Osaka M, Tsuruyama T, Koami K, Matsuo S, Sugiyama T
Department of Pathology, Faculty of Medicine, Kyoto University, Japan.
Cancer Lett. 1998 Feb 27;124(2):199-204. doi: 10.1016/s0304-3835(97)00491-6.
Chemically-induced rodent tumor models help us to understand a series of genetic changes during carcinogenesis. In this study, we present N-nitroso-N-butylurea (NBU)-induced rat leukemia and compare it with the genetic alterations found in 7,12-dimethylbenz[a]anthracene (DMBA)-induced erythroblastic leukemias which consistently have an A to T transversion at the second base of codon 61 in N-ras. By continuous NBU treatment for 120-150 days, 14 primary leukemias were induced in Long-Evans rats. Myeloblastic leukemia cells predominantly increased in all rats except in one case which predominantly had erythroblastic leukemia cells. Point mutations of Ha-, Ki-, N-ras and p53 were determined after RNA was transcribed into cDNA and this cDNA was used as a substrate for polymerase chain reaction (PCR) which was eventually sequenced. No abnormalities in exons 1 and 2 of Ha-, Ki- and N-ras were detected in all leukemias. In the p53 gene, an A to C transition was found at the second base of codon 198 (Asn-Thr) in one leukemia, but others had no mutation. These results suggest that ras and p53 genes are infrequently involved in NBU-induced leukemias. The genetic target of NBU during leukemogenesis seemed to be different from that of DMBA.
化学诱导的啮齿动物肿瘤模型有助于我们了解致癌过程中的一系列基因变化。在本研究中，我们展示了N-亚硝基-N-丁基脲（NBU）诱导的大鼠白血病，并将其与7,12-二甲基苯并[a]蒽（DMBA）诱导的成红细胞白血病中的基因改变进行比较，后者在N-ras基因第61密码子的第二个碱基处始终存在A到T的颠换。通过连续120 - 150天的NBU处理，在Long-Evans大鼠中诱导出了14例原发性白血病。除了1例主要为成红细胞白血病细胞的情况外，所有大鼠中髓母细胞白血病细胞均显著增多。在RNA转录成cDNA后，测定Ha-、Ki-、N-ras和p53的点突变，该cDNA用作聚合酶链反应（PCR）的模板，最终进行测序。在所有白血病中均未检测到Ha-、Ki-和N-ras外显子1和2的异常。在p53基因中，1例白血病在第198密码子（Asn-Thr）的第二个碱基处发现了A到C的转换，但其他病例无突变。这些结果表明，ras和p53基因很少参与NBU诱导的白血病。NBU在白血病发生过程中的遗传靶点似乎与DMBA不同。
