODRELL, D. I
Format: Article
Language:English
Subjects:
Animals
Antimetabolites, Antineoplastic - pharmacokinetics
Antimetabolites, Antineoplastic - pharmacology
Biological and medical sciences
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - metabolism
Choline - metabolism
Deoxycytidine - analogs & derivatives
Deoxycytidine - metabolism
Deoxycytidine - pharmacokinetics
Deoxycytidine - pharmacology
Diphosphates - metabolism
Female
Gastroenterology. Liver. Pancreas. Abdomen
Gemcitabine
Humans
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Nude
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - metabolism
Translational Therapeutics
Tumor Cells, Cultured
Tumors
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Summary: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. LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. 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. GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2014.288