pentostatin and Leukemia--Myeloid--Acute

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Bone Marrow Transplantation; Clinical Trials as Topic; Coformycin; Combined Modality Therapy; Humans; Interferons; Kidney Failure, Chronic; Leukemia, Myeloid, Acute; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Palliative Care; Pentostatin

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Bone Marrow Transplantation; Clinical Trials as Topic; Coformycin; Combined Modality Therapy; Humans; Interferons; Kidney Failure, Chronic; Leukemia, Myeloid, Acute; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Palliative Care; Pentostatin

The rate of nucleoside transport decreased profoundly in human promyelocytic leukemia HL-60 cells after myeloid differentiation was induced by 5-6 days of exposure to 0.8% N,N-dimethylformamide (DMF). The facilitated diffusion of 100 microM radiolabeled adenosine and 2'-deoxyadenosine, measured by rapid transport assays, decreased 10- to 20-fold. The transport of 2 microM coformycin or 2'-deoxycoformycin, which is mediated by the same mechanism and was monitored by the adenosine deaminase titration assay, decreased 29-fold. The reduction in nucleoside transport capacity after DMF treatment was confirmed by a 19-fold decrease in the number of specific binding sites per cell (from 24-30 X 10(4) to 1.2-1.7 X 10(4)) for [3H]-6-p-nitrobenzylthioinosine, a nucleoside transport inhibitor. The binding affinity of 6-p-nitrobenzylthioinosine was not altered significantly and nucleoside transport remained sensitive to the transport inhibitors, 6-p-nitrobenzylthioinosine, dipyridamole, and dilazep after DMF-induced maturation. Time-dependence studies showed that the rate of 100 microM deoxyadenosine transport was unchanged for the first 24 h of exposure to DMF but fell to about 36% of control rates at 24-26 h and then gradually decreased further to about 4-5% of control rates after 5-6 days. In contrast, transport rates of the purine bases were reduced only 2- to 3-fold in HL-60 cells after 5 days of DMF treatment. The rates of adenosine and deoxyadenosine transport were unchanged or reduced by no more than 2-fold after 5-6 days of exposure to 0.8% DMF in the following human tumor cell lines that are not inducible with DMF: ARH-77 (multiple myeloma), KG-1 (acute myelogenous), and K-562 (chronic myelogenous). Thus, changes in nucleoside transport may serve as an early, membrane-associated marker of differentiation of the HL-60 cell line.

Topics: Adenosine; Adenosine Deaminase Inhibitors; Cell Differentiation; Cell Line; Coformycin; Deoxyadenosines; Dimethylformamide; Humans; Leukemia, Myeloid, Acute; Nucleosides; Pentostatin; Purines; Thioinosine

A 6-year-old boy with T-cell acute lymphoblastic leukaemia (ALL) in relapse was treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF). Remarkably, his residual leukaemia underwent an abrupt phenotypic shift, coincident with a massive anti-leukaemic effect of DCF. Both at diagnosis and prior to therapy with DCF, blast cells had typical lymphoblastic morphology and T-cell characteristics (terminal transferase +, T-antigen +, Ia -, cALLa -, myeloperoxidase -, and high in adenosine deaminase content). After four courses of DCF by constant infusion, the blast cells were myeloid in appearance and reactivity to a variety of tests (terminal transferase -, myeloperoxidase +, Sudan black B +, esterase +, My-1 +). We hypothesize that DCF therapy created a selection pressure, blocking pathways of T-cell differentiation and proliferation, permitting the emergence of a newly dominant myeloid subclone of a multipotential leukaemic cell progenitor with the innate capacity for both T-lymphocytic and myeloid differentiation.

Topics: Adenosine Deaminase Inhibitors; Child; Coformycin; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Nucleoside Deaminases; Pentostatin; Ribonucleosides; T-Lymphocytes

Leukemic cells incubated in vitro with 2'-deoxyadenosine (dAdo) plus an inhibitor of adenosine deaminase, 2'-deoxy-coformycin (DCF), show different metabolic responses depending on the histologic and immunologic type of the leukemia. Leukemic cells were obtained from 54 patients with acute lymphoblastic leukemia (ALL), 9 with myeloid or nonlymphoblastic leukemia, 3 with chronic lymphocytic leukemia (CLL), and 3 with lymphoma. There was a wide variation in the LD50, the concentration of dAdo that caused 50% inhibition of the incorporation of 3H-thymidine into cells in the presence of 20 microM DCF. T-cell leukemia specimens were much more sensitive to dAdo than were specimens of pre-B-ALL and null-ALL. In leukemic cells that had been incubated with 14C-dAdo plus DCF, a good correlation was observed between the LD50 and the ratio of 14C-deoxyATP to ATP (correlation coefficient for the fit to a hyperbola = 0.853). The accumulation of deoxyATP by the leukemic cell specimens was correlated best with the activity of ecto-ATPase, less well with cytoplasmic 5'-nucleotidase and deoxyadenosine kinase, and poorly with adenosine deaminase and ecto-5'-nucleotidase. The clinical response to DCF therapy of a patient with T-ALL and another with pre-B-ALL was consistent with the in vitro metabolic response of their cells to DCF and dAdo.

Topics: Adenosine Deaminase; Adolescent; Deoxyadenine Nucleotides; Deoxyadenosines; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Lymphocytes; Lymphoma; Male; Nucleotidases; Pentostatin; Thymidine; Vidarabine

The combination of 2'-deoxycoformycin (DCF), a potent adenosine deaminase (ADA) inhibitor, and 9-beta-D-arabinofuranosyladenine (Ara-A) was used in a patient with acute nonlymphocytic leukemia refractory to all conventional modes of therapy. DCF was given by periodic iv injections to ablate ADA activity. Ara-A was given by continuous iv infusion at an initial dose of 1.5 mg/kg/day, with progressive increases to 6 mg/kg/day. With adequate ADA suppression (less than 2 x 10(-2) mumols of inosine/hr/10(6)h cells), the Ara-A decreased the absolute peripheral blood myeloblast count from 36,332 to 780/microliter. The patient experienced no renal, hepatic, or neurologic complications during therapy.

Topics: Adenosine Deaminase; Adult; Coformycin; Deoxyribonucleotides; Drug Evaluation; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Male; Nucleosides; Pentostatin; Ribonucleosides; Ribonucleotides; Vidarabine

Intracellular deoxynucleoside triphosphate pools of normal bone marrow, thymocytes and cells from patients with ALL and AML were measured after 2 h incubation with deoxycoformycin (dCF) 10(-5) M and deoxyadenosine (AdR) 10(-4) M in vitro and after another 30 min incubation in the absence of dCF and AdR ('chase' experiment). Incubation with dCF and AdR resulted in a significant rise of dATP concentrations in all groups (the highest rises occurring in the leukaemic groups particularly in AML and Thy-ALL). The concentrations of the other three deoxyribonucleoside triphosphates fell in all groups. The dATP level fell during the 'chase' period but in Thy-ALL and thymocytes this fall was insignificant and slower than in the other groups. This suggests that not only intracellular build-up of dATP but also the capacity of the cell to degrade dATP is important for in vivo cytotoxicity of dCF treatment. These results help to explain the differences in response to dCF of the different leukaemias.

Topics: Bone Marrow; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; Deoxyribonucleotides; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Pentostatin; Ribonucleosides; T-Lymphocytes