Received for publication January 14, 2005.
Revised August 25, 2005.
Accepted for publication August 25, 2005.

Role of O⁶-Alkylguanine-DNA Alkyltransferase in Protecting Against BCNU-Induced Long-Term Toxicities

Abstract

O⁶-alkylguanine-DNA alkyltransferase (AGT) protects from the mutagenic and toxic lesions induced by 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), and in many tumors AGT overexpression provides a means of resistance. To circumvent this, O⁶-benzylguanine, an inactivator of AGT, has been developed and is currently in clinical development with BCNU; however, the potential long-term toxicities associated with this treatment are unknown. With the inactivation of AGT by O⁶-benzylguanine, a higher number of toxic and mutagenic O⁶-alkylguanine lesions introduced by methylating or chloroethylating agents would be expected. In this study, cohorts of mice were treated with vehicle, O⁶-benzylguanine (30 mg/kg), BCNU alone (low dose 15 mg/kg or high dose 50 mg/kg) or O⁶-benzylguanine (30 mg/kg) plus BCNU (15 mg/kg) and followed for 12 months post treatment. Mice treated with O⁶-benzylguanine plus BCNU or high dose BCNU died significantly earlier (p <0.0001) than mice in the other three cohorts with a median survival of 8.3 (O⁶-benzylguanine plus BCNU) and 7.9 months (high dose BCNU). Histopathologic sections of tissues revealed the most common morphological diagnosis in animals treated with O⁶-benzylguanine plus BCNU (15 mg/kg) or BCNU (50 mg/kg) was cytomegaly in the lung with greater severity observed in mice receiving the combination O⁶-benzylguanine plus BCNU. Four of 5 mice analyzed in this cohort had alveolar histiocytosis with one also having alveolar edema. These results suggest O⁶-benzylguanine enhances long-term pulmonary toxicity associated with BCNU in mice.

Key words: MGMT, carmustine, lung, pathology, survival, toxicity

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