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Role ofO6-Alkylguanine-DNA Alkyltransferase in Protecting against 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)-Induced Long-Term Toxicities
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 315:1247-1255
- Publication Year :
- 2005
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2005.
-
Abstract
- O 6-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, O 6-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 O 6-benzylguanine, a higher number of toxic and mutagenic O 6-alkylguanine lesions introduced by methylating or chloroethylating agents would be expected. In this study, cohorts of mice were treated with vehicle, O 6-benzylguanine (30 mg/kg), BCNU alone (low dose of 15 mg/kg or high dose of 50 mg/kg), or O 6-benzylguanine (30 mg/kg) plus BCNU (15 mg/kg) and followed for 12 months post-treatment. Mice treated with O 6-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 ( O 6-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 O 6-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 O 6-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 O 6-benzylguanine enhances long-term pulmonary toxicity associated with BCNU in mice.
- Subjects :
- Male
Nitrosourea
Guanine
Time Factors
Maximum Tolerated Dose
Pulmonary toxicity
Pharmacology
Kidney
Drug Administration Schedule
Mice
O(6)-Methylguanine-DNA Methyltransferase
Random Allocation
chemistry.chemical_compound
Edema
medicine
Animals
Drug Interactions
Antineoplastic Agents, Alkylating
Lung
Crosses, Genetic
Dose-Response Relationship, Drug
business.industry
Body Weight
Organ Size
O6-alkylguanine-DNA alkyltransferase
Carmustine
Survival Analysis
Mice, Mutant Strains
Mice, Inbred C57BL
medicine.anatomical_structure
Liver
chemistry
Anesthesia
Toxicity
Molecular Medicine
Female
medicine.symptom
business
Median survival
Alkyltransferase
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 315
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....1792193933951356300d646e0caf2b1f