Biochemical consequences of adenosine deaminase inhibition in vivo. Differential effects in acute and chronic T cell leukemia.

The biochemical mechanisms whereby an inherited deficiency of adenosine deaminase (ADA; EC 3.5.4.4) activity results in selective toxicity to lymphoid cells has been the subject of considerable interest. Experimental evidence obtained with cultured lymphoid cell lines in vitro has indicated that 2'-deoxyadenosine, a substrate for ADA, is selectively phosphorylated to dATP in T lymphoblasts'~2 and that dATP accumulation directly correlates with inhibition of DNA synthesis and cell death.'.' An alternative hypothesis for the lymphocyte depletion in ADA deficiency entails the accumulation of S-adenosylhomocysteine and consequent inhibition of methylation reactions mediated by S-adenosylmethionine?6 Accumulation of S-adenosylhomocysteine could in theory result either from an excess of adenosine generated by ADA inhibition or from inactivation of the catabolic enzyme S-adenosyl-L-homocysteine hydrolase (EC 3.3.1.1) by deoxyadenosine.6 A third possibility is that ATP depletion may be a concomitant of dATP accumulation in mature lymph~ytes'.~ and could directly mediate the toxicity to these cells. In examining the therapeutic efficacy of 2'-deoxycoformycin (dCF), a tight-binding inhibitor of ADA: in refractory lymphoid malignancies we were directly concerned with elucidating the biochemical consequences of inhibiting ADA activity in vivo. Our goal was to correlate the biochemical sequelae with both the efficacy and the clinical toxicity of deoxycoformycin treatment. We also hoped to shed additional light on the mechanism by which lymphoid cells are lysed by pharmacologic inhibition of ADA activity in vivo.