Mutagenesis, Vol. 14, No. 3, 339-347,
May 1999
© 1999 UK Environmental Mutagen Society/Oxford University Press
DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents
1 Department of Cancer Cell Biology, Toxicology Division, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA, 2 Department of Cell Biology and Genetics, Medical Genetics Center and 3 Department of Pathology, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands and 4 Center for Animal Resources and Comparative Medicine, Harvard Medical School, 665 Huntington Avenue, Boston, MA 02115, USA
We have generated mice deficient in O6-methylguanine DNA methyltransferase activity encoded by the murine Mgmt gene using homologous recombination to delete the region encoding the Mgmt active site cysteine. Tissues from Mgmt null mice displayed very low O6-methylguanine DNA methyltransferase activity, suggesting that Mgmt constitutes the major, if not the only, O6-methylguanine DNA methyltransferase. Primary mouse embryo fibroblasts and bone marrow cells from Mgmt –/– mice were significantly more sensitive to the toxic effects of the chemotherapeutic alkylating agents 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin and temozolomide than those from Mgmt wild-type mice. As expected, Mgmt-deficient fibroblasts and bone marrow cells were not sensitive to UV light or to the crosslinking agent mitomycin C. In addition, the 50% lethal doses for Mgmt –/– mice were 2- to 10-fold lower than those for Mgmt +/+ mice for 1,3-bis(2-chloroethyl)-1-nitrosourea, N-methyl-N-nitrosourea and streptozotocin; similar 50% lethal doses were observed for mitomycin C. Necropsies of both wild-type and Mgmt –/– mice following drug treatment revealed histological evidence of significant ablation of hematopoietic tissues, but such ablation occurred at much lower doses for the Mgmt –/– mice. These results demonstrate the critical importance of O6-methylguanine DNA methyltransferase in protecting cells and animals against the toxic effects of alkylating agents used for cancer chemotherapy.
5 To whom correspondence should be addressed. Tel: +1 617 432 1085; Fax: +1 617 432 0400; Email: lsamson{at}sph.harvard.edu
6 Present address: Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
7 These authors contributed equally to this work
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