Role of O6-alkylguanine-DNA alkyltransferase in protecting against 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-induced long-term toxicities.
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 of 15 mg/kg or high dose of 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 that 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 five mice analyzed in this cohort had alveolar histiocytosis, with one also having alveolar edema. In contrast, liver and kidney toxicity was only observed in mice treated with BCNU (50 mg/kg). These results suggest that O6-benzylguanine enhances long-term pulmonary toxicity associated with BCNU in mice.
Hansen
Ryan J
RJ
Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA.
Nagasubramanian
Ramamoorthy
R
Delaney
Shannon M
SM
Cherian
Mathew M
MM
Lin
Shang
S
Kogan
Scott C
SC
Dolan
M Eileen
ME
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D002330:Carmustine / Q000008:administration & dosage* / Q000633:toxicity; D003433:Crosses, Genetic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D016019:Survival Analysis; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine