Swanson S M, Guzman R C, Tsukamoto T, Huang T T, Dougherty C D, Nandi S
Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley 94720, USA.
Cancer Lett. 1996 Apr 19;102(1-2):159-65. doi: 10.1016/0304-3835(96)04175-4.
N-Ethyl-N-nitrosourea (ENU) and N-methyl-N-nitrosourea (MNU) are alkylating agents which respectively ethylate or methylate nucleophilic centers in the cell such as DNA. In vitro studies with naked DNA and bacterial mutagenesis assays suggest that these two compounds induce different spectra of genetic lesions. In addition, the ethyl-DNA adducts induced by ENU persist longer than the methyl-DNA adducts induced by MNU. Since MNU is a known mammary carcinogen in the pituitary-isografted mouse, these data suggest that ENU may be an even more potent carcinogen than MNU. The purpose of this study was to determine whether ENU was a mammary carcinogen in the pituitary-isografted mouse and if so, to compare the genotype and phenotype of ENU-induced mammary tumors with those induced by MNU. Fifteen adult female virgin BALB/c mice were isografted with two pituitaries and subsequently treated with a single intravenous injection of ENU (50 micrograms/g body weight). Mammary adenocarcinomas arose in all of the survivors (n=12) with a median latency of 27 weeks and a mean frequency of 1.4 cancers per mouse. When tumor DNA was analyzed for mutations in the 12th and 61st codons of c-Ki-ras or c-Ha-ras protooncogenes, only wild type sequences were found. This is in contrast to MNU which causes a G to A transition mutation in the 12th codon of the c-Ha-ras proto-oncogene in about one of five mammary cancers induced in pituitary-isografted mice. Furthermore, the ENU-induced tumors were solid viable papillary adenocarcinomas, whereas MNU induced tumors are highly necrotic adenocarcinomas with squamous metaplasia. These results demonstrate that, in the pituitary-isografted mouse, ENU is as potent a mammary carcinogen as MNU and suggest that oncogenes other than c-Ki-ras or c-Ha-ras may be involved in ENU-induced mammary cancers.
N-乙基-N-亚硝基脲（ENU）和N-甲基-N-亚硝基脲（MNU）是烷基化剂，它们分别使细胞中的亲核中心如DNA发生乙基化或甲基化。对裸露DNA的体外研究和细菌诱变试验表明，这两种化合物诱导的遗传损伤谱不同。此外，ENU诱导的乙基-DNA加合物比MNU诱导的甲基-DNA加合物持续时间更长。由于MNU是垂体移植小鼠中已知的乳腺癌致癌物，这些数据表明ENU可能是比MNU更有效的致癌物。本研究的目的是确定ENU在垂体移植小鼠中是否为乳腺癌致癌物，如果是，比较ENU诱导的乳腺肿瘤与MNU诱导的乳腺肿瘤的基因型和表型。15只成年雌性处女BALB/c小鼠移植了两个垂体，随后单次静脉注射ENU（50微克/克体重）。所有存活的小鼠（n = 12）均发生了乳腺腺癌，中位潜伏期为27周，每只小鼠的平均肿瘤发生率为1.4个。当分析肿瘤DNA中c-Ki-ras或c-Ha-ras原癌基因第12和61密码子的突变时，仅发现野生型序列。这与MNU相反，在垂体移植小鼠诱导的约五分之一的乳腺癌中，MNU会导致c-Ha-ras原癌基因第12密码子发生G到A的转换突变。此外，ENU诱导的肿瘤为实性、可存活的乳头状腺癌，而MNU诱导的肿瘤是具有鳞状化生的高度坏死腺癌。这些结果表明，在垂体移植小鼠中，ENU是与MNU一样有效的乳腺癌致癌物，并提示除c-Ki-ras或c-Ha-ras之外的癌基因可能参与ENU诱导的乳腺癌发生。
