Preneoplastic lesions in kidney and carcinogenesis by non-genotoxic compounds

Abstract

Of the non-genotoxic compounds shown to induce renal preneoplasia and renal cancer in rodents, the associated mechanisms are known only for the compounds shown to reversibly bind to the male rat specific protein α2μ-globulin and for the chelator nitrilo-triacetic acid (NTA). The mechanism of the third highly carcinogenic, but not clearly non-genotoxic compound ochratoxin A, is still under investigation. All three mechanisms seem to have one feature in common, namely an overt cytotoxicity which is demonstrated by the presence of necrosis or apoptosis and an ensuing increased rate of cell replication. Increased cell proliferation rates give rise to an enhanced probability of fixing spontaneously occurring mutations due to reduced time available for DNA repair, thus providing a basis for the development of preneoplastic lesions. Not all preneoplastic lesions will progress to veritable tumors, however, the number, size and types of preneoplastic lesions induced appear to determine the probability of malignant progression. Furthermore, exposure to either non-genotoxic or genotoxic agents appears to determine the morphologic types of preneoplastic and neoplastic lesions, i.e. clear cell adenomas and carcinomas are observed rarely following exposure to non-genotoxic agents.