title: The effects of dose, route of administration, drug scheduling and MDR-1 gene transfer on the genotoxicity of etoposide in bone marrow.
abstract: We have used the bone marrow micronucleus assay (BMMN) as a measure of clastogenicity, in response to etoposide exposure in murine bone marrow. Oral delivery of etoposide resulted in a reduced number of micronucleated polychromatic erythrocytes (MPE) relative to the same dose delivered intraperitoneally (P < 0.001). Daily fractionation of the oral schedule of etoposide led to a more than six-fold increase in cumulative MPE frequency over that observed with the same total, unfractionated dose, with the potency of the response increasing with serial exposure (r = 0.79). Retrovirally-mediated expression of MDR1 in murine bone marrow resulted in partial protection against the clastogenic activity of etoposide relative to mock transduced control mice. The model system developed has indicated a variety of factors able to influence the genotoxicity of etoposide. It should now be possible to further exploit this model in order to define other factors governing haemopoietic sensitivity to etoposide.
authors.affiliation: Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK.
authors.forename: S D
authors.initials: SD
authors.lastname: Turner
authors.forename: J A
authors.initials: JA
authors.lastname: Rafferty
authors.forename: L J
authors.initials: LJ
authors.lastname: Fairbairn
authors.forename: J
authors.initials: J
authors.lastname: Ashby
authors.forename: H
authors.initials: H
authors.lastname: Tinwell
authors.forename: H G
authors.initials: HG
authors.lastname: Eckert
authors.forename: C
authors.initials: C
authors.lastname: Baum
authors.forename: L S
authors.initials: LS
authors.lastname: Lashford
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D022761:Gene Transfer, Horizontal; D008297:Male; D051379:Mice; D015162:Micronucleus Tests
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide