pentostatin and Leukemia--Lymphoid

To the authors' knowledge, there is no standard treatment for patients with T-cell large granular lymphocyte (LGL) leukemia. Available data are limited by patient numbers and coexisting pathologies.. The authors report on the use of immunosuppressants (cyclosporin A [CSA] and low-dose oral methotrexate [MTX] given continuously) and cytotoxic agents in the treatment of 29 patients with T-cell LGL leukemia age over the past 20 years.. The overall response rate (ORR) to MTX (n = 8 patients) was 85.7% (complete hematologic response [CHR] rate, 14.3%; partial response [PR] rate, 71.4%) with dose-dependent responses observed and safe usage of doses >10 mg/m2 per week in 2 patients. The ORR to CSA (n = 23 patients) was 78.2% (CHR rate, 30.4%; PR rate, 47.8%). The median time to response for both agents was 1 month. Toxicity, although it was minor in most patients and was more common in the CSA group, included second malignancies in 5 patients. An ORR of 67% (all CHR) was attained with pentostatin (n = 4 patients); recurrences developed after a median of 4.6 years. Successful retreatment with pentostatin was possible but with increasing drug resistance. Cyclophosphamide induced CHR that lasted >7 years with bone marrow clearance in 1 of 4 patients. Alemtuzumab induced a PR in 1 patient who had refractory disease.. Both MTX and CSA were efficacious in the treatment of T-cell LGL leukemia but generally required long-term maintenance therapy. The authors highlight the risks of second malignancies and persistence of bone marrow disease. Although MTX and CSA were effective as first-line therapy, alemtuzumab and pentostatin merit further investigation, particularly for refractory disease.

Topics: Adult; Aged; Aged, 80 and over; Cyclophosphamide; Cyclosporine; Databases as Topic; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphoid; Leukemia, T-Cell; Male; Methotrexate; Middle Aged; Pentostatin; Retrospective Studies

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Humans; Leukemia, Lymphoid; Lymphoma; Nucleosides; Pentostatin; Vidarabine

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

T-cell large granular lymphocytic (T-LGL) leukemia is characterized by cytopenia and clonal proliferation of large granular lymphocytes. We identified 26 patients with T-LGL leukemia seen at our institution over a period of 8 years. The majority of the patients were asymptomatic at diagnosis. Nine patients were treated with cyclosporine; one achieved a complete remission, and four had a hematological response. Other treatment modalities included single agent alemtuzumab, alemtuzumab combined with pentostatin, fludarabine, and combination of fludarabine and cyclophosphamide. Significant responses were not seen with any of these treatment regimens. We conclude that cyclosporine therapy may be beneficial for T-LGL leukemia patients. New treatment modalities are needed for these patients.

Topics: Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Cyclosporine; Female; Flow Cytometry; Humans; Immunophenotyping; Leukemia, Lymphoid; Leukemia, T-Cell; Male; Middle Aged; Pentostatin; Retrospective Studies; Vidarabine

We describe the results of treatment with 2'-deoxycoformycin (DCF) in 68 patients with post-thymic (mature) T-cell malignancies. These included: prolymphocytic leukaemia (T-PLL), 31, HTLV-1 + adult T-cell leukaemia/lymphoma (ATLL), 20, cutaneous T-cell lymphoma (CTCL), comprising mycosis fungoides and Sezary syndrome, 13, and large granular lymphocytic leukaemia, four. Two-thirds of patients were refractory to previous therapy, which included four drug combinations. DCF was given intravenously at 4 mg m-2 weekly for the first 4 weeks and then every 2 weeks until maximal response. Toxicity was very low with only one death resulting from prolonged neutropenia. Overall response rates, partial (PR) and complete. (CR), were 38%, with variations according to diagnosis. Best responses, 54%, were seen in CTCL but limited to Sezary patients, one CR, six PR, whilst none of the mycosis fungoides responded. Responses in T-PLL were recorded in 48% including three CR (of 8-12 months' duration unmaintained) and 12 PR. Fifteen per cent of responses were seen in ATLL. The only ATLL responders - two CR, one PR - were those patients who received combination chemotherapy prior to DCF, with reduction of tumour bulk but short of PR. When results were analysed according to membrane phenotypes it was apparent that responses were seen mainly in cases with CD4+, CD8- T cells -22 of 47 (47%) - contrasting with only three of 19 (16%) with other T-cell phenotypes. We conclude that DCF is a useful therapy for the treatment of T-cell leukaemias, in particular Sezary syndrome and T-PLL, and should play a part in strategies to improve the natural history of this group of lymphoid malignancies.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Lymphoid; Leukemia, Prolymphocytic; Leukemia, T-Cell; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Pentostatin; Sezary Syndrome

Topics: Adenine; Adenosine Deaminase Inhibitors; Adult; Animals; Carcinoma, Ehrlich Tumor; Clinical Trials as Topic; Coformycin; DNA; Drug Evaluation; Drug Synergism; Humans; Leukemia P388; Leukemia, Experimental; Leukemia, Lymphoid; Male; Mice; Nucleoside Deaminases; Pentostatin; Thymidine; Vidarabine

Topics: Child, Preschool; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Coformycin; Deoxyadenosines; Humans; Leukemia, Lymphoid; Male; Pentostatin; Purines; Ribonucleosides; T-Lymphocytes

A 52-year-old woman presented to our clinic for investigation of agranulocytosis and mild lymphocytosis. A diagnosis of T-large granular lymphocyte leukemia was made, based on immunophenotyping findings of the peripheral blood lymphocytes (CD3, CD8, CD16, CD57). Flow cytometric analysis of TCR-Vbeta repertoire showed single Vbeta9 expression on peripheral T-cells. Clonality was also demonstrated with PCR analysis which revealed clonal rearrangement of TCRgamma-chain gene. Granulocyte-macrophage colony-stimulating factor (G-CSF) (G-CSF), cyclosporine, methylprednisolone and oral methotrexate failed to correct the neutropenia. Finally, treatment with 2-deoxycoformycin (DCF) was successful and resulted in complete correction of the neutrophil count. Flow cytometric analysis of TCR-Vbeta repertoire proved to be an effective method to assess the therapeutic response to various treatments and to evaluate residual disease.

Topics: Antibiotics, Antineoplastic; Antigens, CD; Female; Flow Cytometry; Genes, T-Cell Receptor beta; Humans; Immunoglobulin Variable Region; Immunophenotyping; Leukemia, Lymphoid; Leukemia, T-Cell; Middle Aged; Neutropenia; Pentostatin; Remission Induction

We report a case of CD8(+)/V beta 5.1(+) T-cell large granular lymphocyte leukemia (T-LGL leukemia) presenting with mild lymphocytosis, severe autoimmune neutropenia, thrombocytopenia, polyarthritis and recurrent infections with a chronic disease course. Immunophenotyping showed an expansion of CD3(+)/TCR alpha beta(+)/CD8(+bright)/CD11c(+)/CD57(-)/CD56(-) large granular lymphocytes with expression of the TCR-V beta 5.1 family. Southern blot analysis revealed a clonal rearrangement of the TCR beta-chain gene. Hematopoietic growth factors, high dose intravenous immunoglobulin and corticosteroids were of limited therapeutic benefit to correct the cytopenias. During the disease course, the patient developed a severe cutaneous leg ulcer and bilateral vascular mammary skin lesions. Treatment with 2-deoxycoformycin resulted in both clinical and hematological complete responses, including the resolution of vascular skin lesions. Combined immuno-staining with relevant T-cell associated and anti-TCR-V beta monoclonal antibodies proved to be a sensitive method to assess the therapeutic effect of 2-deoxycoformicin and to evaluate the residual disease.

Topics: Aged; Antibiotics, Antineoplastic; Arthritis, Rheumatoid; Breast; CD3 Complex; CD8 Antigens; Female; Gene Rearrangement, T-Lymphocyte; Humans; Immunophenotyping; Leg Ulcer; Leukemia, Lymphoid; Neutropenia; Pentostatin; Receptors, Antigen, T-Cell, alpha-beta; Thrombocytopenia

The association of T-cell large granular lymphocyte (LGL) leukemia and rheumatoid arthritis is well described and it is now recognized that these patients and patients with Felty's syndrome represent different aspects of a single disease process. Most patients have rheumatoid arthritis at the time of diagnosis of LGL leukemia. This is the first detailed report of the development of rheumatoid arthritis after the diagnosis and treatment of LGL leukemia as well as the first report of rheumatoid arthritis that occurred in association with deoxycoformycin treatment. It is likely that the beneficial sustained normalization of neutrophil counts as a result of deoxycoformycin treatment played a significant role in the development of this complication. Hematological improvement occurred despite molecular genetic evidence of persistence of the abnormal T-cell clone. The role of the clonally expanded T cells in the pathogenesis of neutropenia and rheumatoid arthritis is discussed.

Topics: Antibiotics, Antineoplastic; Clinical Trials, Phase II as Topic; Clone Cells; Felty Syndrome; Gene Rearrangement, T-Lymphocyte; Genes, T-Cell Receptor; Histocompatibility Testing; HLA-DR4 Antigen; Humans; Leukemia, Lymphoid; Male; Middle Aged; Neutropenia; Pentostatin; Polymerase Chain Reaction

Topics: Humans; Leukemia, Hairy Cell; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Pentostatin

A case of T-prolymphocytic leukaemia (T-PLL) presenting with deafness and confusion is reported. Computerised tomography (CT) of the head showed several well-defined, rounded, high attenuation areas in the temporal, parietal and occipital regions of the brain substance that were suggestive of metastases. Treatment with weekly intravenous deoxycoformycin produced complete resolution of the CT abnormalities together with haematological evidence of disease regression 6 weeks after treatment was started.

Topics: Antineoplastic Agents; Brain; Coformycin; Humans; Injections, Intravenous; Leukemia, Lymphoid; Male; Middle Aged; Pentostatin; Ribonucleosides; Tomography, X-Ray Computed

Topics: Antineoplastic Agents; Coformycin; Humans; Leukemia, Lymphoid; Male; Middle Aged; Pentostatin; Remission Induction; Ribonucleosides

We report a case of prolymphocytic leukaemia which presented with annular, purpuric, erythematous plaques in the skin. Histology of the lesions showed cutaneous invasion with leukaemic cells. The lesions cleared with chlorambucil and prednisolone, and the leukaemic state responded to deoxycoformycin, an experimental anti T cell agent.

Topics: Chlorambucil; Coformycin; Humans; Leukemia, Lymphoid; Leukocyte Count; Male; Middle Aged; Pentostatin; Prednisolone; Skin; Skin Neoplasms

The effects of irradiation were evaluated in L5178Y lymphoblasts treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin, and deoxyadenosine. A synergistic antitumor effect was observed in resting cells between irradiation and 2'-deoxycoformycin/deoxyadenosine, with the dose required to reduce the surviving cell fraction to 0.1 being 25% lower than predicted for an additive effect. Synergy was enhanced with increasing deoxyadenosine concentration or with increasing radiation dose. When cells were treated with 2'-deoxycoformycin/deoxyadenosine for 1 h prior to irradiation, synergy was increased by prolonging postirradiation drug treatment. With 4-h postirradiation exposure to drug, varying the preirradiation incubation time did not affect synergy. In contrast, only a small enhancement of antitumor activity was observed in irradiated proliferating cells treated with 2'-deoxycoformycin/deoxyadenosine. Incubation of resting cells with 2'-deoxycoformycin/deoxyadenosine resulted in inhibition of the rate and extent of repair of radiation-induced DNA single strand breaks and an increase in dATP, but had no effect on NAD or ATP. With removal of drug, the dATP level fell rapidly and DNA repair resumed. Repair of DNA single strand breaks was more rapid in proliferating cells than in resting cells and was minimally affected by 2'-deoxycoformycin/deoxyadenosine, although the accumulation of dATP in these cells was 2-fold greater than in resting cells. The repair of DNA single strand breaks in chronic lymphocytic leukemia cells was as rapid as for proliferating L5178Y cells, but repair was significantly inhibited by 2'-deoxycoformycin/deoxyadenosine. These results suggest that 2'-deoxycoformycin/deoxyadenosine can function as a radiosensitizer, and this effect is associated with the cellular accumulation of dATP and inhibition of repair of DNA single strand breaks.

Topics: Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Animals; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; DNA Damage; DNA Repair; Drug Synergism; Leukemia L5178; Leukemia, Experimental; Leukemia, Lymphoid; Mice; NAD; 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

Four patients with refractory chronic lymphocytic leukemia were treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin, and initially received 4 mg/m2 i.v. weekly. Clinical responses to therapy varied: Patient A had a minimal response; whereas Patient D showed an 85% decrease in lymphocyte count at 2 wk; and Patients B and C had intermediate responses. The pretreatment mononuclear cell adenosine deaminase activities, which ranged from 1.6 to 44.6 nmol adenosine/h/10(6) cells, decreased to approximately 1 nmol adenosine /h/10(6) cells 24 h following 2'-deoxycoformycin, and increased to 15 to 50% of the pretreatment activity prior to the second drug treatment. The clinical response to 2'-deoxycoformycin was unrelated to the pre- or posttreatment adenosine deaminase activities or to the rate of return of enzyme activities following treatment. The plasma deoxyadenosine levels and the leukemic cell dATP concentrations rose slightly with therapy, but there was no correlation between the magnitude of increase and clinical response. No significant levels of DNA strand breaks were observed in the leukemic cells following treatment, although the NAD levels decreased slightly in two patients. When peripheral mononuclear cells from the patients and two controls were incubated in vitro for 24 h with 2'-deoxycoformycin and increasing concentrations of deoxyadenosine, a concentration-dependent increase in dATP and decrease in NAD were observed in both the patients and normals. The normal cells, and cells from two patients, developed a significant number of DNA strand breaks. However, there was no relationship between the formation of DNA breaks and the degree of accumulation of dATP or depletion of NAD, or between any of these changes and subsequent clinical responses to 2'-deoxycoformycin. Based on this study, it appears that the antitumor activity of 2'-deoxycoformycin in chronic lymphocytic leukemia is unrelated to the induction of DNA strand breaks or to changes in the levels of dATP or NAD in the leukemic cells.

Topics: Adenosine Deaminase Inhibitors; Aged; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; DNA; Humans; Leukemia, Lymphoid; Male; Middle Aged; Monocytes; NAD; Pentostatin; Ribonucleosides

The in-vitro effects of deoxycoformycin (dCF) on dATP, NAD, ATP and DNA strand breaks have been evaluated in the cells from 42 patients with various types of chronic lymphoid leukemia. These included 18 with B-cell chronic lymphoid leukemias of different types (BCL); 10 with hairy cell leukemia (HCL) and 14 with T-cell chronic lymphoid leukemias of different types (TCL). The dATP concentrations in HCL, BCL and TCL increased from means of 2.9, 1.8 and 3.0 to 100.3, 68.2 and 51.3 pmol/10(6) cells respectively after 2 h with 10(-5) M dCF and 10(-4)M deoxyadenosine. After 18-24 h, the NAD levels and total double-stranded DNA decreased to 37 and 12.5% (HCL) to 36 and 21.6% (BCL) and 40 and 20.5% (TCL) of control values respectively. Similar decreases were observed in ATP levels. The results do not suggest that these measurements in vitro would predict which patients with these disorders will respond to dCF therapy. Although HCL responds particularly well to dCF in vivo, no difference in the in-vitro effects of dCF studied here could be detected between cases of HCL and the other types of chronic leukemia.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; DNA Damage; Humans; Leukemia, Lymphoid; NAD; Pentostatin; Ribonucleosides

Topics: Antineoplastic Agents; Coformycin; Drug Evaluation; Humans; Leukemia, Lymphoid; Pentostatin; Ribonucleosides; Sezary Syndrome

Two elderly patients with prolymphocytic leukaemia (PLL) of T helper phenotype were treated with the adenosine deaminase inhibitor--deoxycoformycin--and achieved remission. The first patient has remained in an unmaintained remission for over a year. The second patient, treated with a regime which produced less side effects, subsequently relapsed in skin and lymph nodes and died. In view of the rarity of this condition a multi-centre assessment of the effectiveness of deoxycoformycin is indicated. T-lymphocyte colony formation in both cases was found to be reduced. Co-culture of the patients' lymphocytes with nonadherent mononuclear cells from normal individuals also showed inhibition of T-colony formation indicating that lack of nutrients or accessory cells was not responsible for low T-colony forming capacity.

Topics: Aged; Antineoplastic Agents; Cells, Cultured; Coformycin; Colony-Forming Units Assay; Female; Humans; Leukemia, Lymphoid; Lymphocytes; Male; Pentostatin; Ribonucleosides; T-Lymphocytes, Helper-Inducer; Time Factors

The toxicity of the purine nucleoside, deoxyadenosine in the presence of the adenosine deaminase inhibitor, deoxycoformycin and of deoxyguanosine in the presence of the purine nucleoside phosphorylase inhibitor, 8-aminoguanosine was measured against two Thy-leukemic cell lines. Toxicity was assessed by the survival of clonogenic cells in a colony assay. The kill of clonogenic Thy-leukemic cells was 99.99% with both nucleoside enzyme inhibitor combinations following 4-h incubations when 50 microM concentration of nucleoside were used. With these nucleoside concentrations some reduction in toxicity was apparent when drug treated cells were cultured in the presence of deoxycytidine (50 microM), however, this reduction in toxicity was not apparent when higher nucleoside concentrations were used (100 microM). Survival of bone marrow myeloid progenitor cells (CFU.GM) was only slightly reduced by these nucleoside concentrations following 4 hour incubations. The presence of a twenty-fold excess of normal bone marrow cells reduced the cytotoxic effect but clonogenic cell incubation still ranged from 99.98 to 99.99% for deoxyguanosine and deoxyadenosine respectively. These combinations of nucleosides and enzyme inhibitors may have a therapeutic role in the elimination of malignant Thy cells from human bone marrow.

Topics: Adenosine Deaminase Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Line; Cell Survival; Coformycin; Deoxyadenosines; Deoxycytidine; Deoxyguanosine; Guanosine; Hematopoietic Stem Cells; Humans; Leukemia, Lymphoid; Nucleoside Deaminases; Pentostatin; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Ribonucleosides; Tumor Stem Cell Assay

Topics: Adult; Antigens, Surface; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Coformycin; Drug Administration Schedule; Humans; Leukemia, Lymphoid; Male; Pentostatin; Ribonucleosides; T-Lymphocytes; Vidarabine

4 men with an unusual variant of T-cell chronic lymphocytic leukaemia are reported. The clinical features differed from the virus-associated T-cell disease reported from Japan, the Caribbean, and the southeastern United States. Cytology was pleiomorphic: cells with cerebriform nuclei resembling Sézary cells and lymphocytes with cytoplasmic granules resembling T-suppressor cells occurred in the same patients. Immunofluorescence studies with monoclonal antibodies suggested that the leukaemia cells expressed determinants of both helper- (OKT4+) and suppressor-(OKT8+) related antigens. The cells were TdT-negative. In all patients the disease was very refractory to conventional cytotoxic agents, but there was prompt and extensive response to the adenosine deaminase inhibitor pentostatin (2'-deoxycoformycin). This agent merits further study in the treatment of T-cell chronic lymphocytic leukaemia.

Topics: Adult; Antibodies, Monoclonal; Antineoplastic Agents; Coformycin; Epitopes; Humans; Leukemia, Lymphoid; Male; Middle Aged; Pentostatin; Phenotype; Ribonucleosides; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA), was explored for its antineoplastic potential in 28 patients with advanced lymphoid malignancy. Both normal and malignant B lymphocytes have low levels of ADA activity, and low doses of dCF profoundly inhibit this enzyme in the peripheral blood of patients with chronic lymphocytic leukemia (CLL). The low doses of dCF administered in this trial (4 mg/m2) were not associated with prohibitive toxicity. Five of 28 patients had an objective response. Four additional patients had clinical improvement. No significant difference in the pretreatment ADA activity existed between responding patients and treatment failures. The demonstration of responses to dCF following failure on standard alkylating agents suggests that dCF may not be cross-resistant with current agents used to treat CLL. Additional studies should be pursued using low-dose dCF in patients with advanced malignancy.

Topics: Adenosine Deaminase Inhibitors; B-Lymphocytes; Candidiasis; Coformycin; Conjunctivitis; Drug Administration Schedule; Gastrointestinal Diseases; Herpesviridae Infections; Humans; Leukemia, Lymphoid; Liver Function Tests; Lymphoma, Non-Hodgkin; Middle Aged; Nucleoside Deaminases; Pentostatin; Respiratory Tract Infections; Ribonucleosides

Cultured human T-lymphoblastoid cell lines are more sensitive than B-cell lines to 2'-deoxyadenosine in the presence of 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase. This difference is related to the greater efficiency with which T-lymphoblasts accumulate cytotoxic levels of dATP derived from the adenosine deaminase substrate 2'-deoxyadenosine (dAdo). Previous work has shown that differences in dATP accumulation by cultured T- and B-lymphoblastoid cell lines cannot be explained by large differences in the levels of dAdo-phosphorylating or dAdo nucleotide (dAXP)-degrading activities in cytoplasmic extracts of these cells, although it has been proposed that intact B-cell lines may catabolize intracellular dAXP more rapidly than do T-cell lines. To further examine the determinants of dAdo sensitivity in T- and B-lymphoblasts, we have studied dAdo and dAXP metabolism in the human T- and B-cell lines CEM and WI-L2 and in hybrids generated by fusion of these cell lines. The hybrid nature of the fusion products was established by nutritional studies and by analyses of cellular surface antigens, DNA content, and enzymatic activities. We found that WI-L2 X CEM hybrids and another T X B hybrid derived from fusion of the SB human B-cell line with CEM were 30- to 40-fold less sensitive to dAdo and about 10-fold less sensitive to the dAdo analogue 9-beta-D-arabinofuranosyladenine than was CEM, or about as resistant as were their B-cell parental lines. Our studies confirm that CEM avidly accumulates dAXP from dAdo but does not catabolize intracellular dAXP. In contrast, WI-L2, SB, and WI-L2 X CEM and SB X CEM hybrids rapidly degraded intracellular dAXP, which limited their ability to undergo dAXP pool expansion. Expression of dAXP catabolic activity in T X B hybrids behaved as a dominant mechanism, conferring resistance to dAdo- and dAdo-related nucleosides to T X B hybrids. It has been postulated that cell fusion may play a role in the progression of tumors and contribute to diversity among the cells that compose clonal tumors. We have speculated that fusion of a malignant T-lymphoblast with an activated B-cell might be a mechanism for the evolution of drug resistance in acute T-cell leukemia.

Topics: Adenine Nucleotides; Antigens, Surface; B-Lymphocytes; Cells, Cultured; Coformycin; Culture Media; Deoxyadenosines; Deoxycytidine Kinase; DNA; Drug Resistance; Humans; Hybrid Cells; Leukemia, Lymphoid; Models, Biological; Pentostatin; T-Lymphocytes

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: Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Adenosylhomocysteinase; Aged; Coformycin; Deoxyadenine Nucleotides; Erythrocytes; Female; Humans; Hydrolases; Leukemia, Lymphoid; Nucleoside Deaminases; Pentostatin; T-Lymphocytes

Topics: B-Lymphocytes; Cell Division; Cell Line; Coformycin; DNA; Drug Resistance; Humans; Leukemia, Lymphoid; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Lymphocytes; Pentostatin; Ribonucleosides; T-Lymphocytes

The mechanisms for cell toxicity with adenosine deaminase inhibition by 2'-deoxycoformycin (dCF) in non replicating lymphoid cells include S-adenosylhomocysteine (SAH) hydrolase inactivation and reduction of cellular ATP content. These postulates were explored in a patient with T-CLL receiving dCF with a resultant fall in peripheral blood lymphocytes from 740 X 10(9)/1 to 90 X 10(9)/1 over 15 d. In red cells there was complete inhibition of adenosine deaminase and SAH hydrolase activities, progressive deoxyadenosine triphosphate (dATP) accumulation and ATP depletion but no significant alteration in adenosine monophosphate (AMP) deaminase activity or distribution in purine intermediates from radioactive adenosine. In T-CLL lymphocytes, there was incomplete lymphoid SAH hydrolase inactivation, reduced AMP deaminase activity and progressive dATP accumulation. The limited decrease in lymphocyte ATP content was related more to dCF administration than dATP accumulation, nor accompanied by significant changes in the distribution of purine intermediates from adenosine. These findings suggest that ATP depletion with dCF therapy does not reflect AMP deaminase activity modulation nor is of critical importance for cell toxicity. The exact role for elevated cellular dATP content and SAH hydrolase inactivation in this toxicity remains to be established.

Topics: Adenosine Deaminase; Adenosine Triphosphate; Adenosylhomocysteinase; AMP Deaminase; Coformycin; Cytotoxicity, Immunologic; Deoxyadenine Nucleotides; Deoxyadenosines; Humans; Hydrolases; Leukemia, Lymphoid; Male; Middle Aged; Pentostatin; Ribonucleosides; T-Lymphocytes

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; B-Lymphocytes; Cell Line; Cell Survival; Child; Coformycin; DNA Nucleotidylexotransferase; Humans; Leukemia, Lymphoid; Pentostatin; Purine Nucleotides; Purine-Nucleoside Phosphorylase; T-Lymphocytes; Thymus Neoplasms

A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combination of dCF and 9-beta-D-arabinofuranosyladenine (ara-A). We monitored the levels in plasma and urine of adenosine, 2'-deoxyadenosine, and ara-A as well as the accumulation of their nucleotide derivatives in erythrocytes and circulating lymphoblasts. We also monitored the activities of adenosine deaminase and S-adenosylhomocysteine (AdoHcy) hydrolase and the concentrations of AdoHcy and S-adenosylmethionine in lymphoblasts. Production of 2'-deoxyadenosine was related to both the duration of dCF infusion and the magnitude of cytolysis that occurred during treatment: much more 2'-deoxyadenosine was produced by dCF infusion when disease was active than by the same infusion given during remission. Resistance to dCF was associated with a decrease of greater than 90% in the amount of deoxyadenosine 5'-triphosphate accumulated by circulating lymphoblasts. Infusion of dCF resulted in increases of up to 20-fold in the concentration of AdoHcy in circulating lymphoblasts, causing a decrease in the S-adenosylmethionine:AdoHcy ratio (the "methylation index") from a pretreatment value of greater than 40:1 to less than 4:1. This ratio decreased to 2.5:1 during combined treatment with dCF and ara-A, which caused nearly complete inactivation of lymphoblast AdoHcy hydrolase. Decline in the methylation index was accompanied by inhibition of the methylation of newly synthesized lymphoblast RNA. Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use.

Topics: Acute Disease; Adenosine; Adult; Coformycin; Deoxyadenosines; Drug Resistance; Drug Therapy, Combination; Erythrocytes; Homocysteine; Humans; Leukemia, Lymphoid; Lymphocytes; Male; Pentostatin; Ribonucleosides; S-Adenosylhomocysteine; Time Factors; Vidarabine

The toxicity of the deoxyribonucleosides, 2'-deoxyadenosine, 2'-deoxyguanosine, and thymidine, for human T lymphoblasts is mediated by the accumulation of the corresponding deoxyribonucleoside triphosphate (dATP, dGTP, or dTTP, respectively). We have examined whether leukemic cells of non-T-cell origin are capable of accumulating deoxyribonucleotides in culture and whether this capability correlates with the activities of purine metabolizing enzymes in these cells. We have found that non-T, non-B acute lymphoblastic leukemia cells with low ecto-5'-nucleotidase and high adenosine deaminase activities increase their dATP pools by greater than tenfold when exposed to deoxyadenosine and an inhibitor of adenosine deaminase in culture. Cells from 2 of 9 patients with chronic lymphocytic leukemia and 4 of 11 patients with acute nonlymphoblastic leukemia achieved similar elevations in dATP, but there was no relationship between dATP accumulation and adenosine deaminase, purine nucleoside phosphorylase, or ecto-5'-nucleotidase activities. Treatment of four individuals with acute lymphoblastic leukemia with the adenosine deaminase inhibitor, 2'-deoxycoformycin, resulted in elevations in plasma deoxyadenosine concentrations and in increments in lymphoblast dATP levels that were similar to those measured in lymphoblasts cultured with deoxyadenosine and deoxycoformycin prior to treatment. In vitro incubations of leukemic cells with deoxyribonucleosides may provide a rational basis for the use of these compounds as chemotherapeutic agents.

Topics: Adenosine Deaminase; Adenosine Triphosphate; Coformycin; Enzyme Inhibitors; Guanosine Triphosphate; Humans; Leukemia, Lymphoid; Lymphocytes; Pentostatin; Thymidine

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

The effect of the adenosine deaminase inhibitor, 2'-deoxycoformycin, on cellular nucleotides during therapy with continuous infusion of 9-beta-D-arabinofuranosyladenine (ara-A) has been investigated. In three courses of treatment using increasing doses, the active 5'-triphosphate of ara-A, 9-beta-D-arabinofuranosyladenine 5'-triphosphate (ara-ATP) accumulated in leukemic cells and erythrocytes from a patient treated for acute lymphocytic leukemia in proportion to the dose of ara-A. The cellular ara-ATP concentration increased more than 5-fold after the injection of a single, nontoxic, but pharmacologically active dose of 2'-deoxycoformycin 24 hr after initiation of ara-A infusion. However, this response was associated with a concomitant increase in the cellular deoxyadenosine triphosphate concentrations to levels equal to or greater than those of ara-ATP throughout the three treatment courses studied. Consistent with previous results using cell-free systems, it was demonstrated that a competitive relationship exists between deoxyadenosine triphosphate and ara-ATP for the inhibition of DNA synthesis in cultured human lymphoblastoid cells and that the ratio of the cellular concentrations of these nucleotides could predict the extent of inhibition of DNA synthesis. Application of this rationale to the nucleotides in the leukemic cells of the patient suggested that administration of 2'-deoxycoformycin may create a cellular biochemical milieu that could be antagonistic to the inhibition of DNA synthesis by ara-ATP.

Topics: Adult; Arabinonucleotides; Cell Line; Chromatography, High Pressure Liquid; Coformycin; Deoxyadenine Nucleotides; DNA; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Male; Pentostatin; Ribonucleosides; Vidarabine; Vidarabine Phosphate

Topics: 5'-Nucleotidase; Adenosine Deaminase; Adenosylhomocysteinase; Adolescent; Adult; Coformycin; Humans; Hydrolases; Leukemia, Lymphoid; Nucleotidases; Pentostatin; Ribonucleosides

Loss of ATP accompanying accumulation of dATP has recently been reported to occur in the erythrocytes and lymphoblasts of patients with T lymphocytic leukemia during treatment with deoxycoformycin, an inhibitor of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) that causes the accumulation of deoxyadenosine. We have studied the mechanisms responsible for adenine ribonucleotide depletion in cultured human CEM T lymphoblastoid cells treated with deoxycoformycin and deoxyadenosine. Accumulation of dATP was accompanied by depletion of total soluble adenine ribonucleotides without change in the adenylate energy charge, by the route ATP --> AMP --> IMP --> inosine --> hypoxanthine; conversion of IMP to AMP and de novo purine synthesis were inhibited in these cells. ATP degradation did not occur in a mutant of CEM that was incapable of phosphorylating deoxyadenosine, or in a B cell line with very limited ability to accumulate dATP. We found that dATP and ATP were both able to stimulate markedly the deamination of AMP by lymphoblast AMP deaminase; dAMP was a poor substrate for this enzyme (K(m) = 2.4 mM, vs. 0.4 mM for AMP). Similarly, dATP as well as ATP caused marked activation of IMP dephosphorylation by a lymphoblast cytoplasmic nucleotidase. Inhibition of intracellular AMP deaminase with coformycin prevented degradation of adenine ribonucleotides without affecting dATP accumulation. We propose that ATP-dependent phosphorylation of deoxyadenosine generates ADP and AMP. Simultaneously, dATP accumulation stimulates deamination of AMP, but not dAMP, and the dephosphorylation of IMP to inosine. Coupling of AMP degradation to ATP utilization in deoxyadenosine phosphorylation maintains the adenylate energy charge despite net depletion of cellular ATP.

Topics: 5'-Nucleotidase; Adenine Nucleotides; Adenosine Deaminase Inhibitors; B-Lymphocytes; Cell Line; Coformycin; Deoxyadenosines; Humans; Kinetics; Leukemia, Lymphoid; Nucleoside Deaminases; Nucleotidases; Pentostatin; 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

2'-Deoxycoformycin (DCF) is an inhibitor of the enzyme adenosine deaminase (ADA) and has shown promise as an antileukemia agent. For the assessment of the extent to which systemically administered DCF crosses into the central nervous system (CNS), rhesus monkeys were given iv boluses of DCF. Simultaneous blood and cerebrospinal fluid (CSF) samples were assayed for DCF levels at times ranging from 10 minutes to 6 hours after the drug was given. Average peak CSF drug levels of 5.5 X 10(-8) M and 3 X 10(-7) M were reached 1 1/2 - 2 hours following injections of 0.25 and 1.0 mg DCF/kg, respectively. The ratio of peak CSF to simultaneous plasma levels was 1 to 10. Data obtained from a patient who had acute lymphocytic leukemia and who was given iv DCF were comparable. Drug levels achieved within the CSF following iv administration of 0.25 mg DCF/kg are similar to those previously demonstrated to inhibit ADA. These results may be important both for understanding DCF-related CNS toxicity and for designing combination chemotherapy with DCF.

Topics: Animals; Blood-Brain Barrier; Child; Coformycin; Half-Life; Humans; Injections, Intravenous; Kinetics; Leukemia, Lymphoid; Macaca mulatta; Male; Pentostatin; Ribonucleosides

The occurrence of severe immunodeficiency disease in children with inherited adenosine deaminase deficiency, and reports of remission induction in T-cell acute lymphoblastic leukaemia with the adenosine deaminase inhibitor deoxycoformycin, prompted a study of the effects of deoxyadenosine on resting peripheral blood lymphocytes (PBL) and chronic lymphocytic leukaemic (CLL) lymphocytes in short-term culture. In the presence of an inhibitor of adenosine deaminase, micromolar concentrations of dAdo caused elevation of deoxyadenosine-5'-triphosphate (dATP) pools and in vitro lysis of non-dividing PBL and CLL lymphocytes. This death of non-replicating cells indicates a mechanism of deoxyadenosine toxicity independent of DNA replication and ribonucleotide reductase inhibition. Similar changes occurred in vivo in a patient with advanced CLL who responded to treatment with deoxycoformycin, 0.1 mg/kg, days 1-5, with a fall in the WCC from 102.0 x 10(9)/1 to 6.8 x 10(9)/l over 21 d. Therapeutic blockade of deoxyadenosine catabolism deserves further investigation both in the treatment of lymphoproliferative disease and as a method lympholytic immunosuppression.

Topics: Adenosine Deaminase Inhibitors; Cell Survival; Cells, Cultured; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; DNA Replication; Humans; Leukemia, Lymphoid; Lymphocytes; Male; Middle Aged; 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

It has been suggested that, by inhibiting the adenosine deaminase (ADA)-mediated catabolism of 9-beta-D-arabinofuranosyladenine (ara-A), 2'-deoxycoformycin (DCF) would increase the half-life (t1/2) of ara-A, a compound with known antileukemic activity. To test this hypothesis, we collected serial plasma samples from five patients with refractory acute lymphoblastic leukemia who participated in a Phase I trial of i.v. DCF 915 mg/sq m) in combination with i.v. single-dose ara-A (120-250 mg/sq m). In four of these patients, of whom three were known to have achieved greater than 98% ADA inhibition, a mean ara-A t1/2 of 227 min was achieved. Extrapolated peak levels (i.e., following infusion of ara-A) ranged from 1.5 to 7.4 micrograms/ml (mean, 4.2 micrograms/ml). Elimination of drug appeared to follow a single-compartment model. In two patients who received ara-A without prior DCF and in a third patient who had significant residual ADA activity despite DCF, ara-A was unmeasurable within 5 min of the end of infusion. These data confirm that the kinetics of ara-A catabolism can be altered by inhibition of ADA and suggest that more than one dose of DCF may be necessary for complete inhibition of the enzyme and optimal pharmacological modulation of ara-A.

Topics: Adolescent; Adult; Arabinonucleosides; Child, Preschool; Coformycin; Drug Evaluation; Drug Therapy, Combination; Female; Half-Life; Humans; Hypoxanthines; Kinetics; Leukemia, Lymphoid; Male; Pentostatin; Ribonucleosides; Vidarabine

Topics: Acute Disease; Antineoplastic Agents; Child; Coformycin; Humans; Leukemia, Lymphoid; Male; Methylprednisolone; Pentostatin; Positive-Pressure Respiration; Respiratory Insufficiency; Ribonucleosides

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

Deoxycoformycin (DCF) is an inhibitor of adenosine deaminase (ADA). Twenty-one courses of DCF were administered to 13 patients ranging in age from 15 to 78 yr. Eight patients had T-cell disorders, and five patients had non-T-cell malignancies. The i.v. bolus dose was escalated from 5 to 30 mg/sq m/day, and the duration of the courses ranged from 1 to 5 days. The DCF plasma half-life ranged from 4.9 to 6.2 hr and was independent of dose. The dose-limiting toxicities involved the central nervous system (CNS) and the kidneys. Other toxicities included bronchitis, decreases in hematocrit, arthralgias, and myalgias. Mortality was encountered in three patients. These toxic effects may have been secondary to the accumulation of the metabolites adenosine and deoxyadenosine. Deoxyadenosine and adenosine were both detectable in plasma (10(-6) M) and in urine (10(-3) M). Two partial remissions were observed: one in a patient with T-cell ALL and another in a patient with mycosis fungoides. Minimal responses characterized by either declines in peripheral blast counts or partial resolution of adenopathy were observed in five other patients. No responses were observed in six patients. These observations suggest that DCF is effective in the treatment of T-cell lymphoid malignancies.

Topics: Adenosine; Adenosine Deaminase Inhibitors; Adenosine Kinase; Adolescent; Adult; Aged; Bronchitis; Coformycin; Coma; Conjunctivitis; Deoxyadenosines; Female; Humans; Kidney Diseases; Leukemia, Lymphoid; Lymphoma; Male; Middle Aged; Mycosis Fungoides; Nucleoside Deaminases; Pentostatin; Phosphotransferases; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides

The in vitro effects of deoxyadenosine and an adenosine deaminase inhibitor, deoxycoformycin, on the synthesis of DNA and the metabolism of purines were investigated in human leukemic T-cells. In the presence of 10 microM deoxycoformycin, the synthesis of DNA was completely inhibited by concentrations of deoxyadenosine of 10 microM or greater. In contrast, the synthesis of DNA in normal bone marrow cells was not inhibited in the presence of up to 20 microM deoxycoformycin and up to 10 microM deoxyadenosine. Following incubation of leukemia T-cells with deoxycoformycin and deoxyadenosine, there was a significant rise in the concentration of deoxyadenosine 5'-triphosphate which was accompanied by reductions in the concentrations of adenosine 5'-triphosphate and guanosine 5'-triphosphate, as revealed by high-pressure liquid chromatographic analysis. The effects of deoxycoformycin on T-cell leukemia were examined in vivo. A patient with acute T-cell leukemia in the terminal stage received five daily injections of 250 micrograms of deoxycoformycin per kg. Among the noted changes, most prominent was the drop in the leukocyte count. Initially, the cell count rose from 7,200 cells/microliters on Day 1 to 120,000 cells/microliters on Day 3. On Day 5, the cell count began to decline and reached a nadir of 600 cells/microliter on Day 10. The leukocyte count remained below 1,000 cells/microliter through Day 12. The reduction in cell count was preceded by a decline in the incorporation of [3H]thymidine in the cells, which dropped to negligible amount by Day 7. The other prominent change was a decrease in adenosine deaminase activity in both red cells and leukemic cells. Adenosine deaminase activity of red cells dropped to 5% on Day 4, and that of leukemic cells dropped to 59% on Day 5. In addition, there were considerable alterations in the concentrations of purine metabolites which were characterized by a progressive reduction in the concentrations of total purine metabolites, especially adenosine 5'-triphosphate, and a transient rise in the concentrations of deoxyadenosine 5'-triphosphate, adenosine 5'-monophosphate, and adenosine 5-diphosphate. These findings suggest that treatment with deoxycoformycin may be of therapeutic value for T-cell leukemia. It may provide opportunities for studying the purine metabolism in T-leukemic cells which could lead to better approaches to treatment.

Topics: Adenosine Deaminase Inhibitors; Cells, Cultured; Child, Preschool; Chromatography, High Pressure Liquid; Coformycin; Deoxyadenosines; DNA; Erythrocytes; Humans; Leukemia, Lymphoid; Leukocyte Count; Male; Pentostatin; Purines; Ribonucleosides; T-Lymphocytes

2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzyme elevations, and conjunctivitis. Lymphopenia occurred in all patients. The most serious adverse effects were acute tubular necrosis and central nervous system toxicity, which appeared to be dose related. In addition, two patients given the 0.75-mg/kg dose developed severe hepatic toxicity, although this could not be ascribed definitively to 2'-dCF. Antitumor activity was observed in eight patients, two of whom experienced a complete remission. Inhibition of lymphoblast adenosine deaminase activity was noted in the majority of cases and was observed at all doses. Antileukemic activity occurred at doses of 2'-dCF which were not associated with limiting toxicities. These results suggest that 2'-dCF is active against acute lymphoblastic leukemia and that a starting dose of 0.5 mg/kg/day be utilized in Phase II studies.

Topics: Adenosine Deaminase Inhibitors; Adolescent; Adult; Child; Child, Preschool; Coformycin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia, Lymphoid; Liver; Lymphopenia; Male; Nausea; Pentostatin; Prognosis; Ribonucleosides; Vomiting

Topics: Adenine; Adenosine Deaminase Inhibitors; Cell Line; Coformycin; Deoxyadenosines; Enzyme Inhibitors; Humans; Leukemia, Lymphoid; Nucleoside Deaminases; Pentostatin; Phosphorylation; Vidarabine

In four patients with Thy-acute lymphoblastic leukaemia changes in blast cell deoxynucleoside triphosphate concentrations and, in three, changes in blast cell S-adenosyl homocysteine hydrolase activity were measured during treatment with 2' deoxycoformycin, a potent inhibitor of adenosine deaminase. These studies were aimed at identifying the molecular basis of cell killing by this drug. In three patients an increase in blast deoxyadenosine triphosphate (dATP) concentration occurred which was found to be temporally related to cell killing and was accompanied by decreased concentrations of the other three deoxyribonucleoside triphosphates. In the one patient with Thy-ALL who responded poorly to treatment, the increase in dATP concentration was delayed and was not accompanied by a fall in the concentrations of the other deoxyribonucleoside triphosphates. Progressive inactivation of blast cell S-adenosyl homocysteine hydrolase was found to occur in the three patients tested but was maximal only after a substantial reduction of peripheral blast cell count. These results show that 2' deoxycoformycin has a potent cytoreductive effect in Thy-ALL and suggest that the molecular basis of this toxicity is related both to the intracellular accumulation of dATP with inhibition of ribonucleotide reductase. Inactivation of S-adenosyl homocysteine hydrolase may be of importance as an additional mechanism.

Topics: Adenosine Deaminase; Adenosylhomocysteinase; Adolescent; Adult; Bone Marrow; Coformycin; Deoxyadenine Nucleotides; Deoxycytosine Nucleotides; Deoxyguanine Nucleotides; Humans; Hydrolases; Leukemia, Lymphoid; Leukocyte Count; Male; Pentostatin; Ribonucleosides; Thymine Nucleotides

2'-Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase, has recently undergone Phase I clinical trials and has been found to be therapeutically active in acute lymphoblastic leukemia. In this report, levels of dCF in plasma, plasma concentrations of adenosine and deoxyadenosine, and urine levels of deoxyadenosine were measured in leukemic patients undergoing treatment with dCF during a Phase I clinical trial. dCF was administered i.v. at a dose of 0.25 to 1.0 mg/kg (7.5 to 30 mg/sq m) for 3 consecutive days. Plasma drug levels of 2 to 6 microM were observed following the third dose of dCF, and drug accumulation occurred only at the 1-mg/kg dosage. In this limited series of patients, the plasma concentrations of adenosine and deoxyadenosine and the urine concentrations of deoxyadenosine did not show an obvious correlation with dCF dose, therapeutic response, or toxicity.

Topics: Adenosine; Adolescent; Adult; Child; Child, Preschool; Coformycin; Deoxyadenosines; Drug Evaluation; Female; Humans; Leukemia, Lymphoid; Male; Pentostatin; Ribonucleosides; Time Factors

Two patients with relapsed acute lymphoblastic leukaemia of thymic phenotype (Thy-ALL) resistant to all conventional chemotherapy achieved complete remission when treated with 2'-deoxycoformycin, a selectively lymphocytotoxic compound that acts by inhibition of the enzyme adenosine deaminase. These observations show that malignant thymocytes are dependent on adenosine-deaminase activity and suggest that it may be possible to use deoxycoformycin in other patients with Thy-ALL to induce remission or to kill Thy-ALL blasts in bone marrow harvested before autologous bone-marrow transplantation, leaving normal haemopoietic stem cells intact.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Adult; Child; Coformycin; Female; Humans; Leukemia, Lymphoid; Male; Nucleoside Deaminases; Pentostatin; Phenotype; Ribonucleosides; T-Lymphocytes; Thymus Gland

2'-deoxycoformycin (2'-dCF; Pentostatin), a stoichiometric inhibitor of mammalian adenosine deaminase (ado deaminase), exhibits immunosuppressive and antilymphocytic activity in animal test systems. A clinical pharmacology/phase I study of 2'-dCF administered as a single agent has been completed (18 patients). Dose levels ranged from 0.1 mg/kg X 1 to 0.25 mg/kg/day X 5; ado deaminase and 2'-dCF were measured spectrophotometrically. Plasma decay curves were bi-exponential (alpha and beta t 1/2 values about 1 and 10 h respectively). Recovery of unchanged 2'-dCF from urine (48 h) was 32%--48% of the administered drug. Major toxic manifestations were lymphocytopenia (all patients) and urate nephropathy (1 patient, with subsequent patients in the series receiving allopurinol, 300 mg/day). Three partial responses were seen in seven patients with acute lymphocytic leukaemia receiving 0.25 mg 2'-dCF/kg/day X 5.

Topics: Adenosine Deaminase Inhibitors; Adult; Aged; Animals; Coformycin; Dogs; Female; Humans; Kinetics; Leukemia, Lymphoid; Lymphocytes; Male; Middle Aged; Nausea; Neoplasms; Nucleoside Deaminases; Pentostatin; Ribonucleosides; Uric Acid

Topics: Adenosine Deaminase Inhibitors; Allopurinol; Biological Transport; Coformycin; Humans; Leukemia, Lymphoid; Nucleoside Deaminases; Pentostatin; Ribonucleosides