Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5′-nucleotidase II expression ratio in primary acute myeloid leukemia cells

Yamauchi, Takahiro; Negoro, Eiju; Kishi, Shinji; Takagi, Kaname; Yoshida, Akira; Urasaki, Yoshimasa; Iwasaki, Hiromichi; Ueda, Takanori

doi:10.1016/j.bcp.2009.03.011

Cited by 41 publications

(34 citation statements)

References 25 publications

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“…Reduced hENT1 activity, decreased dCK activity, and increased cN-II activity are so far the only markers that have been shown to be clinically significant markers of the therapeutic efficacy of ara-C-based chemotherapy (17)(18)(19)(20). However, not all the mechanisms of resistance to ara-C can be explained by these factors.…”

Section: Introductionmentioning

confidence: 99%

Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses

Yamauchi

2011

Int J Oncol

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Abstract. Cytarabine (ara-C) is the key drug for treatment of acute myeloid leukemia. Since intracellular cytarabine triphosphate (ara-CTP) is an active metabolite of ara-C, factors that reduce the amount of ara-CTP are known to induce drug resistance. However, these factors do not fully explain the development of resistance to ara-C. The present study was conducted to search for new candidate ara-C resistance factors, including those that are unrelated to ara-CTP production.

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Section: Introductionmentioning

confidence: 99%

Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses

Yamauchi

2011

Int J Oncol

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“…5, A and B). The diagnostic discriminator, assuming that generation of Ara-CTP in AML cells is the major cause of cell death (4,5 ), is the maximal difference in light output between the IPTG (LI) and IPTG ϩ AP (LIP) curves that are shown in Fig. 5E.…”

Section: Resultsmentioning

confidence: 99%

“…The nucleoside analog Ara-C is one of the most active single anticancer agents and is the main drug of chemotherapy for AML (3,4 ). In vivo, Ara-C is trans-ported into the cell via the human equilibrium nucleoside transporter (hENT1) and is rapidly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate form, cytosine arabinoside monophosphate (Ara-CMP), which is further phosphorylated by nucleoside kinases and finally to the triphosphorylated and active form, cytosine arabinoside triphosphate (Ara-CTP).…”

mentioning

confidence: 99%

“…Drug inactivation can result from Ara-CMP conversion into Ara-uracil by cytidine deaminase (cdd), or from dephosphorylation of Ara-CMP by cytoplasmic nucleotidase (3 ). The antiproliferative and cytotoxic effects of Ara-CTP are largely due to its ability to interfere with DNA polymerase and its incorporation into DNA strands leading to chain termination and DNA synthesis arrest (4 ).…”

mentioning

confidence: 99%

“…Intracellular concentrations of Ara-CTP are reported to correlate with response to Ara-C therapy (4 ). In vitro assessment of Ara-C efficacy has previously involved measurement of cell death, assessed by colony forming units-blast clonogenic assays (7 ).…”

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confidence: 99%

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A Bioluminescent Microbial Biosensor for In Vitro Pretreatment Assessment of Cytarabine Efficacy in Leukemia

et al. 2010

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BACKGROUND The nucleoside analog cytarabine (Ara-C [cytosine arabinoside]) is the key agent for treating acute myeloid leukemia (AML); however, up to 30% of patients fail to respond to treatment. Screening of patient blood samples to determine drug response before commencement of treatment is needed. This project aimed to construct and evaluate a self-bioluminescent reporter strain of Escherichia coli for use as an Ara-C biosensor and to design an in vitro assay to predict Ara-C response in clinical samples. METHODS We used transposition mutagenesis to create a cytidine deaminase (cdd)-deficient mutant of E. coli MG1655 that responded to Ara-C. The strain was transformed with the luxCDABE operon and used as a whole-cell biosensor for development an 8-h assay to determine Ara-C uptake and phosphorylation by leukemic cells. RESULTS Intracellular concentrations of 0.025 μmol/L phosphorylated Ara-C were detected by significantly increased light output (P < 0.05) from the bacterial biosensor. Results using AML cell lines with known response to Ara-C showed close correlation between the 8-h assay and a 3-day cytotoxicity test for Ara-C cell killing. In retrospective tests with 24 clinical samples of bone marrow or peripheral blood, the biosensor-based assay predicted leukemic cell response to Ara-C within 8 h. CONCLUSIONS The biosensor-based assay may offer a predictor for evaluating the sensitivity of leukemic cells to Ara-C before patients undergo chemotherapy and allow customized treatment of drug-sensitive patients with reduced Ara-C dose levels. The 8-h assay monitors intracellular Ara-CTP (cytosine arabinoside triphosphate) levels and, if fully validated, may be suitable for use in clinical settings.

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Antimetabolites

2017

Anticancer Therapeutics

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Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5′-nucleotidase II expression ratio in primary acute myeloid leukemia cells

Cited by 41 publications

References 25 publications

Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses

Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses

A Bioluminescent Microbial Biosensor for In Vitro Pretreatment Assessment of Cytarabine Efficacy in Leukemia

Antimetabolites

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