@article{oai:repo.qst.go.jp:00046425,
 author = {Kakinuma, Shizuko and Nishimura, Mayumi and Amasaki, Yoshiko and Takada, Mayumi and Yamauchi, Kazumi and Sudou, Satomi and Shang, Yi and Doi, Kazutaka and Yoshinaga, Shinji and Shimada, Yoshiya and 柿沼 志津子 and 西村 まゆみ and 甘崎 佳子 and 高田 真由美 and 山内 一己 and 須藤 聡美 and 尚 奕 and 土居 主尚 and 吉永 信治 and 島田 義也},
 issue = {1-2},
 journal = {Fundamental and Molecular Mechanisms of Mutagenesis : A Section of Mutation Research},
 month = {Sep},
 note = {Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-indcued point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A,. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens.},
 pages = {43--50},
 title = {Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma},
 volume = {737},
 year = {2012}
}