O6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow.
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.
Chinnasamy
N
N
Cancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Rafferty
J A
JA
Hickson
I
I
Ashby
J
J
Tinwell
H
H
Margison
G P
GP
Dexter
T M
TM
Fairbairn
L J
LJ
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
D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D002330:Carmustine; D000077204:Temozolomide