title: Germ cell mutagenicity of topoisomerase I inhibitor topotecan detected in the male mouse-dominant lethal study.
abstract: To investigate the ability of topotecan, a topoisomerase I-targeting anticancer drug, to induce dominant lethal mutations in male mouse germ cells, males were treated with single doses of 3, 6 and 12 mg/kg topotecan. Each male was mated at 4-day intervals to virgin females for a total of nine 4-day mating intervals. The two highest doses of topotecan are shown to be mutagenic in post-meiotic cells. The greatest effect occurred in those cells which were in the early-spermatid stage at the time of exposure. Mice treated with 12 mg/kg topotecan showed an additional peak of dominant lethal induction in mature sperm during the first 4-day matings after treatment. The mutagenic effects were directly correlated with free radicals accumulation as an obvious increase in the generation reactive oxygen species and 8-hydroxydeoxyguanosine was noted in animals treated with 6 and 12 mg/kg topotecan. Treatment of male mice with N-acetylcysteine, a free radical scavenger, significantly protected mice from topotecan-induce dominant lethality. Moreover, N-acetylcysteine had no antagonizing effect on topotecan-induce topoisomerase-I inhibition. Our study provides evidence that topotecan is a germ cell mutagen and its effect is more pronounced during the post-meiotic stages through a mechanism that may involves increases in DNA oxidative stress.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. 2457, Riyadh 11451, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt. Electronic address: attiasm@yahoo.com.
authors.forename: S M
authors.initials: SM
authors.lastname: Attia
authors.forename: S F
authors.initials: SF
authors.lastname: Ahmad
authors.forename: M F
authors.initials: MF
authors.lastname: Abd-Ellah
authors.forename: F M
authors.initials: FM
authors.lastname: Hamada
authors.forename: S A
authors.initials: SA
authors.lastname: Bakheet
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013094:Spermatozoa / Q000187:drug effects*; D059004:Topoisomerase I Inhibitors / Q000633:toxicity*; D019772:Topotecan / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D009153:Mutagens; D017382:Reactive Oxygen Species; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D000111:Acetylcysteine
keywords: Camptothecins; DNA oxidative stress; Dominant lethality; Genomic alterations; N-acetylcysteine; Topoisomerase I