9-beta-d-arabinofuranosylguanosine-5--triphosphate and Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma

The safety, tolerability, pharmacokinetics and efficacy of nelarabine were evaluated in adult and pediatric patients with relapsed or refractory T-ALL/T-LBL. Adult patients received nelarabine i.v. over 2 hours on days 1, 3 and 5 in every 21 days, and pediatric patients received this regimen over 1 hour for 5 consecutive days in every 21 days. Safety was evaluated in 7 adult and 6 pediatric patients. Adverse events (AEs) were reported in all patients. Most frequently reported AEs included somnolence and nausea in adult patients and leukopenia and lymphocytopenia in pediatric patients. Five grade 3/4 AEs were reported in both adult and pediatric patients, most of which were hematologic events. There were no dose-limiting toxicities. Efficacy was evaluated in 7 adult and 4 pediatric patients. Complete response was noted in 1 adult and 2 pediatric patients. Higher intracellular ara-GTP concentrations were suggested to be associated with efficacy. Japanese adult and pediatric patients with T-ALL/T-LBL well tolerated nelarabine treatment, warranting further investigation.

Topics: Adolescent; Adult; Arabinonucleosides; Arabinonucleotides; Child; Drug Administration Schedule; Female; Guanosine Triphosphate; Humans; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; T-Lymphocytes; Treatment Outcome; Young Adult

The deoxyguanosine (GdR) analog guanine-ß-d-arabinofuranoside (araG) has a specific toxicity for T lymphocytes. Also GdR is toxic for T lymphocytes, provided its degradation by purine nucleoside phosphorylase (PNP) is prevented, by genetic loss of PNP or by enzyme inhibitors. The toxicity of both nucleosides requires their phosphorylation to triphosphates, indicating involvement of DNA replication. In cultured cells we found by isotope-flow experiments with labeled araG a rapid accumulation and turnover of araG phosphates regulated by cytosolic and mitochondrial kinases and deoxynucleotidases. At equilibrium their partition between cytosol and mitochondria depended on the substrate saturation kinetics and cellular abundance of the kinases leading to higher araGTP concentrations in mitochondria. dGTP interfered with the allosteric regulation of ribonucleotide reduction, led to highly imbalanced dNTP pools with gradual inhibition of DNA synthesis and cell-cycle arrest at the G1-S boundary. AraGTP had no effect on ribonucleotide reduction. AraG was in minute amounts incorporated into nuclear DNA and stopped DNA synthesis arresting cells in S-phase. Both nucleosides eventually induced caspases and led to apoptosis. We used high, clinically relevant concentrations of araG, toxic for nuclear DNA synthesis. Our experiments do not exclude an effect on mitochondrial DNA at low araG concentrations when phosphorylation occurs mainly in mitochondria.

Topics: Animals; Apoptosis; Arabinonucleosides; Arabinonucleotides; Biocatalysis; Caspases; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Cytosol; Deoxycytidine Kinase; Deoxyguanine Nucleotides; Deoxyguanosine; Deoxyribonucleotides; DNA; DNA Replication; Fibroblasts; G1 Phase; Guanosine Triphosphate; Humans; Hypoxanthine Phosphoribosyltransferase; Kinetics; Mitochondria; Phosphotransferases (Alcohol Group Acceptor); Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Purine-Nucleoside Phosphorylase; S Phase