O-Benzylguanine Potentiates the In Vivo Toxicity and Clastogenicity of Temozolomide and BCNU in Mouse Bone Marrow

The effects of treatment of mice with O-benzylguanine (Oit was of lower magnitude: 1.20 for marrow cellularity, 1.63 for GM-CFC, and 1.68 for CFU-S. When the clastogenic efBeG) on the levels of O-alkylguanine-DNA alkyltransferase (ATase) in the hematopoietic compartment and on the in fects of BCNU and temozolomide were examined in the mouse bone marrow micronucleus assay, a significantly (P vivo sensitivity of hematopoietic progenitor cells to the toxic and clastogenic effects of the antitumor agents 1,3-bis(2Ú .05 to .001) higher frequency of micronuclei formation was observed in mice that received O-BeG pretreatment chloroethyl)-nitrosourea (BCNU) and temozolomide were studied. When the overall effects of BCNU alone or with Ocompared with mice that received no pretreatment. These data suggest that the use of O-BeG as a tumor-sensitizing BeG pretreatment were compared, dose potentiating factors of 4.17 for marrow cellularity, 4.57 for granulocyte macroagent before treatment of patients with O-alkylating agents may lead to more severe hematological toxicity and possibly phage-colony forming cells (GM-CFC) and 8.25 for colony forming unit-spleen (CFU-S) in O-BeG pretreated versus to an increased incidence of secondary leukemias as a result of elevated mutation frequencies in these patients. nonpretreated animals were observed. A similar trend of dose potentiation was observed for temozolomide, although q 1997 by The American Society of Hematology.