guanosine-triphosphate and Precursor-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

A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate.. Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m(2)) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg/m(2)) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days.. Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P =.001) in responders (890 micromol/L, n = 6) and nonresponders (30 micromol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27).. Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Arabinonucleotides; Biomarkers; Female; Guanosine Triphosphate; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Prolymphocytic; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Treatment Outcome; Vidarabine

The 21-kD protein Ras of the low-molecular-weight GTP-binding (LMWG) family plays an important role in transduction of extracellular signals. Ras functions as a 'molecular switch' in transduction of signals from the membrane receptors of many growth factors, cytokines, and other second messengers to the cell nucleus. Numerous studies have shown that in multiple malignant tumors and hematopoietic malignancies, faulty signal transduction via the Ras pathway plays a key role in tumorigenesis. In this work, a non-radioactive assay was used to quantify Ras activity in hematologic malignancies. Ras activation was measured in six different cell lines and 24 patient samples, and sequence analysis of N- and K-ras was performed. The 24 patient samples comprised of seven acute myelogenous leukemia (AML) samples, five acute lymphocytic leukemia (ALL) samples, four myeloproliferative disease (MPD) samples, four lymphoma samples, four juvenile myelomonocytic leukemia (JMML) samples, and WBC from a healthy donor. The purpose of this study was to compare Ras activity determined by percentage of Ras-GTP with the mutational status of the Ras gene in the hematopoietic cells of the patients. Mutation analysis revealed ras mutations in two of the seven AML samples, one in codon 12 and one in codon 61; ras mutations were also found in two of the four JMML samples, and in one of the four lymphoma samples (codon 12). We found a mean Ras activation of 23.1% in cell lines with known constitutively activating ras mutations, which was significantly different from cell lines with ras wildtype sequence (Ras activation of 4.8%). Two of the five activating ras mutations in the patient samples correlated with increased Ras activation. In the other three samples, Ras was probably activated through "upstream" or "downstream" mechanisms.

Topics: DNA Mutational Analysis; Guanosine Diphosphate; Guanosine Triphosphate; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Juvenile; Lymphoma; Mutation; Myeloproliferative Disorders; Oncogenes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; ras Proteins; Signal Transduction; Tumor Cells, Cultured

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 micromol*h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 micromol*h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P =.007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P =.043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Asparaginase; Biological Availability; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; DNA Adducts; Erythrocytes; Female; Guanosine Triphosphate; Humans; Infant; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Proportional Hazards Models; Recurrence; Thionucleotides; Treatment Outcome; Vincristine

CI-972 (2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2- d]pyrimidin-4-one monohydrochloride, monohydrate) is a competitive inhibitor of PNPase (E.C. 2.4.2.1., Ki = 0.83 microM) entering clinical trials as a T cell-selective immunosuppressive agent. Neither CI-972 (less than or equal to 50 microM) nor dGuo (less than or equal to 10 microM) inhibited [3H]Thd uptake by human MOLT-4 (T cell) or MGL-8 (B cell) lymphoblasts, but in the presence of 10 microM dGuo, the IC50 for CI-972 decreased to 3.0 microM for MOLT-4 but remained at greater than 50 microM for MGL-8. Inhibition of MOLT-4 growth was associated with an increase in dGTP that was dependent on CI-972 concentration and inhibited by 2'-deoxycytidine. Growth could not be restored by hypoxanthine or adenine. No alterations in GTP pools were noted in MOLT-4, and neither GTP nor dGTP were altered in MGL-8.

Topics: Adenine; Cell Division; Deoxycytidine; Deoxyguanine Nucleotides; DNA Replication; Guanosine Triphosphate; Humans; Hypoxanthine; Hypoxanthines; Kinetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine-Nucleoside Phosphorylase; Pyrimidines; T-Lymphocytes; Thiophenes

Arabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate, resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia. In this report, we demonstrate that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 microM araG for 18 hr, up to 6 logs of clonogenic T cells could be eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We discuss the use of this agent in ex vivo elimination of residual malignant T cells from marrow of patients requiring myeloablative chemotherapy with autologous bone marrow rescue.

Topics: Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Bone Marrow Purging; Cell Death; Cell Division; Cell Separation; Clone Cells; Erythroid Precursor Cells; Guanosine Triphosphate; Humans; Leukemia-Lymphoma, Adult T-Cell; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tumor Cells, Cultured