The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy

Abstract

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.

Differential cytotoxicity of deoxyguanosine and 8‐aminoguanosine for human leukemic cell lines and normal bone marrow progenitor cells

“…Successful application of a specific ADA inhibitor, 2' deoxycoformycin (dCF) in the treatment of Thy-ALL, which is characterized by raised ADA activity, has been reported (Koller et al, 1979;Prentice et al, 1980Prentice et al, , 1981. However, other workers have shown that dCF therapy is also effective in some B cell malignancies (Grever et al, 1981;Poplack et aI., 1981).…”

A phase I trial of α‐interferon in combination with pentostatin in hematologic malignancies

“…Key words: pentostatin, interferon, phase I trial, hematologic malignancies I NTRO D U CT 1 0 N Pentostatin, or 2'-deoxycoformycin, was initially isolated from Streptomyces antibioticus [ 11. This compound inhibits adenosine deaminase, thus producing a block in the catabolism of adenosine. This inhibition allows dATP and deoxyadenosine to accumulate intracellularly and may be responsible for cell death [2].…”

The Biochemical and Clinical Consequences of 2′‐Deoxycoformycin in T Cell Chronic Lymphocytic Leukaemia

“…Absence of this activity in genetic immunodeficiency disease (1) or following the use of the A D A inhibitor 2'-deoxycoformycin (dCF), results in toxicity for lymphoid cells, particularly those of T cell lineage (2)(3)(4) and this lymphotoxicity is thought to reflect the metabolic effects of adenosine and dAdo, or the metabolites that accumulate when their deamination is prevented. Increased concentrations of dATP occur in erythrocytes and lymphoid cells of children with A D A deficient immunodeficiency disease (5,6) and of individuals with lymphoid malignancies undergoing treatment with d C F (3,(7)(8)(9). A direct consequence of this raised cellular dATP content is reduced DNA synthesis attributed in part to diminished deoxynucleotide triphosphate synthesis following allosteric inhibition of ribonucleotide reductase by dATP (10).…”

“…The lymphocyte count reached a nadir of 90 x 109/1 on day 15 with moderate reduction in the size of all peripheral lymph nodes and hepatomegaly. In view of reports of renal toxicity with dCF administration(3,8) a high flow of urine was maintained and allopurinol 600 mg given daily. Nevertheless oliguria occurred on day 15 with S-creatinine of 0.22 rnmol/l, S-uric acid 0.84 mmol/l and creatinine clearance of 20 mlimin.…”