title: Is MutaMouse insensitive to clastogens?
abstract: Several studies suggest that MutaMouse is insensitive to clastogens, including the accompanying paper by Mahabir et al., which describes a study with bleomycin, camptothecin, m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide) and its ortho-analogue, o-AMSA (4'-(9-acridinylamino)-methanesulfon-o-anisidide). Only camptothecin was clastogenic in MutaMouse and none of these four compounds induced mutations at the lacZ locus. However, to improve exposure, dose range-finding studies were performed in CD2F1 mice, the parental strain of MutaMouse. Male CD2F1 mice (n=3) were treated with bleomycin (25-100 mg/kg bw, p.o. and i.p.), camptothecin (1-10 mg/kg bw p.o.) and m-AMSA (10-50mg/kg bw p.o. and 1-5 mg/kg bw i.p.) for 5 days and blood was sampled on day 3 and/or day 6 for analysis by flow cytometry to determine % MN-RETs. Camptothecin (1 mg/kg bw, day 6) induced a 3.6-fold increase in % MN-RET (P<0.05) but was toxic at higher doses. All day-3 camptothecin samples were positive (P<0.05). Bleomycin was negative when administered p.o. but positive at all doses on both days when given i.p. (P<0.05) whereas m-AMSA was negative when given i.p. or orally. Based on these results, male MutaMouse mice (5 per group) were dosed daily with bleomycin (50 mg/kg bw) for 5 days or with camptothecin (5 mg/kg bw) for 2 days. Peripheral blood was sampled 24 h after the final dose in each group and tissues were sampled 37 days later. Both compounds induced significant increases in % MN-RET, but only bleomycin induced a significant increase in MF (6-fold in liver, 4.5-fold in kidney and 2-fold in lung) compared with the untreated control. These studies support the view that MutaMouse is insensitive to compounds where the genotoxic mechanism of action is predominantly clastogenesis, but demonstrates that the peripheral blood micronucleus test is a useful adjunct to the transgenic gene-mutation assay.
authors.affiliation: GlaxoSmithKline, Department of Genetic Toxicology, Ware, UK.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Lynch
authors.forename: Anuska G
authors.initials: AG
authors.lastname: Mahabir
authors.forename: Andrea
authors.initials: A
authors.lastname: Bradford
authors.forename: Kate
authors.initials: K
authors.lastname: Brockhurst
authors.forename: Jan
authors.initials: J
authors.lastname: van Benthem
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Robert W
authors.initials: RW
authors.lastname: Rees
mesh_terms: D000677:Amsacrine / Q000633:toxicity; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D002166:Camptothecin / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007763:Lac Operon / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015162:Micronucleus Tests; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*
chemical_list: D009153:Mutagens; D000677:Amsacrine; D001761:Bleomycin; D002166:Camptothecin