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Gastrointestinal cancer
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Justin S Waters, David Cunningham
This drug is absorbed unchanged from the gastrointestinal tract. It is primarily metabolized in the liver by the enzyme carboxylesterase to 5′-deoxy-5-fluorocytidine (5′-DFCR), which is then converted to 5′-deoxy-5-fluorouracil (5′-DFUR) by cytidine deaminase, principally located in the liver and in tumour tissue. The final conversion to 5-fluorouracil is catalysed by the enzyme pyrimidine nucleoside phosphorylase, which is present at higher levels in tumour than in normal tissue. After oral administration, peak plasma levels of capecitabine and its two main metabolites, 5′-DFCR and 5′-DFUR, are reached within 30–90 min, after which concentrations decline exponentially with a half life of about 30–60 min. Plasma levels of 5-fluorouracil are approximately 30 times lower than those produced by an intravenous bolus of 5-fluorouracil.
Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues
Published in Expert Opinion on Drug Discovery, 2022
Sebastian C. Cosgrove, Gavin J. Miller
In addition to the use of purely chemical approaches to synthesize nucleoside analogues, the capability of using enzymes is also not a recent landmark; such syntheses were established more than 50 years ago, particularly for 2’-deoxy systems using thymidine phosphorylase (TP) or pyrimidine nucleoside phosphorylase (PNP) [3]. Typically, simple modifications within the pentose component (e.g. d-arabino vsd-ribo stereochemistry) were effected, alongside changes to the heterocyclic base (e.g. 5-substituted pyrimidines [4]). However, as pharmacophore space surrounding the nucleoside analogue chemotype increased in complexity (compare remdesivir with cytarabine), so thus did the requirements placed upon strategies utilizing enzymes for their synthesis.
The microbiome of pancreatic cancer: from molecular diagnostics to new therapeutic approaches to overcome chemoresistance caused by metabolic inactivation of gemcitabine
Published in Expert Review of Molecular Diagnostics, 2018
Arthur T.F. Choy, Ilaria Carnevale, Stefano Coppola, Laura L. Meijer, Geert Kazemier, Egija Zaura, Dongmei Deng, Elisa Giovannetti
Further studies should take into consideration the pyrimidine nucleoside phosphorylase enzyme (PyNP). This enzyme is reported to catabolize the natural pyrimidine nucleosides uridine, 2ʹ-deoxyuridine and thymidine. These three molecules play a role in the inhibition of Mycoplasma-associated deamination of dFdC [21]. Hence, it would be interesting to consider the role of PyNP in gemcitabine metabolism in Mycoplasma-infected pancreatic cancer tissues.
The role of the microbiome in drug resistance in gastrointestinal cancers
Published in Expert Review of Anticancer Therapy, 2021
Ingrid Garajová, Rita Balsano, Heling Wang, Francesco Leonardi, Elisa Giovannetti, Dongmei Deng, Godefridus J. Peters
Gemcitabine is a pyrimidine nucleoside antimetabolite frequently used in the treatment of pancreatic or biliary tract cancer [78]. Several studies have demonstrated that microbiota reduces the efficacy of gemcitabine. In particular, different bacterial species within pancreatic cancer tissues and microenvironment has been described to be responsible for gemcitabine resistance [79]. This intratumor microbiota can produce bacterial cytidine deaminase (CDD), an enzyme that metabolizes gemcitabine into its inactive metabolite 2ʹ,2'-difluoro-2ʹ-deoxyuridine (dFdU), primarily by the long form of CDD (CDDL). One of the most common bacterial class found in pancreatic cancer tissue is Gammaproteobacteria. Gammaproteobacteria, which can express CDDL leading to inefficacy of gemcitabine. The resistance to gemcitabine could be neutralized by some antibiotics such as ciprofloxacin [79,80]. Moreover, Vande Voorde et al. [3] demonstrated that the Mycoplasma hyorhinis -infected tumor cells were considerably less sensitive to gemcitabine than the non-infected cells, as was also found by Geller et al [79], both in in vitro (using RKO colorectal cancer cells) and in vivo (by using infected MC-26 tumors) systems. These authors also demonstrated an increased degradation of gemcitabine to its inactive metabolite dFdU. The reduced sensitivity is attributed to the breakdown of gemcitabine by mycoplasma CDD [3]. Although gemcitabine is not a substrate for pyrimidine nucleoside phosphorylase, a high mycoplasma pyrimidine nucleoside phosphorylase was also related to a lower sensitivity to gemcitabine, which can be explained by degradation of normal nucleosides so that they cannot compete with gemcitabine for deamination by CDD. Other gut bacterial species such as F. nucleatum or E. coli have been reported to induce gemcitabine resistance as well, but the molecular mechanisms underlying these effects are largely unknown [79–81].