Biochemical correlates of the differential sensitivity of subtypes of human leukemia to deoxyadenosine and deoxycoformycin.
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.
D000243:Adenosine Deaminase / Q000378:metabolism; D000293:Adolescent; D003838:Deoxyadenine Nucleotides / Q000096:biosynthesis; D003839:Deoxyadenosines / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D007945:Leukemia, Lymphoid / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008223:Lymphoma / Q000378:metabolism; D008297:Male; D009708:Nucleotidases / Q000378:metabolism; D015649:Pentostatin; D013936:Thymidine / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D015649:Pentostatin; D009708:Nucleotidases; C029296:purine 5'-nucleotidase; D000243:Adenosine Deaminase; D014740:Vidarabine; D013936:Thymidine