O-6-BENZYLGUANINE POTENTIATES THE IN-VIVO TOXICITY AND CLASTOGENICITYOF TEMOZOLOMIDE AND BCNU IN MOUSE BONE-MARROW

The effects of treatment of mice with O-6-benzylguanine (O-6-BeG) on t he levels of O-6-alkylguanine-DNA alkyltransferase (ATase) in the hema topoietic compartment and on the in vive sensitivity of hematopoietic progenitor cells to the toxic and clastogenic effects of the antitumor agents 1,3-bis(2chloroethyl)-nitrosourea (BCNU) and temozolomide were studied. When the overall effects of BCNU alone or with O-6-BeG pretr eatment were compared, dose potentiating factors of 4.17 for marrow ce llularity, 4.57 for granulocyte macrophage-colony forming cells (GM-CF C) and 8.25 for colony forming unit-spleen (CFU-S) in O-6-BeG pretreat ed versus nonpretreated animals were observed. A similar trend of dose potentiation was observed for temozolomide, although was of lower mag nitude: 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 examine d in the mouse bone marrow micronucleus assay, a significantly (P <.05 to .001) higher frequency of micronuclei formation was observed in mi ce that received O-6-BeG pretreatment compared with mice that received no pretreatment. These data suggest that the use of O-6-BeG as a tumo r-sensitizing agent before treatment of patients with O-6-alkylating a gents may lead to more severe hematological toxicity and possibly to a n increased incidence of secondary leukemias as a result of elevated m utation frequencies in these patients. (C) 1997 by The American Societ y of Hematology.