The biochemical and clinical consequences of 2'-deoxycoformycin in T cell chronic lymphocytic leukaemia.
The mechanisms for cell toxicity with adenosine deaminase inhibition by 2'-deoxycoformycin (dCF) in non replicating lymphoid cells include S-adenosylhomocysteine (SAH) hydrolase inactivation and reduction of cellular ATP content. These postulates were explored in a patient with T-CLL receiving dCF with a resultant fall in peripheral blood lymphocytes from 740 X 10(9)/1 to 90 X 10(9)/1 over 15 d. In red cells there was complete inhibition of adenosine deaminase and SAH hydrolase activities, progressive deoxyadenosine triphosphate (dATP) accumulation and ATP depletion but no significant alteration in adenosine monophosphate (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, nor accompanied by significant changes in the distribution of purine intermediates from adenosine. These findings suggest that ATP depletion with dCF therapy does not reflect AMP deaminase activity modulation nor is 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.
D000659:AMP Deaminase / Q000097:blood; D000243:Adenosine Deaminase / Q000097:blood; D000255:Adenosine Triphosphate / Q000097:blood; D043383:Adenosylhomocysteinase; D003070:Coformycin / Q000008:administration & dosage* / Q000031:analogs & derivatives; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003838:Deoxyadenine Nucleotides / Q000097:blood; D003839:Deoxyadenosines / Q000097:blood; D006801:Humans; D006867:Hydrolases / Q000097:blood; D007945:Leukemia, Lymphoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015649:Pentostatin; D012263:Ribonucleosides / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; D000255:Adenosine Triphosphate; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase; D000659:AMP Deaminase; C026600:2'-deoxyadenosine triphosphate