Department of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.
Oncol Rep. 2010 Feb;23(2):337-44.
Transgenic rats carrying human c-Ha-ras proto-oncogene (Hras128 rats) have been shown to be highly susceptible to induction of tumors. We have found an early induction of tongue tumors in Hras128 rats treated with 4-nitroquinoline 1-oxide (4NQO). 4NQO was administered to the Hras128 and wild-type Sprague-Dawley (SD) rats for 4 and 8 weeks, respectively. The experiment was terminated at 14 (Hras128 rats) and 28 (SD rats) weeks. Either during or after treatment with 4NQO, dysplastic hyperplasia, papilloma and squamous cell carcinoma were found on the tongue of both Hras128 and wild-type rats, with a higher incidence and multiplicity in Hras128 rats. Treatment of the Hras128 rats with 4NQO significantly increased cell proliferation in the tumor compared to the control rats. In the tongue tumors of the Hras128 rats, there was a significant increase in the mRNA expression levels of cyclin D1 and COX2. To examine whether this experimental system is useful for screening of the candidate agents for cancer preventive effect, nimesulide, a selective COX2 inhibitor, was tested in the present model. Nimesulide significantly decreased total multiplicity of tongue lesions compared to the control rats. Treatment of Hras128 rats with nimesulide caused a significant decrease in the levels of mRNA expression of cyclin D1 and COX2 in the tumor. Therefore, the current 4NQO-induced Hras128 rat tongue carcinogenesis model provides a simple and rapid system for investigating carcinogenesis process and evaluating the effect of possible cancer preventive agents for human tongue cancer.
携带人 c-Ha-ras 原癌基因（Hras128 大鼠）的转基因大鼠已被证明易患肿瘤诱导。我们发现，用 4-硝基喹啉 1-氧化物（4NQO）处理 Hras128 大鼠可早期诱导舌肿瘤。4NQO 分别给予 Hras128 和野生型 Sprague-Dawley（SD）大鼠 4 周和 8 周。实验在 14 周（Hras128 大鼠）和 28 周（SD 大鼠）结束。在 4NQO 处理期间或之后，Hras128 和野生型大鼠的舌头上均发现了发育不良性增生、乳头瘤和鳞状细胞癌，Hras128 大鼠的发病率和多发性更高。用 4NQO 处理 Hras128 大鼠可显著增加肿瘤中的细胞增殖。在 Hras128 大鼠的舌肿瘤中，cyclin D1 和 COX2 的 mRNA 表达水平显著增加。为了检查该实验系统是否可用于筛选癌症预防作用的候选药物，在本模型中测试了尼美舒利，一种选择性 COX2 抑制剂。与对照组大鼠相比，尼美舒利显著降低了舌病变的总多发性。尼美舒利处理 Hras128 大鼠可显著降低肿瘤中 cyclin D1 和 COX2 的 mRNA 表达水平。因此，当前的 4NQO 诱导的 Hras128 大鼠舌癌发生模型为研究致癌过程和评估可能的人类舌癌预防剂的效果提供了一个简单快速的系统。
