title: O6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow.
abstract: The effects of treatment of mice with O6-benzylguanine (O6-BeG) on the levels of O6-alkylguanine-DNA alkyltransferase (ATase) in the hematopoietic compartment and on the in vivo sensitivity of hematopoietic progenitor cells to the toxic and clastogenic effects of the antitumor agents 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) and temozolomide were studied. When the overall effects of BCNU alone or with O6-BeG pretreatment were compared, dose potentiating factors of 4.17 for marrow cellularity, 4.57 for granulocyte macrophage-colony forming cells (GM-CFC) and 8.25 for colony forming unit-spleen (CFU-S) in O6-BeG pretreated versus nonpretreated animals were observed. A similar trend of dose potentiation was observed for temozolomide, although it was of lower magnitude: 1.20 for marrow cellularity, 1.63 for GM-CFC, and 1.68 for CFU-S. When the clastogenic effects of BCNU and temozolomide were examined in the mouse bone marrow micronucleus assay, a significantly (P < .05 to .001) higher frequency of micronuclei formation was observed in mice that received O6-BeG pretreatment compared with mice that received no pretreatment. These data suggest that the use of O6-BeG as a tumor-sensitizing agent before treatment of patients with O6-alkylating agents may lead to more severe hematological toxicity and possibly to an increased incidence of secondary leukemias as a result of elevated mutation frequencies in these patients.
authors.affiliation: Cancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
authors.forename: N
authors.initials: N
authors.lastname: Chinnasamy
authors.forename: J A
authors.initials: JA
authors.lastname: Rafferty
authors.forename: I
authors.initials: I
authors.lastname: Hickson
authors.forename: J
authors.initials: J
authors.lastname: Ashby
authors.forename: H
authors.initials: H
authors.lastname: Tinwell
authors.forename: G P
authors.initials: GP
authors.lastname: Margison
authors.forename: T M
authors.initials: TM
authors.lastname: Dexter
authors.forename: L J
authors.initials: LJ
authors.lastname: Fairbairn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002330:Carmustine / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000633:toxicity; D004357:Drug Synergism; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D002330:Carmustine; D000077204:Temozolomide