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

Abstract

The mechanisms for cell toxicity with adenosine deaminase inhibition by 2''-deoxycoformycin (dCF) in nonreplicating lymphoid cells include S-adenosylhomocysteine (SAH) hydrolase inactivation and reduction of cellular ATP content. These postulates were explored in a patient with T-CLL [T cell chronic lymphocytic leukemia] receiving dCF with a resultant fall in peripheral blood lymphocytes from 740 .times. 109/l to 90 .times. 109/l over 15 days. In red blood cells there was complete inhibition of adenosine deaminase and SAH hydrolase activities, progressive dATP accumulation and ATP depletion, but no significant alteration in 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, and was not accompanied by significant changes in the distribution of purine intermediates from adenosine. ATP depletion with dCF therapy probably does not reflect AMP deaminase activity modulation and probably is not 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.