Toxicity and immunosuppressive activity of binary combinations of 2'-deoxycoformycin and 2'-deoxyadenosine.
Treatment of mice with 2'-deoxycoformycin (dCf) for 5 days produced inhibition of spleen and lymph node adenosine deaminase (E. C. 3.5.4.4) activity but no hematologic toxicity or weight loss. A 64-fold elevation of erythrocyte dATP was observed. However, if mice were injected with 2'-deoxyadenosine (AdR) in combination with dCf, weight loss, hematologic toxicity, and liver cell necrosis occurred. These mice had a severe blood coagulation defect and a 73-fold elevation of plasma alanine transaminase activity, plasma prealbumin became undetectable, and erythrocyte dATP levels were elevated 1500-fold. Death during treatment appeared to be from acute liver failure since bone marrow toxicity was only detected following termination of treatment. These effects were not seen in mice receiving adenosine in combination with dCf. dCf, either alone or in combination with AdR, inhibited the contact sensitization to oxazalone in mice. The inhibition was associated with signs of systemic toxicity which were more pronounced in the combination-treated groups. If dATP is the toxic metabolic accumulated in the malignant cells of patients treated with dCf, we propose that AdR supplementation of treatment should be considered with extreme caution since severe damage to normal tissues might result.
D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity*; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003839:Deoxyadenosines / Q000494:pharmacology / Q000633:toxicity*; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015649:Pentostatin; D012263:Ribonucleosides / Q000633:toxicity*; D013154:Spleen / Q000187:drug effects / Q000201:enzymology
D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; D000243:Adenosine Deaminase