forodesine and Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma

Forodesine inhibits purine nucleoside phosphorylase, resulting in an accumulation of intracellular dGTP and consequently cell death. 9-β-D-Arabinofuranosylguanine (ara-G) is an active compound of nelarabine that is intracellularly phosphorylated to a triphosphate form, which inhibits DNA synthesis. Both agents show cytotoxicity toward T-cell malignancies. In the present study, we investigated the cytotoxicity of forodesine in vitro using ara-G-resistant leukemia cells.. T-Lymphoblastic leukemia cell line CCRF-CEM and ara-G-resistant CEM variant cell line CEM/ara-G that we had previously established were used.. A growth-inhibition assay demonstrated that CEM cells were insensitive to single-agent forodesine treatment. The cells were also insensitive to deoxyguanosine at a maximal concentration of 10 μM. CEM/ara-G cells were 80-fold more resistant to ara-G than were CEM cells, and the mode of sensitivity to forodesine and deoxyguanosine was similar to that of CEM cells. In the presence of 10 μM deoxyguanosine, forodesine effectively inhibited the growth of CEM cells but not that of CEM/ara-G cells. Flow cytometric analyses showed that combination of forodesine and deoxyguanosine induced apoptosis of CEM cells but not of CEM/ara-G cells. The addition of ara-G did not augment the cytotoxicity of the forodesine/deoxyguanosine combination towards CEM cells or CEM/ara-G cells. The combination index revealed antagonism between forodesine and ara-G. The intracellular production of ara-G triphosphate was reduced in the presence of forodesine.. Nelarabine-resistant CEM/ara-G cells are insensitive to forodesine.

Topics: Antineoplastic Agents; Arabinonucleosides; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; HL-60 Cells; Humans; Lymphoma, B-Cell; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones

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.

Topics: Antineoplastic Agents; Arabinonucleosides; Cell Line, Tumor; Child; Deoxycytidine Kinase; Deoxyguanine Nucleotides; Drug Resistance, Neoplasm; Equilibrative Nucleoside Transporter 1; Equilibrative-Nucleoside Transporter 2; Gene Expression; Humans; In Vitro Techniques; Leukemia, Myeloid, Acute; Leukemia, Prolymphocytic, B-Cell; Phosphotransferases (Alcohol Group Acceptor); Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Purine Nucleosides; Purines; Pyrimidinones; RNA, Messenger; RNA, Neoplasm

This article presents two case studies of patients diagnosed with T-cell acute lymphoblastic leukemia who relapsed following allogeneic hematopoietic stem cell transplantation and were subsequently enrolled in a clinical trial in which they received forodesine hydrochloride, a rationally designed, potent, transition-state inhibitor of purine nucleoside phosphorylase. Forodesine induced complete remission in both patients. Graft-versus-host disease developed subsequently but was treated successfully with conventional immunosuppressive therapy. Both patients remain in complete remission at the most recent follow-up. We hypothesize that forodesine contributed to a primary anti-leukemic cytotoxic effect as well as a secondary immunologic effect by allowing the development of an ongoing graft-versus-leukemia effect in these patients.

Topics: Adult; Antineoplastic Agents; Child, Preschool; Disease-Free Survival; Female; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Male; Neoplasm Recurrence, Local; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones