Study of the Long-Evans Cinnamon (LEC) rat for a model of human renal carcinogenesis

1.探讨铜、铁在Long-Evans Cinnamon(LEC)大鼠自发性肾细胞肿瘤形成中的作用。发生坏死性肝炎的LEC大鼠16~20周肾脏铜含量是F344大鼠的24倍。然后铜含量下降，直到40周，但始终高于F344大鼠。LEC大鼠肾脏铁含量在16~20周时也达到高峰，但在62周龄后低于F344大鼠。LEC大鼠肾脏铜染色示皮质近端小管和髓质外条呈阳性染色。长期使用铜螯合剂D-青霉胺处理LEC大鼠，可抑制核肿大和BrdU阳性发育不良小管的发育。这些结果提示，铜介导的DNA氧化损伤在LEC大鼠自发性肾细胞肿瘤的发生发展中起重要作用。用聚合酶链式反应-单链构象多态方法研究了VHL和TSC2基因在LEC和F344大鼠肾细胞肿瘤发生中的作用，未发现VHL基因突变。然而，我们在DEN和EHEN诱发的肾细胞肿瘤中发现了TSC2基因突变，而在自发肿瘤中没有发现。在8只(F344xLEC)F1大鼠中有1只发现了10号染色体杂合性缺失。

1. The role of copper and iron on the development of spontaneous renal cell tumors in Long-Evans Cinnamon (LEC) rats was investigated. Copper content in the kidneys of LEC rats in weeks 16-20 when necrotizing hepatitis occurred was 24 times higher than that in F344 rats. Then copper content decreased until 40 weeks, but it was always higher than that in F344 rats. Iron content in the kidney of LEC rats also peaked in weeks 16-20, but it was lower than that in F344 rats after 62 weeks old. Copper staining of the kidney in LEC rats showed positive staining in proximal tubules of the cortex and the outer stripe of the medulla. Long-term treatment of LEC rats with D-penicillamine, a copper-chelating agent, inhibited the development of karyomegaly and BrdU-positive dysplastic tubules. These results suggest that the copper-mediated oxidative DNA damage play an important role in the development of the spontaneous renal cell tumors in LEC rats.2. The role of VHL and Tsc2 genes on the development of renal cell tumors in LEC and F344 rats was investigated by PCR-SSCP.We could not find any mutation in VHL gene. However, we found the Tsc2 gene mutation in the renal cell tumors induced by DEN and EHEN,but not in spontaneous tumors. Loss of heterozygousity on chromosome 10 was found in one of eight (F344xLEC) F1 rats.