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: Irene Homminga, C Michel Zwaan, Chantal Y Manz, Cynthia Parker, Shanta Bantia, Willem Korstiaan Smits, Fiona Higginbotham, Rob Pieters, Jules P P Meijerink
• Journal: Blood (Blood) Vol. 118 Issue 8 Pg. 2184-90 (Aug 25 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21730354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, genetics, metabolism)
• Leukemia, Prolymphocytic, B-Cell (drug therapy, genetics, metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (genetics)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism)
• Prodrugs (therapeutic use)
• Purine Nucleosides (therapeutic use)
• Purines (metabolism)
• Pyrimidinones (therapeutic use)
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)