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.
Subject(s)
Antineoplastic Agents/therapeutic use , Arabinonucleosides/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Prolymphocytic, B-Cell/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prodrugs/therapeutic use , Purine Nucleosides/therapeutic use , Pyrimidinones/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/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Prolymphocytic, B-Cell/genetics , Leukemia, Prolymphocytic, B-Cell/metabolism , Phosphotransferases (Alcohol Group Acceptor)/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Purines/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolismABSTRACT
Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy, characterized by a monoclonal proliferation of malignant cells in the bone marrow. Despite recent advances in treatment strategies, MM remains incurable and new therapeutical targets are needed. Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels. We therefore tested whether forodesine was able to inhibit proliferation and/or induce apoptosis in both murine and human MM cells through a similar pathway. We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis. When investigating the pathways leading to cell cycle arrest and apoptosis, we observed an upregulation of p27, caspase 3, and BIM. We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells. Forodesine might be however potentiating towards other established cytotoxic drugs in MM.
