Pathway Gemcitabine Pathway

Cancer cell
Model non-tissue specific cancer cell displaying genes which may be involved in the gemcitabine pathway.
Gemcitabine Pathway
gemcitabine gemcitabine dctd slc29a2
clickable pathway icons

Description

Introduction
Gemcitabine (2', 2'-difluoro 2'deoxycytidine, dFdC) is a cancer drug of the anti-metabolite class. It is a deoxycytidine analog that interferes with DNA synthesis by incorporating into elongating DNA, and indirectly interferes with DNA replication by inhibiting the nucleoside salvage pathway. Gemcitabine is a "first line treatment" in various types of solid tumors including pancreatic, non-small cell lung cancer (NSCLC), breast cancer, and some blood cancers, such as non-Hodgkin's lymphoma [Article:19514966]. Gemcitabine is administered intravenously, or with injection, and it can be administered alone, or in combination with other antimetabolites such as fluorouracil, DNA damaging agents such as cisplatin, or various other chemotherapeutic agents DailyMed. Although the pharmacokinetic pathway of gemcitabine is similar to other deoxycytidine analogs it has certain attributes that render it a more broadly efficacious anti-metabolite [Article:16807468].

Pharmacokinetics
Gemcitabine is a hydrophilic molecule, and three nucleoside transporters mediate most of its uptake into cells: SLC29A1 SLC28A1, and SLC28A3. Gemcitabine is also a pro-drug that requires serial phosphorylation by multiple kinases to become pharmacologically active. Deoxycytidine kinase (DCK) catalyzes the initial, and rate-limiting monophosphorylation of gemcitabine to gemcitabine monophosphate (dFdCMP). Phosphorylation to gemcitabine di- (dFdCDP) and tri- phosphate (dFdCTP) is catalyzed by UMP/CMP kinase (CMPK1) and nucleoside-diphosphate kinase (NDPK, NME), respectively. The majority (~ 90%) of intracellular gemcitabine is inactivated by deamination by cytidine deaminase (CDA) to form 2'2' difluorodeoxyuridine (dFdU). Additional inactivation steps include deamination of gemcitabine monophosphate by deoxycytidine deaminase (DCTD) and dephosphorylation of dFdCMP by cytosolic 5' nucleotidases (NT5C) [Article:16807468].

Pharmacodynamics
Gemcitabine diphosphate (dFdCDP) depletes a cells deoxyribonucleotide (dNTP) pools via inhibition of ribonucleotide reductase 1 (RRM1). RRM1 is a sub-unit of an enzyme complex that catalyzes the formation of deoxyribonucleotides (dNTPs) from ribonucleotides (rNTPs) through the nucleoside salvage pathway [Articles:2233693, 1732039]. Gemcitabine triphosphate (dFdCTP) integrates into elongating DNA, and prevents base-excision repair by allowing for a native dNTP to be added next to it, which is termed "masked chain termination". This irreparable error leads to inhibition of DNA synthesis, and eventually apoptosis [Articles:7481842, 1718594]. Decreasing dNTP pools increasingly favor gemcitabine uptake, and low concentrations of native deoxycytidines (dCTP) promote DCK activity, and inhibit DCTD activity. The attribute of "self-potentiation" is part of why gemcitabine is so widely used as part of a "first-line" chemotherapy treatment.

Pharmacogenomics
Given the widespread use of gemcitabine, its narrow therapeutic index, and inter-individual variability in patient response it is reasonable to expect that pharmacogenomics could be used to specifically tailor gemcitabine dosage to patients. Small study sizes, heterogeneity of the samples, including of the types and stages of cancers, and differences in chemotherapy make comparing patient responses to gemcitabine between groups very difficult.
Currently, intrinsic and acquired resistance to gemcitabine has been attributed to variation in the expression of genes involved in the transport (SLC29A1, SLC29A2, SLC28A1,SLC28A3), activation (DCK, CMPK1), and inactivation (DCTD, CDA, NT5C) of gemcitabine, as well as its molecular target (RRM1, RRM2, RRM2B). Although gemcitabine is generally well-tolerated, hematological toxicities such as neutropenia are commonly reported. A certain percentage of patients also experience serious, and life-threatening complications after administration of gemcitabine. Decreased activity of the principal inactivating enzyme, CDA, is reported to be associated with toxicity, but further studies are needed to validate these findings [Article:19933910]. Nucleoside diphosphate kinases (NDPKs) are less intensively studied than other genes in the gemcitabine pathway, although there are indications that alterations in their expression may affect gemcitabine resistance and prognoses in some patients [Articles:22325559, 22892044].

No SNPs show consistent associations with any clinically relevant phenotypes, which could be due to one of many factors. Heterogeneity of the patients, including differences in the type of malignancy, the stage of malignancy, the type of combination chemotherapy, and differences in the ethnic background of patients, makes comparing the results between studies very difficult. In addition many studies reported here include less than one hundred patients, so if the effect size of an individual SNP is small, true associations may be missed.

Variability of gene expression, and protein levels of SLC29A1, CDA, and RRM1 present the most compelling associations with patient response to gemcitabine. Two recent meta-analyses (12 studies, that included 875 pancreatic cancer patients, and 16 studies that included 632 pancreatic cancer patients), both concluded that a high level of SLC29A1 protein is prognostic of improved survival outcomes in patients administered gemcitabine compared to patients with low levels of SLC29A1 protein [Articles:24475233, 24152955]. Although more evidence is needed, it appears that low CDA enzymatic activity is a good predictor of whether patients are more likely to experience gemcitabine-associated toxicity [Articles:21625252, 17885621, 15814642, 17194903]. High baseline protein levels of RRM1 are also good predictors of not only whether patients are likely to develop resistance to gemcitabine, but whether they might derive more benefit from forgoing gemcitabine treatment in favor of surgical resection with curative intent [Article:21163702].

In summary, gemcitabine pharmacogenomic studies investigating single nucleotide variants have yielded little in terms of clinically actionable findings. Fortunately, some relevant associations have come from association studies that investigate expression levels, or protein levels of key genes and proteins, respectively, of genes in the pharmacokinetic and pharmacodynamic pathways of gemcitabine. In addition, further research efforts extending beyond the known pharmacodynamic and pharmacokinetic pathways have uncovered additional biology associated with gemcitabine efficacy, and additional genes outside these pathways have already been identified to play a role in gemcitabine response [Articles:19732725, 22590527]. Ultimately, more research is needed to discover clinically relevant single nucleotide variants to improve upon current gemcitabine therapies for cancer patients.

Authors: ML Alvarellos, JK Lamba, K. Sankuhl, CF Thorn, L. Wang, DJ Klein.
Citation:
Alvarellos Maria L, Lamba Jatinder, Sangkuhl Katrin, Thorn Caroline F, Wang Liewei, Klein Daniel J, Altman Russ B, Klein Teri E. "PharmGKB summary: gemcitabine pathway" Pharmacogenetics and genomics (2014).
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History:
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (12)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
DCK DCK dNTPs 12142171, 17595663
gemcitabine monophosphate dFdUMP DCTD 17595663
gemcitabine dFdU CDA 12477049, 16807468, 17595663
RRM1, RRM2, RRM2B RRM1, RRM2, RRM2B gemcitabine diphosphate 21163702
dNDPs dNTPs 17595663
gemcitabine diphosphate gemcitabine triphosphate 17595663
gemcitabine monophosphate gemcitabine NT5C 17595663, 19514966
gemcitabine monophosphate gemcitabine diphosphate CMPK1 17595663
gemcitabine gemcitabine monophosphate DCK 14514691
NDPs dNDPs RRM1, RRM2, RRM2B 17595663, 21163702
dNTPs dNTPs
gemcitabine gemcitabine SLC28A1, SLC28A3, SLC29A1, SLC29A2 10547395, 17345146
gemcitabine triphosphate gemcitabine triphosphate

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