Hakura A, Tsutsui Y, Sonoda J, Mikami T, Tsukidate K, Sagami F, Kerns W D
Drug Safety Research Laboratories, Eisai, 1, Takehaya-machi, Kawashima-cho, Hashima-gun, Gifu 501-6195, Japan.
Mutat Res. 1999 May 3;426(1):71-7. doi: 10.1016/s0027-5107(99)00046-9.
We have recently demonstrated that not all organs with high rates of mutation in the lacZ transgene develop tumors using the Muta Mouse. To better understand the role of in vivo mutation in carcinogenesis, we examined the mutant frequencies (MF) of the lacZ transgene in tumor-bearing and non tumor-bearing organs. MF, recovered after 2 weeks (the data taken from our previous study) and after 26 weeks following oral doses of 125 mg kg-1 day-1 benzo[a]pyrene (BP) for five days were compared. The organs examined included the target organs (forestomach, spleen, and lung) and non-target organs (colon, glandular stomach, and liver) for BP carcinogenesis. The data indicated that lacZ MF were markedly increased over spontaneous frequencies in the organs examined and that the organ which showed the highest MF was the colon, followed by the forestomach>spleen>glandular stomach, liver, and lung in that order. These findings indicate that the MF of the lacZ transgene in each organ, even 26 weeks after the start of the treatment does not fully correlate with the known target organs of BP. Furthermore, the lacZ MF in a non-papilloma region of a forestomach with a papilloma was equivalent to the two highest MF observed in the healthy colon (non-target organ) of mice at 26 weeks. These observations also indicate that the generation of tumors requires the induction of mutations as well as other factor(s) specific to the target organs. These results clearly suggest that highly mutated organs do not always progress to tumors in the transgenic mouse.
我们最近证明，并非所有在lacZ转基因中具有高突变率的器官都会利用突变小鼠发生肿瘤。为了更好地理解体内突变在致癌过程中的作用，我们检查了荷瘤和非荷瘤器官中lacZ转基因的突变频率（MF）。比较了口服125mg kg-1天-1苯并[a]芘（BP）连续五天后2周（数据取自我们之前的研究）和26周后的MF。检查的器官包括BP致癌作用的靶器官（前胃、脾脏和肺）和非靶器官（结肠、腺胃和肝脏）。数据表明，在所检查的器官中，lacZ MF比自发频率显著增加，且MF最高的器官是结肠，其次依次是前胃>脾脏>腺胃、肝脏和肺。这些发现表明，即使在治疗开始26周后，每个器官中lacZ转基因的MF也与BP已知的靶器官不完全相关。此外，患有乳头瘤的前胃非乳头瘤区域的lacZ MF相当于26周时在小鼠健康结肠（非靶器官）中观察到的两个最高MF。这些观察结果还表明，肿瘤的发生需要诱导突变以及靶器官特有的其他因素。这些结果清楚地表明，在转基因小鼠中，高突变器官并不总是会发展为肿瘤。
