Manam S, Storer R D, Prahalada S, Leander K R, Kraynak A R, Hammermeister C L, Joslyn D J, Ledwith B J, van Zwieten M J, Bradley M O
Department of Safety Assessment, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Mol Carcinog. 1992;6(1):68-75. doi: 10.1002/mc.2940060111.
As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.
作为使用ras突变分析区分致癌物诱导肿瘤与自发肿瘤有效性评估的一部分，我们检测了Crl:CD-1(ICR)BR（CD-1）小鼠自发的、经7,12-二甲基苯并[a]蒽（DMBA）诱导的和经N-亚硝基二乙胺（DEN）诱导的肺肿瘤中ras基因点突变情况。尽管对所有肺肿瘤都检测了Ha-ras、Ki-ras和N-ras基因（密码子12、13和61）的突变，但仅发现了Ki-ras突变，这与其他研究一致，那些研究指出在小鼠、大鼠和人类肺肿瘤中强烈倾向于激活Ki-ras基因。我们发现自发的CD-1小鼠肺肿瘤中Ki-ras基因激活频率非常高（20个肿瘤中有17个；85%），分布在密码子12（20个中有5个）、13（20个中有1个）和61（20个中有11个）。DMBA诱导的肺肿瘤中Ki-ras基因突变频率略高（16个中有16个；100%），同样分布在密码子12（16个中有5个）、13（16个中有2个）和61（16个中有9个）。然而，7个DMBA肿瘤的突变在性质上与自发肿瘤中的不同。与DMBA诱导的肿瘤相反，与自发肺肿瘤相比，DEN诱导的肿瘤中Ki-ras突变频率较低（36%），这表明DEN主要通过ras基因激活以外的机制诱导肺癌发生。因此，尽管自发的和诱导的CD-1小鼠肺肿瘤在携带激活的Ki-ras基因方面有很强的组织特异性偏好，但起始致癌物的性质可影响Ki-ras突变的频率或模式。
