title: In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia.
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.
authors: Department of Pediatric Hemato-Oncology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Irene
authors: I
authors: Homminga
authors: C Michel
authors: CM
authors: Zwaan
authors: Chantal Y
authors: CY
authors: Manz
authors: Cynthia
authors: C
authors: Parker
authors: Shanta
authors: S
authors: Bantia
authors: Willem Korstiaan
authors: WK
authors: Smits
authors: Fiona
authors: F
authors: Higginbotham
authors: Rob
authors: R
authors: Pieters
authors: Jules P P
authors: JP
authors: Meijerink
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002648:Child; D003842:Deoxycytidine Kinase / Q000235:genetics; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics; D033722:Equilibrative-Nucleoside Transporter 2 / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054403:Leukemia, Prolymphocytic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use*; D011684:Purine Nucleosides / Q000627:therapeutic use*; D011687:Purines / Q000378:metabolism; D011744:Pyrimidinones / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D003848:Deoxyguanine Nucleotides; D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D011355:Prodrugs; D011684:Purine Nucleosides; D011687:Purines; D011744:Pyrimidinones; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C438649:SLC29A1 protein, human; C438654:SLC29A2 protein, human; C028771:9-arabinofuranosylguanine; C113101:forodesine; C104457:nelarabine; C029603:deoxyguanosine triphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase; D003842:Deoxycytidine Kinase