Abstract
Forodesine and nelarabine (the pro-drug of ara-G) are 2 nucleoside analogues with promising anti-leukemic activity. To better understand which pediatric patients might benefit from forodesine or nelarabine (ara-G) therapy, we investigated the in vitro sensitivity to these drugs in 96 diagnostic pediatric leukemia patient samples and the mRNA expression levels of different enzymes involved in nucleoside metabolism. Forodesine and ara-G cytotoxicities were higher in T-cell acute lymphoblastic leukemia (T-ALL) samples than in B-cell precursor (BCP)-ALL and acute myeloid leukemia (AML) samples. Resistance to forodesine did not preclude ara-G sensitivity and vice versa, indicating that both drugs rely on different resistance mechanisms. Differences in sensitivity could be partly explained by significantly higher accumulation of intracellular dGTP in forodesine-sensitive samples compared with resistant samples, and higher mRNA levels of dGK but not dCK. The mRNA levels of the transporters ENT1 and ENT2 were higher in ara-G-sensitive than -resistant samples. We conclude that especially T-ALL, but also BCP-ALL, pediatric patients may benefit from forodesine or nelarabine (ara-G) treatment.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / therapeutic use*
-
Arabinonucleosides / therapeutic use*
-
Cell Line, Tumor
-
Child
-
Deoxycytidine Kinase / genetics
-
Deoxyguanine Nucleotides / metabolism
-
Drug Resistance, Neoplasm
-
Equilibrative Nucleoside Transporter 1 / genetics
-
Equilibrative-Nucleoside Transporter 2 / genetics
-
Gene Expression
-
Humans
-
In Vitro Techniques
-
Leukemia, Myeloid, Acute / drug therapy*
-
Leukemia, Myeloid, Acute / genetics
-
Leukemia, Myeloid, Acute / metabolism
-
Leukemia, Prolymphocytic, B-Cell / drug therapy*
-
Leukemia, Prolymphocytic, B-Cell / genetics
-
Leukemia, Prolymphocytic, B-Cell / metabolism
-
Phosphotransferases (Alcohol Group Acceptor) / genetics
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
-
Prodrugs / therapeutic use*
-
Purine Nucleosides / therapeutic use*
-
Purines / metabolism
-
Pyrimidinones / therapeutic use*
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
RNA, Neoplasm / genetics
-
RNA, Neoplasm / metabolism
Substances
-
Antineoplastic Agents
-
Arabinonucleosides
-
Deoxyguanine Nucleotides
-
Equilibrative Nucleoside Transporter 1
-
Equilibrative-Nucleoside Transporter 2
-
Prodrugs
-
Purine Nucleosides
-
Purines
-
Pyrimidinones
-
RNA, Messenger
-
RNA, Neoplasm
-
SLC29A1 protein, human
-
SLC29A2 protein, human
-
9-arabinofuranosylguanine
-
forodesine
-
nelarabine
-
deoxyguanosine triphosphate
-
Phosphotransferases (Alcohol Group Acceptor)
-
deoxyguanosine kinase
-
Deoxycytidine Kinase