Modulation of 9-β-d-Arabinofuranosyladenine 5′-Triphosphate and Deoxyadenosine Triphosphate in Leukemic Cells by 2′-Deoxycoformycin during Therapy with 9-β-d-Arabinofuranosyladenine¹

The effect of the adenosine deaminase inhibitor, 2′-deoxy-coformycin, on cellular nucleotides during therapy with continuous infusion of 9-β-d-arabinofuranosyladenine (ara-A) has been investigated. In three courses of treatment using increasing doses, the active 5′-triphosphate of ara-A, 9-β-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.