The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy.
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.
D000243:Adenosine Deaminase / Q000097:blood; D000255:Adenosine Triphosphate / Q000097:blood; D000293:Adolescent; D000328:Adult; D002648:Child; D003070:Coformycin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D004912:Erythrocytes; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D007962:Leukocytes / Q000201:enzymology; D008223:Lymphoma / Q000188:drug therapy*; D008875:Middle Aged; D009705:Nucleosides / Q000032:analysis; D015649:Pentostatin; D012075:Remission, Spontaneous; D012263:Ribonucleosides / Q000627:therapeutic use*
D009705:Nucleosides; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; D000255:Adenosine Triphosphate; D000243:Adenosine Deaminase