Enzyme activities of leukemic cells and biochemical changes induced by deoxycoformycin in vitro--lack of correlation with clinical response.
Deoxycoformycin (DCF) is a specific inhibitor of adenosine deaminase (ADA) and has been shown to be active in lymphoid neoplasms. Cytotoxicity is thought to be mediated by the accumulation of deoxyadenosine (AdR) and deoxyadenosine triphosphate (dATP) which inhibits ribonucleotide reductase and DNA synthesis in rapidly proliferating cells. Others suggested mechanisms leading to cell death particularly in non-dividing cells include depletion of ATP and NAD pools, inhibition of S-adenosylhomocysteine (SAH) hydrolase and induction of DNA strand breaks. In patients with high leukemic counts who were subsequently treated with DCF, we have studied (a) the levels of ADA, ecto-5'-nucleotidase (5NT), deoxyadenosine kinase (AdR-kinase) and SAH-hydrolase in the leukemic cells; [b) the in-vitro effects of DCF on dATP, ATP, NAD, SAH-hydrolase levels and on DNA strand breaks; and (c) the correlation between these parameters with clinical response to DCF. No significant difference in ADA, 5NT, AdR-kinase and SAH-hydrolase activities could be found between responders and non-responders. Incubation of the leukemic cells in vitro with DCF caused an inhibition of ADA, an accumulation of dATP, a moderate reduction in ATP and NAD levels, a suppression of SAH-hydrolase activity and an increase in DNA strand breaks in practically all the leukemic samples, irrespective of clinical response. Our results show that neither measurement of these enzymes nor studies of these biochemical sequelae of ADA inhibition in vitro predicts clinical responsiveness to DCF therapy.
Ho
A D
AD
Department of Internal Medicine V, University of Heidelberg, Federal Republic of Germany.
Ganeshaguru
K
K
Knauf
W
W
Dietz
G
G
Trede
I
I
Hoffbrand
A V
AV
Hunstein
W
W
D058892:Adenosine Deaminase Inhibitors; D000255:Adenosine Triphosphate / Q000097:blood; D043383:Adenosylhomocysteinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004249:DNA Damage; D003838:Deoxyadenine Nucleotides / Q000097:blood; D006801:Humans; D006867:Hydrolases / Q000097:blood; D007938:Leukemia / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D007943:Leukemia, Hairy Cell / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D015463:Leukemia, Prolymphocytic / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D015461:Leukemia, Prolymphocytic, T-Cell / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D009243:NAD / Q000097:blood; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D015649:Pentostatin; D012263:Ribonucleosides / Q000494:pharmacology*
D058892:Adenosine Deaminase Inhibitors; D000970:Antineoplastic Agents; D003838:Deoxyadenine Nucleotides; D012263:Ribonucleosides; D009243:NAD; D003070:Coformycin; D015649:Pentostatin; D000255:Adenosine Triphosphate; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D009700:Nucleoside Deaminases; C026600:2'-deoxyadenosine triphosphate