Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase.
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.
Shiraishi
A
A
Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Sakumi
K
K
Sekiguchi
M
M
D000236:Adenoma / Q000139:chemically induced; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D003520:Cyclophosphamide / Q000633:toxicity; D003606:Dacarbazine / Q000633:toxicity; D005260:Female; D007928:Lethal Dose 50; D008175:Lung Neoplasms / Q000139:chemically induced; D008223:Lymphoma / Q000139:chemically induced; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015376:Nimustine / Q000633:toxicity; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000172:deficiency* / Q000235:genetics; D013737:Testis / Q000187:drug effects; D013953:Thymus Neoplasms / Q000139:chemically induced
D018906:Antineoplastic Agents, Alkylating; D015376:Nimustine; D003606:Dacarbazine; D003520:Cyclophosphamide; D019853:O(6)-Methylguanine-DNA Methyltransferase