Renal cell carcinoma was induced in rats by p.o. administration of dimethylnitrosamine, 500 ppm daily, followed by N-(3,5-dichlorophenyl)succinimide (NDPS), 5000 ppm daily. Fine structural changes of the proximal convoluted tubule cells were observed by sequential examinations of the kidney cortices at 3, 5, 12, and 24 weeks after drug administration. Early prominent structural changes of the cells induced by dimethylnitrosamine alone were the appearance of microspherules in nucleoli and of numerous lamellar bodies on the membrane structure of the cells. With the addition of NDPS, the cells exhibited edematous cytoplasm that, in contrast to the relatively intact nuclear structure, contained numerous small vesicles and dark mitochondria, with markedly disarranged microvilli. After prolonged treatment with these drugs, some of the cells showed regenerating features, while others became necrotic. In the former case, large clear nuclei appeared with enlarged nucleoli containing a large amount of granular components. Ribosomes in the cytoplasm also increased in number in accordance with nucleolar changes, and edema in cytoplasm and microvilli markedly decreased. However, a considerable number of vesicles still remained in some cells. Mitochondria decreased in number and showed pleomorphism and relatively high electron density. At 24 weeks, when clear cell carcinoma was induced, the cells in the cancer tissue exhibited a variety of features in their nuclei and cytoplasm. Some cells showed intact nuclear structure and dark cytoplasm containing a large number of vesicles; others had large round clear nuclei with enlarged nucleoli and clear cytoplasm containing no vesicles. Among these cells were mixed populations of large clear cells, showing a structure similar to the cells at 12 weeks, i.e., to nodular hyperplastic cells. The starting point of malignant transformation seemed to be 1 week after treatment with NDPS (i.e., cells at 5 weeks) and, of the precancerous stage, at 12 weeks.

These results suggest that the proximal convoluted tubule cells previously damaged by dimethylnitrosamine treatment were marked for mutation and were transformed to cancer cells by additional treatment with NDPS in such a way as to disturb the permeability of the membrane system of the cell and to condense chromatin fibers.


This work was supported in part by Grants-in-Aid 801075 (1973) and 901072 (1974) for Scientific Research from the Ministry of Education, Japan.

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