TY - JOUR
T1 - Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes
AU - Kawate, Hisaya
AU - Sakumi, Kunihiko
AU - Tsuzuki, Teruhisa
AU - Nakatsuru, Yoko
AU - Ishikawa, Takatoshi
AU - Takahashi, Seiichi
AU - Takano, Hiroshi
AU - Noda, Tetsuo
AU - Sekiguchi, Mutsuo
PY - 1998/4/28
Y1 - 1998/4/28
N2 - Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6- methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT(-/-)MLH1(+/+) mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT(-/-) MLH1(-/-) mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.
AB - Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6- methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT(-/-)MLH1(+/+) mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT(-/-) MLH1(-/-) mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.
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U2 - 10.1073/pnas.95.9.5116
DO - 10.1073/pnas.95.9.5116
M3 - Article
C2 - 9560238
AN - SCOPUS:0032574814
SN - 0027-8424
VL - 95
SP - 5116
EP - 5120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -
