PharmGKB summary

Alvarellos, Maria L.; Lamba, Jatinder K.; Sangkuhl, Katrin; Thorn, Caroline F.; Wang, Liewei; Klein, Daniel; Altman, Russ B.; Klein, Teri E.

doi:10.1097/fpc.0000000000000086

Cited by 54 publications

(26 citation statements)

References 58 publications

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“…The gemcitabine metabolic pathway has been well characterized (Alvarellos et al, 2014), however the critical genes have not been treated as an ensemble in conferring resistance (see Supplementary Table 14 for interpretation of the MFA results for all genes). The MFA analyses indicated gemcitabine genes predominately contribute to drug resistance through overexpression.…”

Section: Discussionmentioning

confidence: 99%

Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning

et al. 2015

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GemcitabineResistance Drug sensitivity Genomic profiles Breast cancer A B S T R A C TIncreasingly, the effectiveness of adjuvant chemotherapy agents for breast cancer has been related to changes in the genomic profile of tumors. We investigated correspondence between growth inhibitory concentrations of paclitaxel and gemcitabine (GI50) and gene copy number, mutation, and expression first in breast cancer cell lines and then in patients.Genes encoding direct targets of these drugs, metabolizing enzymes, transporters, and those previously associated with chemoresistance to paclitaxel (n ¼ 31 genes) or gemcitabine (n ¼ 18) were analyzed. A multi-factorial, principal component analysis (MFA) indicated expression was the strongest indicator of sensitivity for paclitaxel, and copy number and expression were informative for gemcitabine. The factors were combined using support vector machines (SVM). Expression of 15 genes (ABCC10, BCL2, BCL2L1, BIRC5, BMF, FGF2, FN1, MAP4, MAPT, NFKB2, SLCO1B3, TLR6, TMEM243, TWIST1, and CSAG2) predicted cell line sensitivity to paclitaxel with 82% accuracy. Copy number profiles of 3 genes (ABCC10, NT5C, TYMS ) together with expression of 7 genes (ABCB1, ABCC10, CMPK1, DCTD, NME1, RRM1, RRM2B), predicted gemcitabine response with 85% accuracy. Expression and copy number studies of two independent sets of patients with known responses were then analyzed with these models.These included tumor blocks from 21 patients that were treated with both paclitaxel and gemcitabine, and 319 patients on paclitaxel and anthracycline therapy. A new paclitaxel SVM was derived from an 11-gene subset since data for 4 of the original genes was * Corresponding author.E-mail address: progan@uwo.ca (P.K. Rogan).

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Section: Discussionmentioning

confidence: 99%

Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning

et al. 2015

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“…Their diffusion away from the PLOS ONE blood vessels will be in competition with their uptake and entrapment by tumor cells. For gemcitabine, uptake is through nucleoside transporters [20,21] followed by phosphorylation by deoxycytidine kinase, which traps the drug within the cell. Capecitabine is metabolized to 5-FU-the final step occurring inside the tumor-and 5-FU is converted to a phosphorylated metabolite in one of two ways: through direct phosphorylation to fluorouridine monophosphate via orotate phosphoribosyl transferase and in a two-step reaction to fluorodeoxyuridine monophosphate.…”

Section: Plos Onementioning

confidence: 99%

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma

et al. 2020

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To develop a technique to compare the intra-tumoral distribution of the drug gemcitabine, its surrogate [ 18 F]-fluoroarabinocytosine ([ 18 F]-FAC) and related chemotherapeutics 5-FU and capecitabine in a pre-clinical model of pancreatic ductal adenocarcinoma (PDAC). Experimental design Using a KPC-organoid derived model of PDAC, we obtained autoradiographic images of the tumor distribution of, [ 14 C]-gemcitabine, [ 14 C]-5-FU, [ 3 H]-capecitabine. These were compared indirectly by co-administering [ 18 F]-FAC, a close analog of gemcitabine with a proven equivalent intra-tumor distribution. The short half-life of 18 F allows for clean separation of 3 H/ 14 C labeled drugs in specimens by dual isotope digital autoradiography. Autoradiographic images of [ 14 C]-gemcitabine, [ 3 H]-capecitabine and [ 14 C]-5-FU were each correlated to [ 18 F]-FAC on a pixel-by-pixel basis. The tumor drug penetration was compared using cumulative histograms. Results Gemcitabine distribution correlated strongly with FAC as expected. 5-FU also gave a similar microdistribution to that of FAC, whereas no correlation was found between capecitabine or its metabolic products and FAC distribution. Accumulation of Gemcitabine and 5-FU was lower in hypoxic regions of the tumor, whereas no such correlation was observed for capecitabine and its metabolites.

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“…Intracellularly, GEM is converted into therapeutically active GEM 5′‐diphosphate and 5′‐triphosphate metabolites by sequential phosphorylation with multiple kinases. The initial step, also the rate‐limiting step, is the monophosphorylation of GEM, which is catalyzed by deoxycytidine kinase . Enzyme–substrate recognition between deoxycytidine kinase and GEM relies on hydrogen bonding between the 4‐NH 2 group of the nucleobase cytosine and Asp133, located in the active site of the enzyme .…”

Section: Resultsmentioning

confidence: 99%

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

et al. 2019

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The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate‐ester‐caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2‐activatable GEM (A‐GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A‐GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A‐GEM treatment compared with that following GEM treatment.

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PharmGKB summary

Cited by 54 publications

References 58 publications

Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning

Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

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