Induction of gene mutations by 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), an antiviral pyrimidine nucleoside analogue.
5-(2-chloroethyl)-2'-deoxyuridine (CEDU) had been developed for the treatment of herpes simplex infections. In the Salmonella reverse mutation test, the compound was found to be mutagenic in strains TA1535 and TA102 at very high concentrations (> or =2500 micro g/plate), both with and without S9-mix. The mutagenic potential of CEDU was further investigated in vivo and in vitro. It did not induce DNA repair in rat hepatocyte primary cultures, and was negative in the micronucleus test in V79 cells and in the comet assay in human leukocytes. In vivo, CEDU was negative in the bone marrow micronucleus test in CD1 mice. The mouse spot test provided a clearly positive result. Treatment of mice on day 9 of pregnancy with 2000 mg/kg resulted in 5.9% of the F1 animals having genetically relevant spots, whereas the corresponding vehicle control group had a spot rate of 1.9%. Since these data clearly identified CEDU as an inducer of gene mutations in vivo, this potential was further investigated in lacZ transgenic Muta Mouse. Six female animals were treated daily on five consecutive days with 2000 mg/kg/day and sacrificed, after a treatment-free sampling time, 14 days later. The data showed a clear increase in the mutant frequency in the bone marrow, the lung and in the spleen. CEDU is an exception in the group of nucleoside analogues, because it was found to be a strong gene mutagen and, in contrast to the other compounds of this group investigated so far, had no considerable clastogenic effects.
Suter
Willi
W
Preclinical Safety, Novartis Pharma AG, MUT 2881.2.35, CH 4002 Basel, Switzerland. willi.suter@pharma.novartis.com
Plappert-Helbig
Ulla
U
Glowienke
Susanne
S
Poetter-Locher
Franziska
F
Staedtler
Frank
F
Racine
Robert
R
Martus
Hans-Joerg
HJ
D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D020552:Comet Assay; D004260:DNA Repair / Q000235:genetics*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009154:Mutation / Q000235:genetics*; D011247:Pregnancy; D051381:Rats; D012475:Salmonella; D012880:Skin Pigmentation / Q000187:drug effects
D000998:Antiviral Agents; C047370:5-(2-chloroethyl)-2'-deoxyuridine; D003857:Deoxyuridine