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- W2092148745 abstract "In vitro, gemcitabine has potent growth inhibitory effects on pancreatic cancer cells. However, clinically, its effectiveness is modest, despite being used widely as the reference treatment for both advanced disease and as adjuvant therapy. Drug delivery, due to the dense stroma associated with pancreatic cancer, has been identified as a potential limiting factor in the utility of gemcitabine. Gemcitabine (difluorodeoxycytidine, dFdC) requires metabolic activation by phosphorylation, the diphosphate metabolite inhibiting ribonucleotide reductase and the triphosphate form (dFdCTP) being incorporated into DNA. It is also a substrate for the enzyme cytidine deaminase (CDA), which is an inactivating reaction. As a result of this, its pharmacokinetics (PK) would be expected to impact on outcome following treatment. However, measurement of activated gemcitabine (dFdCTP) in tumor tissue had proved elusive, but a new LC-MS/ MS approach developed recently (Bapiro et al, CCP, 2011) has allowed the routine assessment of intratumoral dFdCTP concentrations in small fragments of tissue (≥ 10mg), following gemcitabine administration in mouse models (both allograft and in situ pancreatic adenocarcinoma in a genetically engineered mouse model). The assay is also providing new insights into the pharmacology of gemcitabine and further development allows the assessment of dFdCTP incorporation into DNA. It has been applied to the preclinical assessment of gemcitabine combination strategies, demonstrating increased dFdCTP formation following nabpaclitaxel, due to destabilization of CDA protein (Frese et al, Cancer Discovery, 2012) and depletion of hyaluronan, using PEGPH20 (Jacobetz et al, Gut, 2012). In studies with the γ-secretase inhibitor (MRK003), the increased activity of the combination was not associated with increased dFdCTP formation, prompting the search for the alternative mechanism; endothelial damage leading to hypoxic necrosis (Cook et al, J. Exp Med. 2012). These studies demonstrate the ongoing importance of assessing whether the drug gets to its target and our current focus is on improving the sensitivity further, for it to be applicable to needle biopsy specimens in clinical trials. Citation Format: Duncan I. Jodrell, Tashinga Bapiro, Natalie Cook, Kristopher Frese, Mike Jacobetz, Albrecht Neesse, Frances Richards, David Tuveson. How much gemcitabine reaches the target… and does it matter? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr IA13." @default.
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- W2092148745 date "2012-07-15" @default.
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- W2092148745 title "Abstract IA13: How much gemcitabine reaches the target… and does it matter?" @default.
- W2092148745 doi "https://doi.org/10.1158/1538-7445.panca2012-ia13" @default.
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