Mammalian 3-methyladenine DNA glycosylase protects against the toxicity and clastogenicity of certain chemotherapeutic DNA cross-linking agents.
DNA repair status is recognized as an important determinant of the clinical efficacy of cancer chemotherapy. To assess the role that a mammalian DNA glycosylase plays in modulating the toxicity and clastogenicity of the chemotherapeutic DNA cross-linking alkylating agents, we compared the sensitivity of wild-type murine cells to that of isogenic cells bearing homozygous null mutations in the 3-methyladenine DNA glycosylase gene (Aag). We show that Aag protects against the toxic and clastogenic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C (MMC), as measured by cell killing, sister chromatid exchange, and chromosome aberrations. This protection is accompanied by suppression of apoptosis and a slightly reduced p53 response. Our results identify 3-methyladenine DNA glycosylase-initiated base excision repair as a potentially important determinant of the clinical efficacy and, possibly, the carcinogenicity of these widely used chemotherapeutic agents. However, Aag does not contribute significantly to protection against the toxic and clastogenic effects of several chemotherapeutic nitrogen mustards (namely, mechlorethamine, melphalan, and chlorambucil), at least in the mouse embryonic stem cells used here. We also compare the Aag null phenotype with the Fanconi anemia phenotype, a human disorder characterized by cellular hypersensitivity to DNA cross-linking agents, including MMC. Although Aag null cells are sensitive to MMC-induced growth delay and cell cycle arrest, their sensitivity is modest compared to that of Fanconi anemia cells.
Allan
J M
JM
Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Engelward
B P
BP
Dreslin
A J
AJ
Wyatt
M D
MD
Tomasz
M
M
Samson
L D
LD
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002330:Carmustine / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D045647:DNA Glycosylases; D004260:DNA Repair; D016195:G2 Phase / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016685:Mitomycin / Q000633:toxicity*; D008938:Mitosis / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity*; D009699:N-Glycosyl Hydrolases / Q000494:pharmacology*
D018906:Antineoplastic Agents, Alkylating; D009153:Mutagens; C044502:3-methylguanine; D016685:Mitomycin; D006147:Guanine; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D002330:Carmustine