thioinosine and Acute-Disease

Chemotherapy remains the major treatment modality in childhood acute nonlymphocytic leukemia (ANLL). Current remission induction rates range from 60% to 80%; but even with the improved rate of response to therapy, the median duration of remission has seldom exceeded 1 year. On the other hand, an increasing number of children with ANLL who were treated with intensive induction and maintenance chemotherapy regimens for a prescribed period followed by discontinuation of therapy are remaining in remission. The evolution of present-day chemotherapy approaches to childhood ANLL are reviewed in this article.

Topics: Acute Disease; Adolescent; Adult; Asparaginase; Azauridine; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Prednisone; Thioguanine; Thioinosine; Vincristine

Despite advances in oncology drug development, most commonly used cancer therapeutics exhibit serious adverse effects. Often the toxicities of chemotherapeutics are due to the induction of significant DNA damage that is necessary for their ability to kill cancer cells. In some clinical situations, the direct induction of significant cytotoxicity is not a requirement to meet clinical goals. For example, differentiation, growth arrest, and/or senescence is a valuable outcome in some cases. In fact, in the case of acute myeloid leukemia (AML), the use of the differentiation agent all-trans-retinoic acid (ATRA) has revolutionized the therapy for a subset of leukemia patients and led to a dramatic survival improvement. Remarkably, this therapeutic approach is possible even in many elderly patients, who would not be able to tolerate therapy with traditional cytotoxic chemotherapy. Because of the success of ATRA, there is widespread interest in identifying differentiation strategies that may be effective for the 90-95% of AML patients who do not clinically respond to ATRA. Utilizing an AML differentiation agent that is in development, we found that AML differentiation can be induced through ATP depletion and the subsequent activation of DNA damage signaling through an ATR/Chk1-dependent and p53-independent pathway. This study not only reveals mechanisms of AML differentiation but also suggests that further investigation is warranted to investigate the potential clinical use of low dose chemotherapeutics to induce differentiation instead of cytotoxicity. This therapeutic approach may be of particular benefit to patients, such as elderly AML patients, who often cannot tolerate traditional AML chemotherapy.

Topics: Acute Disease; Adenosine; Adenosine Triphosphate; Antibiotics, Antineoplastic; Ataxia Telangiectasia Mutated Proteins; Blotting, Western; Caffeine; Cell Cycle Proteins; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; Comet Assay; DNA Damage; Doxorubicin; HEK293 Cells; Humans; Leukemia, Myeloid; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction; Staurosporine; Thioinosine; Tumor Suppressor Protein p53

Accumulation of cytosine arabinoside triphosphate (araCTP) from a range of cytosine arabinoside (araC) concentrations (1-50 microM) was measured during incubations of leukemic cells freshly isolated from patients with acute leukemia. In all but one patient, increments in extracellular araC above 10 microM did not increase intracellular araCTP levels. This maximal level of araCTP accumulation ranged from 254 to 1607 pmol/10(7) cells attained after 1 h incubation and did not correlate with either the number of nucleoside transporters on the cell membrane or the Vmax of araC phosphorylation in cell free extracts. Extremely low araCTP accumulation (103 pmol/10(7) cells/h at 50 microM araC) was observed in an AML patient with the unusual finding of micromyeloblasts. These cells also had very low numbers of nucleoside transport sites (less than 500 sites/cell) and were mitotically inactive. The unique feature of the myeloblasts from this patient was that intracellular araCTP accumulation showed a linear dependence on extracellular araC up to 50 microM with no evidence of saturation.

Topics: Acute Disease; Arabinofuranosylcytosine Triphosphate; Arabinonucleotides; Binding Sites; Biological Transport; Cell Membrane; Cytarabine; Deoxycytidine Kinase; Extracellular Space; Humans; Leukemia; Lymphocytes; Nucleosides; Phosphorylation; Thioinosine; Tumor Cells, Cultured

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Inhibitors of adenylate kinase, 5'nucleotidase, adenosine translocase and adenosine deaminase were studied. Following 30 minutes of ischemia, only hearts infused with alpha, beta, methylene adenosine diphosphate (5' nucleotidase inhibitor) recovered significantly better ventricular function than control (p less than 0.05), but all hearts had increased adenosine triphosphate regeneration (p less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites was not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion.

Topics: 5'-Nucleotidase; Acute Disease; Adenine; Adenine Nucleotides; Adenosine; Adenosine Deaminase Inhibitors; Adenosine Diphosphate; Adenosine Triphosphate; Adenylate Kinase; Animals; Coronary Circulation; Coronary Disease; Dinucleoside Phosphates; Male; Nucleotidases; Rats; Rats, Inbred Strains; Thioinosine

The membrane transport of cytosine arabinoside (araC) has been studied in blasts freshly isolated from a variety of acute leukaemias. The major fraction of araC influx was facilitated and this fraction was 80-87% at l microM araC and 68-80% at 200 microM araC. Competitive kinetics were observed between araC and deoxycytidine for entry into leukaemic blasts and, moreover, araC influx was blocked by phloretin, a broad-spectrum inhibitor of facilitated transport systems. Kinetic analysis of facilitated araC influx gave KmS which varied over a 10-fold range between patients and which were positively correlated to the Vmax. Nucleoside influx Vmax also varied over an 80-fold range between individuals, although the mean araC transport was 4-fold greater in myeloblasts than in lymphoblasts. Larger transport of araC may explain the greater sensitivity of acute myeloid leukaemia to this drug.

Topics: Acute Disease; Adolescent; Adult; Aged; Biological Transport; Cell Membrane; Child; Child, Preschool; Cytarabine; Deoxycytidine; Humans; Infant; Kinetics; Leukemia; Leukocytes; Middle Aged; Phloretin; Thioinosine

Although cytosine arabinoside (araC) can induce a remission in a majority of patients presenting with acute myeloblastic leukemia (AML), a minority fail to respond and moreover the drug has less effect in acute lymphoblastic leukemia (ALL). The carrier-mediated influx of araC into purified blasts from patients with AML, ALL, and acute undifferentiated leukemia (AUL) has been compared to that of normal lymphocytes and polymorphs. Blasts showed a larger mediated influx of araC than mature cells, since mean influxes for myeloblasts and lymphoblasts were 6- and 2.3-fold greater than polymorphs and lymphocytes, respectively. Also, the mean influx for myeloblasts was fourfold greater than the mean for lymphoblasts. The number of nucleoside transport sites was estimated for each cell type by measuring the equilibrium binding of [(3)H]nitrobenzylthioinosine (NBMPR), which inhibits nucleoside fluxes by binding with high affinity to specific sites on the transport mechanism. The mean binding site numbers for myeloblasts and lymphoblasts were 5- and 2.8-fold greater, respectively, than for the mature cells of the same maturation series. The mean number of NBMPR binding sites for myeloblasts was fourfold greater than for lymphoblasts. Patients with AUL were heterogeneous since blasts from some gave values within the myeloblastic range and others within the lymphoblastic range. The araC influx correlated closely with the number of NBMPR binding sites measured in the same cells on the same day. Transport parameters were measured on blasts from 15 patients with AML or AUL who were then treated with standard induction therapy containing araC. Eight patients entered complete remission, while seven failed therapy, among whom were the three patients with the lowest araC influx (<0.4 pmol/10(7) cells per min) and NBMPR binding (<3,000 sites/cell) for the treated group. In summary, myeloblasts have both higher araC transport rates and more nucleoside transport sites than lymphoblasts and this factor may contribute to the greater sensitivity of AML to this drug. AraC transport varied >10-fold between leukemic blasts and normal leukocytes, but transport capacity related directly to the number of nucleoside transport sites on the cell. Finally, low araC transport rates or few NBMPR binding sites on blasts were observed in a subset of patients with acute leukemia who failed to achieve remission with drug combinations containing araC.

Topics: Acute Disease; Adolescent; Adult; Aged; Binding Sites; Bone Marrow Cells; Carrier Proteins; Cell Transformation, Neoplastic; Child; Child, Preschool; Cytarabine; Humans; Infant; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Middle Aged; Nucleosides; Thioinosine; Time Factors

Topics: Acute Disease; Bacterial Infections; Child; Child, Preschool; Humans; Leukemia; Leukemia, Lymphoid; Methotrexate; Prednisolone; Thioinosine; Vincristine

Topics: Acute Disease; Cell Transformation, Neoplastic; Cytarabine; Daunorubicin; Humans; Leukemia; Prednisolone; Thioinosine

Topics: Acute Disease; Adolescent; Adult; Cytarabine; Daunorubicin; Female; Humans; Leukemia; Male; Middle Aged; Prednisolone; Thioinosine

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Middle Aged; Prednisolone; Thioguanine; Thioinosine

Survival and response to chemotherapy were evaluated in 84 adults with granulocytic leukemia (AGL) and 22 with acute lymphocytic leukemia (ALL). Twenty-two of the 84 patients with AGL reveived no chemotherapy (untreated group). The median survival for patients with AGL who achieved complete remission (CR) was 17.1 months, compared to 6.5 months for those who achieved partial remission (PR (p less than 0.05), 2.8 months for those who failed chemotherapy (p less than 0.01), and 2.1 months for the untreated group (p less than 0.01). The median survival for patients with ALL who achieved a CR was 18.2 months, compared to 7.3 months for those who achieved a PR and 7.0 months for those who failed chemotherapy. Of patients with AGL who reveived an adequate trial of chemotherapy, 43% achieved a CR and 16% a PR; 75% of patients with ALL achieved a CR and 13% a PR. Improved survival depends on the induction of a complete or partial remission with the use of aggressive chemotherapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Cyclophosphamide; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Thioguanine; Thioinosine; Vincristine