| First Author | Shiraishi A | Year | 2000 |
| Journal | Carcinogenesis | Volume | 21 |
| Issue | 10 | Pages | 1879-83 |
| PubMed ID | 11023546 | Mgi Jnum | J:65240 |
| Mgi Id | MGI:1913236 | Doi | 10.1093/carcin/21.10.1879 |
| Citation | Shiraishi A, et al. (2000) Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase. Carcinogenesis 21(10):1879-83 |
| abstractText | O:(6)-methylguanine-DNA methyltransferase plays vital roles in preventing induction of mutations and cancer as well as cell death related to alkylating agents. Mice defective in the MGMT: gene, encoding the methyltransferase, were used to evaluate cell death-inducing and tumorigenic activities of therapeutic agents which have alkylation potential. MGMT:(-/-) mice were considerably more sensitive to dacarbazine, a monofunctional triazene, than were wild-type mice, in terms of survival. When dacarbazine was administered i.p. to 6-week-old mice and survival at 30 days was enumerated, LD(50) values of MGMT:(-/-) and MGMT:(+/+) mice were 20 and 450 mg/kg body wt, respectively. Increased sensitivity of MGMT:(-/-) mice to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosou rea (ACNU), a bifunctional nitrosourea, was also noted. On the other hand, there was no difference in survival of MGMT:(+/+) and MGMT:(-/-) mice exposed to cyclophosphamide, a bifunctional nitrogen mustard. It appears that dacarbazine and ACNU produce O:(6)-alkylguanine as a major toxic lesion, while cyclophosphamide yields other types of modifications in DNA which are not subjected to the action of the methyltransferase. MGMT:(-/-) mice seem to be less refractory to the tumor-inducing effect of dacarbazine than are MGMT:(+/+) mice. Thus, the level of O:(6)-methylguanine-DNA methyltransferase activity is an important factor when determining susceptibility to drugs with the potential for alkylation. |
