pentostatin and Leukemia

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Pentostatin; Purines; Stem Cell Transplantation; Vidarabine

The purine analogs, fludarabine, 2-chlorodeoxy-adenosine, and 2'-deoxycoformycin, have revolutionized our approach to the treatment of a variety of indolent lymphoid malignancies. Because of their impressive single agent activity, they should be considered as an initial therapeutic option, not only for hairy cell leukemia, but also for chronic lymphocytic leukemia, indolent non-Hodgkin's lymphomas, and Waldenström's macroglobulenemia. Combinations of purine analogs with alkylatng agents, topisomerase II inhibitors, and other new compounds are in development, and their role as radiation sensitizers is being explored in clinical trials. Substantial activity has also been noted in several of the rheumatologic and immunologic disorders, and in multiple sclerosis. Continued progress requires innovative strategies which can modulate the biology and immunology of these diseases toward the goal of curing these patients.

Topics: Antineoplastic Agents; Cladribine; Forecasting; Humans; Leukemia; Pentostatin; Purines; Vidarabine

Purine nucleoside analogues are a new class of drugs with activity against nondividing lymphocytes; thus, they should play a major role in the treatment of low grade lymphoid malignancies. As these drugs are active against resting lymphocytes, harmful effects related to this action were expected and have been reported. However, the toxic effects on resting lymphocytes observed during treatment of lymphoid malignancies may potentially be of some benefit in patients with autoimmune diseases. To substantiate this possibility, a considerable amount of work needs to be carried out in order to better define the mechanism of action of these drugs, as well as their potential activity on different immunological effectors. Also, studies in animal models of autoimmune disease should be undertaken.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cladribine; Humans; Immunosuppressive Agents; Leukemia; Pentostatin; Purine Nucleosides; Vidarabine

Topics: Adenosine Deaminase Inhibitors; Animals; Clinical Trials as Topic; Humans; Leukemia; Lymphoma; Lymphoproliferative Disorders; Pentostatin

There are three new purine analogs, fludarabine, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine, all of which have major activity in the treatment of indolent lymphoid malignancies. These three agents, with cytotoxicity against dividing and resting lymphocytes, have revolutionized the treatment of these diseases and, accordingly, represent a significant therapeutic advance. The development of these drugs emanated from an enhanced understanding of purine metabolism in lymphocytes and the mechanism of lymphocytotoxicity in severe combined immunodeficiency disease. Preclinical studies and phase I clinical trials are reviewed, as are phase II studies of these three purine analogs in chronic lymphocytic leukemia, hairy cell leukemia, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and the myeloid leukemias. Potential future strategies exploring possible synergy between these purine analogs and the concurrent administration of both alkylators and biologic response modifiers are explored. The development of the purine analogs and their appropriate clinical applications exemplifies the model for rational drug design and development.

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Lymphoma; Pentostatin; Vidarabine

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Multiple Myeloma; Pentostatin; Vidarabine

Topics: Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Humans; Leukemia; Lymphoma; Molecular Structure; Pentostatin; Purine Nucleosides; Vidarabine

Several new antimetabolites have been evaluated in clinical trials in recent years. Those with the most promising activity include the structurally related purine analogs fludarabine, 2-chlorodeoxyadenosine, and 2'-deoxycoformycin. These compounds have shown impressive activity against a broad spectrum of indolent lymphoproliferative disorders, including hairy-cell leukemia, chronic lymphocytic leukemia, and low-grade non-Hodgkin's lymphomas. They may also be useful in the treatment of acute leukemias. In contrast, they lack activity against common solid tumors. They have been generally well tolerated in large clinical trials; however, each of them is myelosuppressive and immunosuppressive. It is unlikely that any one of these drugs, when used as a single agent, will provide optimal therapy for any disease other than, possibly, hairy-cell leukemia. Combinations with other cytotoxic agents and biologics are in development, and perhaps they will lead to more effective regimens in the future.

Topics: Animals; Antimetabolites, Antineoplastic; Cladribine; Clinical Trials as Topic; Drugs, Investigational; Forecasting; Humans; Immunosuppression Therapy; Leukemia; Lymphoma; Pentostatin; Purines; Vidarabine

This article focuses on the chemotherapeutic agents which alter purine metabolism as a means to achieve selective killing of leukemic cells. We present an overview of purine metabolism in order to highlight enzymatic steps which are targeted by antileukemic drugs. Purine antimetabolites used in the treatment of leukemia can be grouped into three classes: (1) structural analogs of normal purines (6-mercaptopurine and 6-thioguanine); (2) inhibitors of de novo purine biosynthesis (methotrexate and hydroxyurea); and (3) inhibitors of purine salvage (2'-deoxycoformycin). In addition, a number of investigational drugs (trimetrexate, fludarabine and 2'-chlorodeoxyadenosine) have been recently introduced and show promise in early clinical trials. Purine antimetabolites are active in a variety of lymphoid and myeloid leukemias and represent an important component of the therapy of these disorders. Several of the drugs have been developed with the specific intent of perturbing enzymes involved in purine metabolism. Refinements in our understanding of purine biochemistry in normal and leukemic cells may aid future efforts to design more effective drugs.

Topics: Antineoplastic Agents; Drugs, Investigational; Humans; Hydroxyurea; Leukemia; Mercaptopurine; Methotrexate; Pentostatin; Purines; Thioguanine

A few enzymes of the purine degradative pathway have proved valuable in diagnosis and treatment of lymphomas and lymphocytic leukemia. Of particular interest are the enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and ecto-5'-nucleotidase (5NT). Intact activities of ADA and PNP have been shown to be vital for lymphoid cells. During development, lymphoid precursors go through remarkable changes in the concentrations of these enzymes and the neoplasms derived from them show a "frozen" biochemical profile similar to the corresponding normal cell of origin. Knowledge of the role of these enzymes has led to the pharmacological use of enzyme inhibitors for the specific treatment of lymphoid neoplasms. This review concerns the enzymatic make-up of normal and neoplastic lymphocytes and exploitation of this knowledge for the treatment of lymphomas. Special emphasis will be put on the clinical use of an ADA-inhibitor, deoxycoformycin.

Topics: 5'-Nucleotidase; Adenosine Deaminase Inhibitors; Antineoplastic Agents; Coformycin; Humans; Leukemia; Lymphoma; Nucleoside Deaminases; Nucleotidases; Pentostatin; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Purines

A new antimetabolite, 2'-deoxycoformycin (pentostatin), has striking antitumor activity in several lymphoid neoplasms. Isolated from cultured soil organisms, this purine analogue is a potent inhibitor of adenosine deaminase (ADA), and is thus selectively toxic to lymphocytes. Early clinical trials showed that high doses of pentostatin caused severe and unpredictable toxicity, but responses in refractory lymphoid malignancies were encouraging. Careful pharmacologic studies led to the definition of a safe and effective low weekly dose, at which protracted ADA inhibition occurs in neoplastic cells. The most sensitive tumor identified is hairy cell leukemia, in which durable remissions are achieved in more than 90% of patients with a relatively brief course of treatment. Other responsive diseases include chronic lymphocytic leukemia, prolymphocytic leukemia, mycosis fungoides, and acute T-cell lymphoma or leukemia. Response has been seen in acute lymphocytic leukemia, but the higher doses required are substantially more toxic. Pentostatin is valuable for treatment of indolent lymphoid malignancies and may be useful in non-cancer-related lymphocyte research.

Topics: Adenosine Deaminase Inhibitors; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Coformycin; Drug Evaluation; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Pentostatin; Ribonucleosides

Topics: Adult; Animals; Antibodies, Monoclonal; Burkitt Lymphoma; Cats; Cattle; Cell Differentiation; Chickens; Child; Coformycin; Disease Models, Animal; Humans; Interleukin-2; Japan; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred AKR; Pentostatin; T-Lymphocytes

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Child; Child, Preschool; Coformycin; Erythrocytes; Female; Humans; Immunologic Deficiency Syndromes; Leukemia; Male; Nucleoside Deaminases; Pentostatin; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Transcobalamins

Therapy for patients with chronic graft-versus-host disease (cGVHD) is based on prolonged immunosuppression with corticosteroids. There is no standard therapy for patients whose cGVHD does not resolve with corticosteroid treatment. Pentostatin, a potent inhibitor of adenosine deaminase, has activity in acute GVHD. We examined the toxicity and efficacy of pentostatin in a prospective phase II trial in corticosteroid-refractory cGVHD.. Patients of any age were eligible. Patients received pentostatin 4 mg/m2 intravenously every 2 weeks for 12 doses, and continued therapy as long as benefit was documented. Corticosteroid taper was begun after three doses of pentostatin. Responses were graded in real time in the skin, mouth, and liver using objective response criteria.. Fifty-eight heavily pretreated (median, four prior regimens) patients (median age, 33 years) were enrolled. Results are shown as an intent-to-treat analysis. Of the 58 patients, a total of 32 (55%; 95% CI, 42% to 68%) had an objective response, as evaluated by use of a new grading scale. Infection was the most significant toxicity, with 11 grade 3 to 4 infectious events. The survival at 1 and 2 years was 78% (95% CI, 64% to 86%) and 70% (95% CI, 57% to 80%), with cGVHD with/without infection accounting for the majority of deaths.. Pentostatin has immunosuppressive effects that are currently being explored further for treatment of cGVHD.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Drug Resistance; Graft vs Host Disease; HLA Antigens; Humans; Immunosuppressive Agents; Leukemia; Middle Aged; Pentostatin; Treatment Outcome

Topics: 2',5'-Oligoadenylate Synthetase; Humans; Interferon-alpha; Leukemia; Leukemia, Hairy Cell; Pentostatin; RNA, Messenger

Pentostatin, a novel inhibitor of adenosine deaminase, has shown activity in various lymphoid malignancies of both the T and B cell lineage. This agent has unique side effects and in general myelosuppression has been mild. Interferon has both antiviral and antineoplastic properties. This agent has shown activity in hairy cell leukemia, chronic granulocytic leukemia, low grade lymphoma, and myeloma. Side effects from interferon are in general dissimilar to those that have been seen with pentostatin and in particular myelosuppression has not been a major toxicity with low doses of interferon. This current trial explored the combination of pentostatin and interferon in hematologic malignancies. Fifteen patients were enrolled in this phase I trial at a fixed dose of pentostatin of 4 mg/m2 biweekly and interferon at doses of 0.5, 1, 2, or 4 million units/m2 of interferon. At the first three dose levels of interferon nausea and vomiting were the predominant toxicity and appeared to worsen with time on study. Fatigue also was seen at the lowest level of interferon and was severe enough to cause two individuals to discontinue the study medications. At higher dose levels of interferon, myelosuppression, nausea and vomiting, and fatigue were the predominant toxicities. One patient with hairy cell leukemia had a complete response and a second patient with T cell cutaneous lymphoma had a partial response which lasted for 6 to 7 weeks. The maximum tolerated dose of interferon with pentostatin in this patient population was four million units/m2.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Female; Hematologic Diseases; Humans; Interferon Type I; Leukemia; Lymphoma; Male; Middle Aged; Monitoring, Physiologic; Pentostatin; Remission Induction

A new antimetabolite, 2'-deoxycoformycin (pentostatin), has striking antitumor activity in several lymphoid neoplasms. Isolated from cultured soil organisms, this purine analogue is a potent inhibitor of adenosine deaminase (ADA), and is thus selectively toxic to lymphocytes. Early clinical trials showed that high doses of pentostatin caused severe and unpredictable toxicity, but responses in refractory lymphoid malignancies were encouraging. Careful pharmacologic studies led to the definition of a safe and effective low weekly dose, at which protracted ADA inhibition occurs in neoplastic cells. The most sensitive tumor identified is hairy cell leukemia, in which durable remissions are achieved in more than 90% of patients with a relatively brief course of treatment. Other responsive diseases include chronic lymphocytic leukemia, prolymphocytic leukemia, mycosis fungoides, and acute T-cell lymphoma or leukemia. Response has been seen in acute lymphocytic leukemia, but the higher doses required are substantially more toxic. Pentostatin is valuable for treatment of indolent lymphoid malignancies and may be useful in non-cancer-related lymphocyte research.

Topics: Adenosine Deaminase Inhibitors; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Coformycin; Drug Evaluation; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Pentostatin; Ribonucleosides

Topics: Adenosine Deaminase; Antineoplastic Agents; Clinical Trials as Topic; Coformycin; Erythrocytes; Humans; Kinetics; Leukemia; Nucleoside Deaminases; Pentostatin; Ribonucleosides; Vidarabine

We describe a case of natural killer (NK) cell leukemia with acute presentation, systemic symptoms and hepatosplenomegaly. The uniform and aberrant phenotype of NK cells with infiltration of bone marrow and spleen was in keeping with a malignant diagnosis. Aggressive presentation was demonstrated by marked constitutional symptoms and significant tumor burden (liver, spleen, blood, bone marrow). The subsequent clinical course has been indolent, but this may have been influenced by treatment. Treatment consisted sequentially of splenectomy, intravenous pentostatin and the combination of cyclosporine A and recombinant human erythropoietin and has resulted in survival of over 48 months. We discuss the difficulties in the diagnosis of this condition, explore possible causes of cytopenia(s), and highlight the role of immunosuppression in controlling disease manifestations in large granular lymphocyte proliferative disorders.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclosporine; Erythropoietin; Flow Cytometry; Humans; Immunophenotyping; Killer Cells, Natural; Leukemia; Male; Middle Aged; Pentostatin; Recombinant Proteins; Splenectomy

dCF (2'-deoxycoformycin) is a potent inhibitor of ADA (adenosine deaminase), an enzyme regulating intra- and extracellular concentrations of purine metabolites. ADA exists as cytosolic and extracellular forms, the latter colocalized on the cell surface with CD26. Once the surface expression of CD26 and ADA in a panel of cell lines and primary samples of T-cell leukemia/lymphoma was defined, we correlated this expression with the antiproliferative and apoptotic effect of dCF.. Surface expression of CD26 inversely correlated with the capability of dCF to inhibit cell growth and induce apoptosis both in T-cell lines and primary samples of T-cell malignancies. This conclusion was sustained by a decreased sensitivity to dCF-mediated proapoptotic and/or antiproliferative in vitro effects of: (a) leukemia/lymphoma T-cell lines expressing surface CD26/ADA complex; (b) primary CD26(+) T cell malignancies; and (c) normal T cells (CD26(+)) as compared with tumor T cells (CD26(-)) in unpurified samples from three cases of T-cell receptor gammadelta(+) T-cell malignancies characterized by a mixture of normal and neoplastic cells. This latter point was confirmed in vivo, in a patient affected by CD26(-) T-cell receptor gammadelta(+) hepatosplenic gammadelta(+) T-cell lymphomas treated on a compassionate basis with dCF. The inverse correlation between CD26 expression and sensitivity to dCF was also demonstrated in a lymphoblastic lymphoma case in which CD26 was expressed on circulating blasts at relapse but not at diagnosis, as well as in two H9 T-cell clones expressing or not expressing CD26 mRNA and protein.. This study corroborates the notion of CD26 as a marker of poor prognosis for T-cell malignancies and delineates a role for CD26 as a predictor of poor response to dCF.

Topics: Antibiotics, Antineoplastic; Apoptosis; Biomarkers, Tumor; Blotting, Western; Bone Marrow Cells; Cell Division; Cell Line; Cell Line, Tumor; Cell Survival; Cells, Cultured; Cytosol; Dipeptidyl Peptidase 4; Flow Cytometry; Humans; Leukemia; Leukemia, T-Cell; Lymphoma; Pentostatin; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; RNA; T-Lymphocytes; Transfection

The nucleoside analogue cordycepin (3'-deoxyadenosine, 3'-dA) is substantially more cytotoxic to terminal deoxynucleotidyl transferase positive (TdT+) leukemic cells than to TdT leukemic cells in vitro in the presence of an adenosine deaminase inhibitor, deoxycoformycin (dCF), and has been considered as a therapeutic agent for TdT+ leukemia. The intracellular metabolism of 3'-dA was examined with HPLC, and the mechanism of its anti-TdT+ leukemic activity was analyzed. In the presence of dCF (2.5 microM), TdT+ leukemic cells (N = 5) were sensitive to the cytotoxic effect of 3'-dA, whereas TdT (N = 6) cells were not. A high level of 3'-dA-5'-triphosphate (3'-dATP) formation was detected in TdT+ NALM-6 cells (67 pmol/10(6) cells) and TdT- K562 cells (49 pmol/10(6) cells) when cultured with 1 microM [3'-3H]-labeled 3'-dA. A substantial level of 3'-dATP was detected in TdT HUT-102 cells (27 pmol/10(6) cells), whereas the level of 3'-dATP in TdT+ MOLT-4 cells was low (0.3 pmol/10(6) cells). The mean IC50 values of 3'-dA against phytohemagglutinin (PHA)-activated and resting peripheral blood mononuclear cells (PBM) (N = 5) were 8 and 32 microM, respectively. There was a modest level of 3'-dATP (7 pmol/10(6) cells) in PHA-PBM, whereas a lower level of 3'-dATP was detected in resting PBM (2.5 pmol/10(6) cells). These data suggest that the presence of 3'-dATP is not sufficient for the antileukemic effect of 3'-dA, but that TdT positivity is essential, and that PBM are significantly less sensitive to the cytotoxicity of 3'-dA in vitro. Further development of 3'-dA as a potential antileukemic agent to treat patients with TdT+ leukemia is warranted.

Topics: Adenosine Deaminase; Antineoplastic Agents; Deamination; Deoxyadenosines; DNA Nucleotidylexotransferase; Humans; Inosine; Leukemia; Leukocytes, Mononuclear; Pentostatin; Phosphorylation; Phytohemagglutinins; Tumor Cells, Cultured

Topics: Adenosine Deaminase Inhibitors; Antibiotics, Antineoplastic; Autoimmune Diseases; Enzyme Inhibitors; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Pentostatin

We summarize the results of our experience over the past 15 years using pentostatin (Nipent; SuperGen, San Ramon, CA) to treat a range of mature B- and T-cell malignancies. This includes 145 patients with postthymic T-cell malignancies in whom disease subtype was found to be the most significant predictor of response, with the best response rates seen in Sézary syndrome (62%) and T-prolymphocytic leukemia (45%). However, there are no long-term survivors among patients with this group of disorders, and strategies using pentostatin in combination with other therapies, such as CAMPATH-1H, are currently being explored. Among the mature B-cell diseases, pentostatin in both standard- and low-dose regimens is effective in advanced, relapsed/refractory B-chronic lymphocytic leukaemia, showing no cross-resistance with other purine analogs such as fludarabine. Our largest series treated with pentostatin consists of 165 patients with hairy cell leukemia. The follow-up period in this group extends to more than 10 years, with a projected event-free survival rate at 5 years of 60% and an overall survival rate of 97%.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Immunosuppressive Agents; Leukemia; Leukemia, B-Cell; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, T-Cell; Lymphoma; Lymphoma, B-Cell; Lymphoma, T-Cell; Pentostatin; Sezary Syndrome; Survival Rate; Vidarabine

In spite of the chemosensitivity seen with the initial treatment of malignant lymphoid disorders, relapse is common and death most often occurs as a result of disease progression. This is related to a multitude of resistance mechanisms associated with the various lymphoproliferative disorders. As a result, therapies targeting intrinsic drug-resistance mechanisms are evolving and have become an active area of research. In vitro studies of human chronic lymphocytic leukemia cells incubated with theophylline, a phosphodiesterase inhibitor, resulted in downregulation of bcl-2 concomitant with induction of apoptosis. We describe the preclinical basis for a novel combination therapy involving pentostatin (Nipent; SuperGen, San Ramon, CA), chlorambucil, and theophylline in the treatment of patients with relapsed chronic lymphoproliferative disorders. An ongoing study based on such justification, which is currently accruing patients, is also described. Results from this trial appear promising, and a phase II study is now being planned.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cause of Death; Chlorambucil; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Neoplasm Recurrence, Local; Pentostatin; Phosphodiesterase Inhibitors; Theophylline

The adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cell lines. When cells were incubated in the presence of both dCF and 2'-deoxyadenosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for myeloid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentration of dCF that effectively inhibited the proliferation of U937 cells was 1/1,000 of that required for lymphoma cell lines, on a molar basis. However, the uptake of dCF or dAd in U937 cells was comparable with that in other leukemia and lymphoma cell lines. The intracellular accumulation of dATP in U937 cells was only slightly higher than that in other leukemia cells in dCF-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apoptosis was reduced by treatment with caspase inhibitors. Induction of caspase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd. No activation of CPP32 was observed in cytosol prepared from exponentially growing leukemia and lymphoma cells. However, dATP effectively induced CPP32 activation in cytosol from monocytoid cells, but not in that from nonmonocytoid cells, suggesting that dATP-dependent CPP32 activation is at least partly involved in the preferential induction of apoptosis in monocytoid leukemia cells. The combination of dCF and dAd may be useful for the clinical treatment of acute monocytic leukemia.

Topics: Apoptosis; Caspase 3; Caspases; Cytosol; Deoxyadenine Nucleotides; Deoxyadenosines; Enzyme Activation; Growth Inhibitors; HL-60 Cells; Humans; Leukemia; Leukemia, Monocytic, Acute; Lymphoma; Neoplasm Proteins; Pentostatin; Tumor Cells, Cultured; U937 Cells

Topics: 2-Chloroadenosine; Antineoplastic Agents; Cladribine; Deoxyadenosines; Humans; Leukemia; Lymphoma, Non-Hodgkin; Pentostatin; Vidarabine

Topics: 2-Chloroadenosine; Antineoplastic Agents; Cladribine; Deoxyadenosines; Humans; Leukemia; Pentostatin; Vidarabine

Topics: Biological Transport; Carrier Proteins; Humans; Leukemia; Lymphocytes; Lymphoma; Membrane Proteins; Nucleoside Transport Proteins; Pentostatin; Thioinosine; Tumor Cells, Cultured

Growth-inhibitory activity of 2'-deoxycoformycin (DCF) and 9-beta-D-arabinofuranosyladenine (Ara-A) used either singly or in combination was assessed in 30 human cultured cell lines (seven T-cell, nine B-cell, five non-T,non-B and nine myeloid cell lines) derived from leukemias and lymphomas. DCF had little activity even at 100 microM on any of the cell lines, while Ara-A had an obvious inhibitory effect on them, especially on non-T,non-B cell lines at 10 microM or less. Lymphoid cell lines were apparently more sensitive to the combined use of Ara-A and DCF than myeloid cell lines. DCF potentiated the antiproliferative activity of Ara-A not only in T-cell lines with high adenosine deaminase (ADA) activity, but also in some other cell lines with low ADA activity. DCF was stable in the culture medium, but Ara-A in the medium containing cultured cells was rapidly inactivated. DCF completely inhibited the inactivation of Ara-A in the medium containing P12/ICH or NALM-6, but not in the medium containing Daudi. This suggests that there is some unknown mechanism(s) of inactivation of Ara-A other than ADA in Daudi, which was insensitive to Ara-A in the presence of 1 microM DCF. The capacity of DCF to inhibit degradation of Ara-A in the medium containing these cultured cells correlated with the level of Ara-A sensitivity potentiated by DCF. In all seven T-cell lines, seven of the nine B-cell lines, all five non-T,non-B cell lines, and only three of nine myeloid cell lines, the IC50 value for Ara-A decreased to 5 microM or less in the presence of 1 microM DCF. These results suggest that the combination of DCF and Ara-A may be effective against various types of lymphoid malignancies and some myeloid leukemias.

Topics: Adenosine Deaminase; Antineoplastic Agents; Cell Division; Coformycin; Drug Stability; Drug Synergism; Humans; Leukemia; Lymphoma; Pentostatin; Ribonucleosides; Tumor Cells, Cultured; Vidarabine

The in vitro cytotoxicity of various purine nucleosides and purine enzyme inhibitors, alone or in combination, and of the alkylating agent mafosfamide (Asta Z7557), incubated for 4 and 24 h have been studied in 17 leukaemic cell lines and normal bone marrow (BM). The purine nucleosides and their analogues included: 2'chlorodeoxyadenosine (CdA), 2'deoxyadenosine (AdR), 3'deoxyadenosine (3'AdR) (cordycepin), adenosine (AR), adenine arabinoside (Ara-A), deoxyguanosine (GdR) and guanine arabinoside (Ara-G). Purine enzyme inhibitors included 2-deoxycoformycin (dCF) and 8-aminoguanosine (8-AG). Cytotoxicity was based on inhibition of (i) incorporation of 3H-leucine into cell proteins and (ii) colony forming units--granulocytic/monocytic (CFU-GM) and for mixed cell colonies (CFU-GEMM). Marked and selective inhibition of T-cell growth was shown by the combinations dCF with either AdR or Ara-A, 8-AG and GdR and by CdA or Ara-G alone; these compounds even at high concentrations produced only partial inhibition of the growth of normal bone marrow CFU-GM and CFU-GEMM except for CdA which completely inhibited the formation of CFU-GEMM colonies. The combination dCF + cordycepin and alkylating agent mafosfamide were, however, toxic to all the cell lines at the concentrations employed, as well as to CFU-GM and CFU-GEMM. The high therapeutic index of some of the purine nucleosides with a relatively short exposure time makes them candidates for selective in vitro removal of residual neoplastic cells in autologous bone marrow transplantation (ABMT) for T-ALL.

Topics: Adenosine Deaminase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Drug Screening Assays, Antitumor; Guanosine; Humans; Leukemia; Nucleoside Deaminases; Pentostatin; Pentosyltransferases; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Tumor Cells, Cultured

Deoxycoformycin (DCF) is a specific inhibitor of adenosine deaminase (ADA) and has been shown to be active in lymphoid neoplasms. Cytotoxicity is thought to be mediated by the accumulation of deoxyadenosine (AdR) and deoxyadenosine triphosphate (dATP) which inhibits ribonucleotide reductase and DNA synthesis in rapidly proliferating cells. Others suggested mechanisms leading to cell death particularly in non-dividing cells include depletion of ATP and NAD pools, inhibition of S-adenosylhomocysteine (SAH) hydrolase and induction of DNA strand breaks. In patients with high leukemic counts who were subsequently treated with DCF, we have studied (a) the levels of ADA, ecto-5'-nucleotidase (5NT), deoxyadenosine kinase (AdR-kinase) and SAH-hydrolase in the leukemic cells; [b) the in-vitro effects of DCF on dATP, ATP, NAD, SAH-hydrolase levels and on DNA strand breaks; and (c) the correlation between these parameters with clinical response to DCF. No significant difference in ADA, 5NT, AdR-kinase and SAH-hydrolase activities could be found between responders and non-responders. Incubation of the leukemic cells in vitro with DCF caused an inhibition of ADA, an accumulation of dATP, a moderate reduction in ATP and NAD levels, a suppression of SAH-hydrolase activity and an increase in DNA strand breaks in practically all the leukemic samples, irrespective of clinical response. Our results show that neither measurement of these enzymes nor studies of these biochemical sequelae of ADA inhibition in vitro predicts clinical responsiveness to DCF therapy.

Topics: Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Adenosylhomocysteinase; Antineoplastic Agents; Coformycin; Deoxyadenine Nucleotides; DNA Damage; Humans; Hydrolases; Leukemia; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; NAD; Nucleoside Deaminases; Pentostatin; Ribonucleosides

Knowledge of the vital role of the purine degradative enzyme adenosine deaminase (ADA) in the differentiation of T and B lymphocytes has stimulated interest in the pharmacologic inhibition of ADA as specific cytotoxic therapy for lymphoproliferative diseases. 2'-Deoxycoformycin (DCF) is a tight-binding ADA-inhibitor and has shown activity in T and B cell neoplasms. In this phase-II study, the efficacy and toxicity of DCF in chronic T and B cell neoplasms is investigated. We report the preliminary results of treatment in 27 patients (8 with Sézary syndrome, 11 with B-chronic lymphocytic leukemia (CLL), and 8 with hairy cell leukemia (HCL)), who were refractory to conventional therapy. DCF was applied at a dosage of 4 mg/m2 weekly x 3, then 4 mg/m2 every other week x 3. Three of the 8 patients with Sézary syndrome and 3 of the 11 patients with B-CLL attained a partial remission. One complete and 7 partial remissions have been achieved thus far in the 8 patients with HCL refractory to interferon alpha treatment. Other than nausea in 10 patients (mainly grade 1 and 2), transient skin rash in 4 patients and Herpes infections in 4 patients (mainly grade 2), no other major toxicities were observed. Thus DCF is highly active in hairy cell leukemia that did not respond to interferon alpha, and shows moderate activity in refractory Sézary syndrome and B-CLL.

Topics: Antineoplastic Agents; B-Lymphocytes; Coformycin; Drug Evaluation; Humans; Leukemia; Leukemia, Hairy Cell; Leukemia, Lymphoid; Lymphoma; Pentostatin; Ribonucleosides; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes

The adenosine deaminase inhibitor deoxycoformycin was used in low doses to treat 19 patients with clinically aggressive T cell malignancy with a mature membrane phenotype. The patients comprised eight with prolymphocytic leukaemia, two with chronic lymphocytic leukaemia, four with adult T cell leukaemia-lymphoma, three with Sézary syndrome, and two with T cell lymphoma. Two thirds of the patients had been resistant or minimally responsive to combination chemotherapy. Complete remission was obtained in five patients (two with prolymphocytic leukaemia and one each with chronic lymphocytic leukaemia, adult T cell leukaemia-lymphoma, and Sézary syndrome) and partial remission in two others. Unmaintained complete remission lasting more than one year was seen in three patients. Responses were obtained only in patients with CD4+,CD8-membrane markers (seven out of 10), and no responses were recorded in any of the nine patients with a different phenotype. In this series remission appeared to correlate with the membrane phenotype of the neoplastic cell and not with the cytopathological diagnosis. Future studies should establish the biochemical basis for the greater sensitivity of CD4+ lymphoid cells to deoxycoformycin.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Membrane; Coformycin; Cyclophosphamide; Deltaretrovirus Infections; Doxorubicin; Female; Follow-Up Studies; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Male; Middle Aged; Pentostatin; Phenotype; Prednisone; Prognosis; Ribonucleosides; Sezary Syndrome; T-Lymphocytes; Vincristine

Topics: Adenosine Deaminase Inhibitors; Adult; Antineoplastic Agents; Coformycin; Deltaretrovirus; Humans; Leukemia; Male; Nucleoside Deaminases; Pentostatin; Retroviridae Infections; Ribonucleosides

Pentostatin (dCF), an inhibitor of adenosine deaminase, has shown activity in the treatment of several lymphoid malignancies, even in the earliest phase I trials. An analysis of the first 300 patients treated in such trials shows a high incidence of severe infection (8%) during the relatively brief period of treatment. Of 24 patients in whom infection was diagnosed, 17 had no evidence of myelosuppression. The causative organisms included viruses, fungi, and bacteria of both high and low pathogenicity. Two-thirds of the infections were fatal. It is suggested that dCF may cause a syndrome similar to severe combined immunodeficiency during the course of treatment. Patients treated with dCF who show evidence of infection, even in the absence of neutropenia, should receive vigorous and rapid diagnostic evaluation to establish the cause of their infection, and aggressive treatment of suspected organisms.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Coformycin; Drug Evaluation; Female; Herpes Zoster; Humans; Leukemia; Lymphoma; Male; Middle Aged; Mycoses; Neoplasms; Pentostatin; Ribonucleosides

Five patients from the Kyushu area in Japan with adult T-cell leukaemia (ATL) refractory to conventional chemotherapeutic agents were treated with 5 mg/m2 of the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF), intravenously (i.v.) for 3 consecutive days, followed by 5 mg/m2 i.v. weekly. Two patients showed a good response, and three were resistant to DCF. One patient with ATL receiving DCF had a continuous remission without further therapy. Another patient in the terminal stage received three daily injections of 7.5 mg of DCF. The most prominent change was the drop in the leucocyte count. The cell count fell from 116.4 X 10(9)/l to 2.0 X 10(9)/l on day 7. The only adverse effects of DCF therapy were gastrointestinal toxicity, nausea and vomiting. These results suggest that DCF may be a valuable drug for treating refractory ATL.

Topics: Adenosine Deaminase Inhibitors; Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Coformycin; Female; Humans; Leukemia; Male; Middle Aged; Pentostatin; Ribonucleosides; T-Lymphocytes

It remains unclear how lympholysis occurs in children with an inherited deficiency of adenosine deaminase (ADA) and in leukemic patients undergoing treatment with an inhibitor of ADA, deoxycoformycin. Adenosine deaminase deficiency with subsequent lympholysis can be simulated in vitro by treatment of lymphoid cells with deoxyadenosine plus deoxycoformycin. We found that such in vitro treatment caused fragmentation of the nucleus, disintegration of nuclear chromatin, and the formation of cytoplasmic blebs in T-lymphoblast lines, but not in B-lymphoblast lines. For all but one of the cell lines tested, the extent of morphological changes paralleled the sensitivity to growth inhibition by deoxyadenosine plus deoxycoformycin. Similar morphological changes were observed in normal peripheral blood lymphocytes treated with deoxyadenosine plus deoxycoformycin. These morphological changes were energy-dependent processes. They were preceded by inhibition of DNA synthesis and deoxyadenosine triphosphate (dATP) accumulation, but followed by depletion of adenosine triphosphate (ATP) and cell lysis. These changes may represent an intermediate step between metabolic alterations and lympholysis.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Coformycin; Deoxyadenosines; Dose-Response Relationship, Drug; Humans; Leukemia; Lymphocytes; Pentostatin; Ribonucleosides; Time Factors

A new cytotoxic drug, 2'-deoxycoformycin, has been shown to be highly active in the treatment of lymphocytic leukemias and lymphomas, particularly T cell acute lymphoblastic leukemia, in which the drug, used as a single agent, can induce CRs in patients who have failed to respond to a wide variety of other compounds. Further work is required to elucidate the cause of the renal failure that has occurred in some patients, but prescribed within the dose range of the patients reported in this paper, toxicity is acceptable in consideration of the results achieved and the prognosis of this highly malignant group of diseases.

Topics: Acute Kidney Injury; Adenosine Deaminase Inhibitors; Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Coformycin; Female; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Male; Middle Aged; Mycosis Fungoides; Pentostatin; Ribonucleosides; T-Lymphocytes

Topics: Antineoplastic Agents; Coformycin; Drug Administration Schedule; Drug Evaluation; Humans; Injections, Intravenous; Leukemia; Lymphoma; Pentostatin; Ribonucleosides

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Azepines; Biological Transport, Active; Cell Line; Coformycin; Dilazep; Dipyridamole; Enzyme Reactivators; Erythrocytes; Humans; Leukemia; Lymphoma; Mathematics; Nucleoside Deaminases; Nucleosides; Pentostatin; Platelet Aggregation; Ribonucleosides

Four compounds that inhibit adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine, 2'-deoxycoformycin, coformycin, and 9-(1-hydroxy-2-octyl)adenine have been studied in an in vitro lymphocyte-mediated cytolysis assay. At low concentration (congruent to 10 microM) these agents enhance the activities of a number of inhibitory purine nucleosides, including adenosine and 2'-deoxyadenosine. The LMC-inhibitory activity of Ado but not dAdo is further enhanced by 5-iodotubercidin, uridine, 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, or L-homocysteine and is antagonized by theophylline. The inhibition of LMC by Ado and dAdo is increased by nitrobenzyl-thioinosine. Lymphocyte-mediated cytolysis was inhibited by EHNA or HOA alone (IC50 congruent to 150 microM), but not by dCF and CF (even at 400 microM). Inhibition of LMC by EHNA, HOA, Ado, or dAdo could not be attributed to changes in nucleoside 5'-triphosphate or S-adenosylhomocysteine levels. Inhibition of LMC by Ado appears to be related to increases in lymphocyte cAMP levels, while the mechanism of action of dAdo remains obscure. Lymphocyte-mediated cytolysis may be inhibited by EHNA and HOA through modulation of cAMP metabolism.

Topics: Adenine; Adenosine; Adenosine Deaminase Inhibitors; Animals; Cell Line; Coformycin; Cytotoxicity, Immunologic; Immunity, Cellular; Immunosuppressive Agents; Leukemia; Mice; Nucleoside Deaminases; Pentostatin; T-Lymphocytes, Cytotoxic

Both established cell lines and human leukemic cells in circulating blood which were incubated in vitro with 2'-deoxyadenosine (AdR) plus adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), showed different metabolic responses depending upon the histologic and immunologic types of leukemia. The leukemic T-cell lines in tissue culture were 200-fold more sensitive than B-cell lines to the toxic effect of deoxyadenosine. The increased sensitivity of T-cell lines to AdR plus dCF was associated with the accumulation of deoxyadenosine triphosphate (dATP) in the cells. In established cell lines, an inverse correlation was observed between ED 50 of AdR plus dCF and the relative increase of dATP levels in the cells after the incubation of the cells with AdR plus dCF. In circulating leukemic cells that had been incubated with AdR and dCF, dATP arose in all groups but the correlation was not found between the sensitivity of AdR and the relative dATP accumulation. The failure to find the correlation in patients's leukemic cells may be attributed to the heterogeneity of the response of the blasts to AdR and dCF.

Topics: Acute Disease; B-Lymphocytes; Cell Line; Cells, Cultured; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; Growth Inhibitors; Humans; Leukemia; Leukemia, Experimental; Leukemia, Myeloid; Pentostatin; Ribonucleosides; T-Lymphocytes; Thymidine

A patient from the Caribbean area with active T-cell lymphoma-leukaemia was primarily treated with deoxycoformycin (DCF), 5 mg/m2 i.v. on 3 consecutive days, followed by 5 mg/m2 i.v. weekly. A complete remission was attained and maintained during several weeks with DCF. A single consolidation course with other cytostatics was then given. The patient continues in complete remission without further therapy, 24 months after diagnosis, 17 months after the last cytostatic drugs. T-cell lymphoma-leukaemia has a bad prognosis with conventional anti-lymphoma therapy but was exquisitely sensitive to DCF in this patient.

Topics: Adult; Antineoplastic Agents; Coformycin; Deltaretrovirus; Drug Administration Schedule; Female; Humans; Leukemia; Lymphoma; Pentostatin; Retroviridae Infections; Ribonucleosides; T-Lymphocytes

Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between the two cell populations. Pretreatment T lymphoblasts and posttreatment promyelocytes had the same abnormal karyotype. Upon culture in vitro, the former transformed spontaneously over several weeks into mature myeloid cells. We conclude that the leukemia arose from a multipotent stem cell capable of both lymphoid and myeloid differentiation. Effects of ADA inhibition on leukemia cells during treatment included expansion of the deoxyadenosine nucleotide pool and accumulation of S-adenosylhomocysteine, a potent inhibitor of S-adenosylmethionine-dependent methylation. The influence of these changes on the leukemic phenotype is discussed in terms of (i) selective cytotoxicity to T lymphoblasts, which accumulated deoxyadenosine nucleotides more efficiently than did the patient's promyelocytes during in vitro incubation with deoxycoformycin plus deoxyadenosine, and (ii) induction of an altered program of differentiation.

Topics: Acute Disease; Adenosine Deaminase Inhibitors; Adolescent; Antibodies, Monoclonal; Antigens, Surface; Bone Marrow; Coformycin; Humans; Karyotyping; Leukemia; Leukemia, Myeloid; Male; Nucleoside Deaminases; Pentostatin; Phenotype; Ribonucleosides; T-Lymphocytes

Topics: Adenosine Triphosphate; Antineoplastic Agents; Coformycin; Deoxyadenine Nucleotides; DNA Replication; Humans; Leukemia; Pentostatin; Ribonucleosides

Topics: Adenosine; Adult; Antineoplastic Agents; Coformycin; Deoxyadenosines; Drug Administration Schedule; Drug Therapy, Combination; Half-Life; Humans; Kinetics; Leukemia; Male; Pentostatin; Ribonucleosides; Vidarabine

Topics: Adenine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Cell Survival; Cells, Cultured; Coformycin; Deoxyadenosines; Humans; Interphase; Leukemia; Lymphopenia; Nucleoside Deaminases; Pentostatin; Purines; 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 current status of three drugs of clinical interest to the National Cancer Institute is reviewed. m-AMSA, a drug with a wide spectrum of activity in murine tumors, is now in phase II trial and has shown itself to have a high order of activity in acute nonlymphocytic leukemia. Dihydroxyanthracenedione, a compound with some of the characteristics of anthracyclines but with no cardiac toxicity in animal toxicology studies, is in phase I evaluation. Deoxycoformycin, an adenosine analog which is a potent inhibitor of adenosine deaminase, has shown moderate activity in acute leukemia patients in phase I trials, and has the potential to produce synergistic antitumor toxicity when used with arabinofuranosyladenine.

Topics: Adenosine Deaminase Inhibitors; Aminoacridines; Amsacrine; Anthracenes; Antineoplastic Agents; Coformycin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia; Mitoxantrone; Neoplasms; Nucleoside Deaminases; Pentostatin; Ribonucleosides

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

Seventeen patients with acute leukaemia refractory to conventional chemotherapeutic agents were treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF). Of the twelve patients with acute lymphoblastic leukaemia of the thymic phenotype (Thy-ALL), seven went into complete remission after one or two courses of therapy. Two other (Thy-ALL) patients showed good partial response, and three were resistant to dCF. The five patients with acute leukaemia of other phenotypes had progression of disease despite treatment with dCF. Response to dCF can be predicted from the pattern of change in cellular nucleotide levels in blood and/or bone marrow blasts which have been treated in vitro with dCF and deoxyadenosine. The main adverse effects of dCF therapy were renal and liver dysfunction, conjunctivitis, and haemolysis.

Topics: Acute Disease; Adenosine Deaminase; Adolescent; Adult; Child; Child, Preschool; Coformycin; Conjunctivitis; Female; Hemolysis; Humans; Infant; Kidney; Leukemia; Leukemia, Lymphoid; Liver; Male; Pentostatin; Phenotype; Ribonucleosides; T-Lymphocytes

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2'-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short-lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2'-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.

Topics: Adenosine Deaminase; Adenosine Triphosphate; Adolescent; Adult; Child; Coformycin; Erythrocytes; Humans; Leukemia; Leukocytes; Lymphoma; Middle Aged; Nucleosides; Pentostatin; Remission, Spontaneous; Ribonucleosides

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Arabinofuranosylcytosine Triphosphate; Coformycin; Cytarabine; Humans; Leukemia; Methotrexate; Pentostatin; Phosphorylation; Tissue Distribution