Role of Deoxycytidine Kinase (dCK), Thymidine Kinase 2 (TK2), and Deoxycytidine Deaminase (dCDA) in the Antitumor Activity of Gemcitabine (dFdC)

Kroep, Judith R.; Moorsel, C.J.A. van; Veerman, G.; Voorn, D.A.; Schultz, Richard M.; Worzalla, John F.; Tanzer, Lee R.; Merriman, Ronald L.; Pinedo, H.M.; Peters, Godefridus J.

doi:10.1007/978-1-4615-5381-6_127

Cited by 26 publications

(16 citation statements)

References 9 publications

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“…dFdCTP is an inhibitor of DNA polymerase and may also incorporate into DNA, leading to chain termination, strand breakage and the trapping of topoisomerase I cleavage complexes, which is critical for gemcitabine‐induced apoptosis and cell cycle arrest (8,9). However, in the plasma and liver, gemcitabine can be rapidly inactivated to form a uridine metabolite through the deamination by deoxycytidine deaminase (10,11). Thus, gemcitabine is not effective against hepatocarcinoma by injection.…”

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confidence: 99%

Synthesis and Biological Evaluation of Oral Prodrugs Based on the Structure of Gemcitabine

Zhao

Xue²,

Li³

et al. 2012

Chem Biol Drug Des

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A series of oral prodrugs based on the structure of gemcitabine (2¢,2¢-difluorodeoxycytidine) were synthesised by introducing an amide group at the N4-position of the cytidine ring. A total of 16 compounds were obtained, and their chemical and biological characteristics were evaluated. The halfmaximal inhibitory concentrations (IC 50 s) for most of these compounds were higher than that of gemcitabine in vitro. Compounds 5d and 5m, the representative compounds, were examined in terms of their physiological stabilities and pharmacokinetics. Compound 5d showed good stability in PBS and simulated intestinal fluid, and an analysis of its pharmacokinetics in mice suggested that the introduction of an amide group to gemcitabine could greatly improve its bioavailability. Further evaluation of compound 5d in vivo showed that this compound possesses higher activity than gemcitabine against the growth of HepG2 human hepatocellular carcinoma cells and HCT-116 colon adenocarcinoma cells with less toxicity to animals. These results suggest that compound 5d could be further developed as a potential oral anticancer agent for clinical applications in which gemcitabine is currently used.

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confidence: 99%

Synthesis and Biological Evaluation of Oral Prodrugs Based on the Structure of Gemcitabine

Zhao

Xue²,

Li³

et al. 2012

Chem Biol Drug Des

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“…7 Gemcitabine is activated via phosphorylation to its 5′-monophosphate (dFdCMP) by deoxycytidine kinase (dCK). 8,9 The dFdCMP then undergoes subsequent phosphorylation by intracellular kinases to the diphosphate (dFdCDP) and triphosphate (dFdCTP) forms. 10,11 The dFdCTP can incorporate into DNA and inhibit DNA polymerases by chain termination during DNA replication and repair processes, invariably triggering apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Cytostatic Evaluation of 4-N-Alkanoyl and 4-N-Alkyl Gemcitabine Analogues

Pulido

Sobczak²,

Balzarini

et al. 2013

J. Med. Chem.

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Couplings of gemcitabine with the functionalized carboxylic acids (C9-C13) or reactions of 4-N-tosylgemcitabine with the corresponding alkyl amines afforded 4-N-alkanoyl and 4-N-alkyl gemcitabine derivatives. The analogues with a terminal hydroxyl group on the alkyl chain were efficiently fluorinated under conditions that are compatible with protocols for 18F labeling. The 4-N-alkanoylgemcitabines showed potent cytostatic activities in the low nM range against a panel of tumor cell lines while cytotoxicity of the 4-N-alkylgemcitabines were in the low μM range. The cytotoxicity for the 4-N-alkanoylgemcitabine analogues were reduced approximately by two orders of magnitude in the 2′-deoxycytidine kinase (dCK)-deficient CEM/dCK- cell line whereas cytotoxicity of the 4-N-alkylgemcitabines were only 2-5 times lower. None of the compounds acted as efficient substrates for cytosolic dCK, and therefore, the 4-N-alkanoyl analogues need to be converted first to gemcitabine to display a significant cytostatic potential, while 4-N-alkyl derivatives attain the modest activity without “measurable” conversion to gemcitabine.

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“…In the future, mathematical models of cancer relevant systems will be needed to optimize multi-agent anticancer dose timings [1]. For example, gemcitabine (dFdC, diflourodeoxycytdine) [2] absorption is rate limited by dCK [3,4], dFdC targets RNR [5], dFdC resistance is associated with RNR over expression [6,7], and differential ionizing radiation (IR) sensitivity that dFdC imparts onto mismatch repair (MMR) defective cells may be due to mismatches caused by dNTP pool imbalances caused by RNR inhibition, rather than differential dFdC incorporation into DNA [8], so mathematical models of dNTP supply will be needed to optimize dFdC-IR therapies of MMR defective cancers; MMR defective cancers are significant as they comprise ~10% of colorectal [9], gastric [10], pancreatic [11], urinary [12], gynecologic [13,14] and glioma [15] cancers.…”

Section: Introductionmentioning

confidence: 99%

Automated mass action model space generation and analysis methods for two-reactant combinatorially complex equilibriums: An analysis of ATP-induced ribonucleotide reductase R1 hexamerization data

Radivoyevitch

2009

Biology Direct

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BackgroundRibonucleotide reductase is the main control point of dNTP production. It has two subunits, R1, and R2 or p53R2. R1 has 5 possible catalytic site states (empty or filled with 1 of 4 NDPs), 5 possible s-site states (empty or filled with ATP, dATP, dTTP or dGTP), 3 possible a-site states (empty or filled with ATP or dATP), perhaps two possible h-site states (empty or filled with ATP), and all of this is folded into an R1 monomer-dimer-tetramer-hexamer equilibrium where R1 j-mers can be bound by variable numbers of R2 or p53R2 dimers. Trillions of RNR complexes are possible as a result. The problem is to determine which are needed in models to explain available data. This problem is intractable for 10 reactants, but it can be solved for 2 and is here for R1 and ATP.ResultsThousands of ATP-induced R1 hexamerization models with up to three (s, a and h) ATP binding sites per R1 subunit were automatically generated via hypotheses that complete dissociation constants are infinite and/or that binary dissociation constants are equal. To limit the model space size, it was assumed that s-sites are always filled in oligomers and never filled in monomers, and to interpret model terms it was assumed that a-sites fill before h-sites. The models were fitted to published dynamic light scattering data. As the lowest Akaike Information Criterion (AIC) of the 3-parameter models was greater than the lowest of the 2-parameter models, only models with up to 3 parameters were fitted. Models with sums of squared errors less than twice the minimum were then partitioned into two groups: those that contained no occupied h-site terms (508 models) and those that contained at least one (1580 models). Normalized AIC densities of these two groups of models differed significantly in favor of models that did not include an h-site term (Kolmogorov-Smirnov p < 1 × 10-15); consistent with this, 28 of the top 30 models (ranked by AICs) did not include an h-site term and 28/30 > 508/2088 with p < 2 × 10-15. Finally, 99 of the 2088 models did not have any terms with ATP/R1 ratios >1.5, but of the top 30, there were 14 such models (14/30 > 99/2088 with p < 3 × 10-16), i.e. the existence of R1 hexamers with >3 a-sites occupied by ATP is also not supported by this dataset.ConclusionThe analysis presented suggests that three a-sites may not be occupied by ATP in R1 hexamers under the conditions of the data analyzed. If a-sites fill before h-sites, this implies that the dataset analyzed can be explained without the existence of an h-site.ReviewersThis article was reviewed by Ossama Kashlan (nominated by Philip Hahnfeldt), Bin Hu (nominated by William Hlavacek) and Rainer Sachs.

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Role of Deoxycytidine Kinase (dCK), Thymidine Kinase 2 (TK2), and Deoxycytidine Deaminase (dCDA) in the Antitumor Activity of Gemcitabine (dFdC)

Cited by 26 publications

References 9 publications

Synthesis and Biological Evaluation of Oral Prodrugs Based on the Structure of Gemcitabine

Synthesis and Biological Evaluation of Oral Prodrugs Based on the Structure of Gemcitabine

Synthesis and Cytostatic Evaluation of 4-N-Alkanoyl and 4-N-Alkyl Gemcitabine Analogues

Automated mass action model space generation and analysis methods for two-reactant combinatorially complex equilibriums: An analysis of ATP-induced ribonucleotide reductase R1 hexamerization data

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