Mutagenicity to Salmonella, Drosophila and the mouse bone marrow of the human antineoplastic agent fotemustine: prediction of carcinogenic potency.
The antineoplastic agent fotemustine is shown to be a base-pair mutagen to Salmonella. Activity is more marked in the uvrB-proficient strain G46 than in the repair-deficient strain TA1535. This is consistent with its ability to cross-link DNA. Potent activity as a somatic and germ-cell mutagen to Drosophila was also observed. A potent clastogenic response was given by fotemustine in the mouse bone marrow following either oral gavage or intraperitoneal injection of a single dose of 5 mg/kg. In each of these respects it is shown to be indistinguishable from the structurally related antineoplastic agent and human carcinogen MeCCNU. It is concluded that fotemustine should be regarded as having clear potential to induce cancer in humans. Based on these data, including the preponderance of chromosome breakages over recessive lethal mutations in Drosophila, an estimated rodent carcinogenic potency (TD50) of between 15-150 mg/kg is suggested for fotemustine.
Ashby
J
J
ICI Central Toxicological Laboratory, Macclesfield, Ches., UK.
Vogel
E W
EW
Tinwell
H
H
Callander
R D
RD
Shuker
D E
DE
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001681:Biological Assay; D001853:Bone Marrow / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002872:Chromosome Deletion; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009607:Nitrosourea Compounds / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011237:Predictive Value of Tests; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012673:Semustine / Q000633:toxicity; D014960:X Chromosome / Q000187:drug effects
D000970:Antineoplastic Agents; D002273:Carcinogens; D009153:Mutagens; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D012673:Semustine; C054368:fotemustine