Biochemical pharmacology and toxicology of 8-azaadenosine alone and in combination with 2'-deoxycoformycin (pentostatin).
The toxicology and metabolism of 8-azaadenosine (8-azaAdo) were examined both as a single agent and in combination with the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF). The LD10 (mice) for 8-azaAdo alone on a once daily for 5 days (q.d. x 5) schedule was 30 mg . kg-1 . day-1. When the animals were pretreated with 0.1 mg . kg-1 . day-1 of dCF, the LD10 dose  was reduced to 10 mg . kg-1 . day-1 x 5. The major organ toxicity seen was hepatic. Bone marrow cellularity was only slightly altered at the LD10 dose. 8-AzaAdo nucleotides were detected in the livers of treated mice as determined by high performance liquid chromatography. Further, after 2 hr of incubation, isolated rat hepatocytes accumulated 8-azaATP to levels of 2.2 mumoles/g of cells with 8-azaAdo (1 mM) alone and to 4.3 mumoles/g of cells when 8-azaAdo was used in combination with dCF (1 microgram/ml). ATP levels decreased to below the limits of detection after 2 hr in cells treated with the combination. The replacement of cellular ATP by 8-azaATP may provide an explanation for the hepatotoxicity observed in the murine toxicology studies.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001774:Blood Chemical Analysis; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D007928:Lethal Dose 50; D007958:Leukocyte Count; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D015649:Pentostatin; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology*; D013950:Thymus Gland / Q000502:physiology
D012263:Ribonucleosides; C002155:8-azaadenosine; D003070:Coformycin; D015649:Pentostatin; D000241:Adenosine