Toxicity and metabolism of 3'-deoxyadenosine N1-oxide in mice and Ehrlich ascites tumor cells.
The toxic effect of 3'-deoxyadenosine N1-oxide (3'-dANO) on mice, on their different organs, and on Ehrlich ascites tumor cells was studied. In both healthy and tumour-bearing animals, the lethal dose for 10% of the mice receiving i.p. injections (LD10) of 3'-dANO was estimated to be about 300 mg/kg x 4 days in one mouse strain (Theiller). In another mouse strain (NMRI), we obtained a markedly higher LD10 value (675 mg/kg x 5 days). At nonlethal doses (250 mg/kg x 4 days), we observed reversible neurological symptoms on days 4-12 after treatment, but no macroscopical or microscopical changes was detected in the brain, heart, thymus, lung, lymph node, spleen, liver, kidney, bone marrow, or gastrointestinal tract. At doses of 450 mg/kg x 4 days, severe neurological symptoms were observed, and atony of the gastrointestinal canal and damage to the kidney and liver were registered. Even at doses that were lethal to the mice, no histopathological change was observed in the bone marrow or in the gastrointestinal canal. Pharmacokinetics studies showed that after the i.p. injection of 3'-dANO, the maximal plasma concentration was reached after 10 min, after which it declined showing a half-life of about 40 min. A transient accumulation of 3'-deoxyadenosine triphosphate (3'-dATP) was observed within 24 h in the liver and kidney, with the maximal concentration being reached after about 2-3 h. 3'-dANO was excreted partly as the unchanged substance and partly as the metabolite 3'-deoxyinosine within 24 h. Flow-cytometric DNA analysis of Ehrlich tumor cells treated either in vitro or in vivo with 3'-dANO revealed no therapy-induced change in the cell-cycle perturbations, which indicates that cells were randomly killed during all phases of the cycle.
Svendsen
K R
KR
Department of Biochemistry C, Panum Institute, University of Copenhagen, Denmark.
Overgaard-Hansen
K
K
Frederiksen
S
S
Engelholm
S A
SA
Pedersen
N T
NT
Vindeløv
L L
LL
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D003839:Deoxyadenosines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction
D003839:Deoxyadenosines; C052326:3'-deoxyadenosine N(1)-oxide