Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression

Cancer Medicine
Meixian HuangKanji Sugita

Abstract

Cytosine arabinoside (Ara-C) is one of the key drugs for the treatment of acute myeloid leukemia. It is also used for consolidation therapy of acute lymphoblastic leukemia (ALL). Ara-C is a deoxyadenosine analog and is phosphorylated to form cytosine arabinoside triphosphate (Ara-CTP) as an active form. In the first step of the metabolic pathway, Ara-C is phosphorylated to Ara-CMP by deoxycytidine kinase (DCK). However, the current cumulative evidence in the association of the Ara-C sensitivity in ALL appears inconclusive. We analyzed various cell lines for the possible involvement of DCK in the sensitivities of B-cell precursor ALL (BCP-ALL) to Ara-C. Higher DCK expression was associated with higher Ara-C sensitivity. DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced marked resistance to Ara-C, but not to vincristine and daunorubicin, indicating the involvement of DCK expression in the Ara-C sensitivity of BCP-ALL. DCK gene silencing due to the hypermethylation of a CpG island and reduced DCK activity due to a nonsynonymous variant allele were not associated with Ara-C sensitivity. Clofarabine is a second-generation deoxyadenosine analog rationally synthesized to improve stabi...Continue Reading

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Citations

Apr 22, 2020·Nucleosides, Nucleotides & Nucleic Acids·Adrian Christopher JaramilloGodefridus J Peters
Jun 10, 2020·Hematological Oncology·Koshi AkahaneTakeshi Inukai
Mar 8, 2020·Cancer Chemotherapy and Pharmacology·Hiroaki GotoShoko Goto
Jul 19, 2018·BMC Biotechnology·Adrián MontañoRocío Benito

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Methods Mentioned

BETA
transfection
xenograft
flow cytometry
PCR

Software Mentioned

Excel
Torrent Suite
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