Absence of mutations in the deoxycytidine kinase (dCK) gene in patients with relapsed and/or refractory acute myeloid leukemia (AML)

Heuvel‐Eibrink, MM van den; Wiemer, Erik A.C.; Kuijpers, Marianne A.; Pieters, Rob; Sonneveld, Pieter

doi:10.1038/sj.leu.2402112

Cited by 27 publications

(14 citation statements)

References 6 publications

(12 reference statements)

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“…Mutational inactivation of dCK is, however, not thought to confer resistance to AraC in patients with AML because mutations in the dCK gene are rarely found in patients with refractory or relapsed AML. 19,20 In a recent study we demonstrated 4 different alternatively spliced dCK variants in coexpression with wt dCK in purified leukemic blasts from 7 of 12 patients with resistant AML and in 6 of 12 PHA-stimulated T cells generated from patients with resistant AML. These 4 alternatively spliced dCK forms code for dCK proteins with lower molecular weights and are shown to be inactive in vitro.…”

Section: Discussionmentioning

confidence: 94%

“…[12][13][14][15][16][17][18] This leads to the inability of AraC to incorporate into DNA. Mutational inactivation of dCK in patients with refractory or relapsed AML is, however, rarely observed, [19][20][21] indicating that a different resistance mechanism might be responsible for AraC resistance in vivo. Recently, we demonstrated the expression of alternatively spliced dCK fragments in coexpression with wild-type (wt) dCK in purified leukemic blasts and phytohemagglutinin (PHA)-stimulated T cells from patients with resistant AML.…”

Section: Introductionmentioning

confidence: 99%

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Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells

Veuger

Heemskerk

Honders

et al. 2002

Blood

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Development of resistance to cytarabine (AraC) is a major problem in the treatment of patients with acute myeloid leukemia (AML). Inactivation of deoxycytidine kinase (dCK) plays an important role in AraC resistance in vitro. We have identified inactive, alternatively spliced dCK forms in leukemic blasts from patients with resistant AML. Because these dCKspliced variants were only detectable in resistant AML, it was hypothesized that they might play a role in AraC resistance in vivo. In the current study, the biologic role of the alternatively spliced dCK forms in AraC resistance was further investi-

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells

Veuger

Heemskerk

Honders

et al. 2002

Blood

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“…[20][21][22][23] In this connection, it is noteworthy that mutational inactivation of dCK in patients with refractory or relapsed acute myeloid leukemia is rarely observed. 33,34) Though the mechanisms of dCK inhibition remain to be fully elucidated, we consider that decreased gemcitabine metabolism to its active form by dCK inactivation is one of the mechanisms of development of acquired resistance.…”

Section: Discussionmentioning

confidence: 99%

Determinants of sensitivity and resistance to gemcitabine: The roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non‐small cell lung cancer

et al. 2004

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Gemcitabine is one of the most commonly used agents for lung cancer chemotherapy, but the determinants of sensitivity and/or resistance to this agent are not yet fully understood. In this study we used quantitative RT-PCR to examine the expression levels of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK) genes in non-small cell lung cancer (NSCLC) cell lines in relation to sensitivity and resistance to gemcitabine. The basal expression levels of hENT1 were significantly correlated with the IC 50 values for gemcitabine (r = = = =-0.6769, P = = = =0.0005), whereas dCK expression levels were not. In a highly gemcitabinesensitive cell line, NCI-H23, the sensitivity to gemcitabine was inhibited by nitrobenzylmercaptopurine ribonucleoside (NBMPR), an inhibitor of hENT1, without significant modulation of hENT1 expression. These data suggest that hENT1 is associated with gemcitabine sensitivity in lung cancer. We also continuously exposed NCI-H23 cells to gemcitabine and subsequently established the drug-resistant clone H23/GEM-R, which showed a significant decrease of dCK expression; however, hENT1 expression was not altered in the continuously exposed sublines or in the resistant clone. We conclude that increased hENT1 expression is a determinant of gemcitabine sensitivity, while decreased dCK expression is associated with acquired resistance to gemcitabine in NSCLC cells. Thus, hENT1 and dCK might be useful as predictive markers for efficacy of gemcitabine therapy in NSCLC. (Cancer Sci 2004; 95: 753-757) ung cancer is one of the most common malignancies worldwide 1) and remains the leading cause of cancer-related deaths in Western countries.2) Several randomized clinical trials and meta-analyses have demonstrated that survival in patients with advanced stage III or IV non-small cell lung cancer (NSCLC) can be slightly but significantly prolonged with chemotherapy.3, 4) Several new anticancer agents have recently been shown to have encouraging activity against NSCLC, and a recent randomized study provided data supportive of the efficacy and safety of a regimen including gemcitabine. 5)

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“…However, mutational inactivation of dCK is not thought to confer resistance to ara-C in AML patients because mutations in the dCK gene are rarely found in refractory or relapsed AML patients. 153,154 Alternatively, inactivation of dCK by the formation of alternatively spliced dCK transcripts has been demonstrated in seven out of 12 patients with resistant AML compared to one out of 10 patients with sensitive AML. 155 This mechanism is probably a cause of therapy failure in patients with resistant AML.…”

Section: Jg Maring Et Almentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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Absence of mutations in the deoxycytidine kinase (dCK) gene in patients with relapsed and/or refractory acute myeloid leukemia (AML)

Cited by 27 publications

References 6 publications

Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells

Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells

Determinants of sensitivity and resistance to gemcitabine: The roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non‐small cell lung cancer

Genetic factors influencing Pyrimidine-antagonist chemotherapy

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