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Preneoplastic lesions in kidney and carcinogenesis by non-genotoxic compounds.

D. Dietrich,T. Rasonyi

Published 1994 in Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement

ABSTRACT

Carcinogenesis is known to be a multislep process which involves two 01' m(Jn.~ events C<lt1 result from point mutations, chromosomal rearmngements (Cr<Jcc amI Klein 1990), inscrtions or dcletions of genes, and gene amplification. Cell replicmiof} is required to cOßvert DNA damage to mutations, irrespective ofwhether this dmnagt: is occurring sp<.mtaneous1y 01' induced by DNA damaging (genotoxic) compounds. Spontancous mutations ure assumed to stern from spontaneous genetic evenL'l such as depurination and deamination of DNA, formation of covalent DNA adducts by physiologica1 reactive cellular constituents, DNA damage by oxygen free radicals pnxluccd in ceUular metabolism, errors in DNA replication (Loch 1989). Normally thc cell Ilas the possibility to either repair the damaged DNA, 01', if the damage is irrepaird.ble, to destroy itself via tumor suppressor gene product (e.g. p53) mediated apoptosis (Lane 1993). Abrogated DNA fepmr or apoptosis of damaged cells in conjunctic)n witll a cell prolüerative stimulus can lead to the fomlation of clusters nf mutated cells and clonal expansion. Continued enhanced proliferation and ex.pmlsinn of such clones increases the probability of additional genet1c events withinthe:sc populations (Knudson 1987) thus providing a basis for the fonnation of preneopluslic lesions and progression to veritable tumors (Swenberg et al. 1987; Dietrich und Swenberg 1991 b). Although the sequence of events described above appears reasonablc, little direct evidence has been put forward so far. However, same corroboration 1s provided by thc observation that control animals from strains of Inboratory rodents present with an appreciable incidence of spontancous preneoplastic lesions and tumors (Dietrich and Swenberg 1991b). The incidence ur spontaneous tumors vades greatly 1'rom tissue to tissue, strain to strain, sex to sex, and species to species (Swenberg und Short 1987). Non-genotoxic compounds by definition do not induce DNA damage lhcrnsclvcs. However, non-genotoxic carcinogens can induce enhanced cell proliferation und rhuli contribute to lhe fixation of spontaneous mutations as weil as to the fonnation aml progression of preneoplastic und neoplastic lesions. Similarly, non-genotoxic carcinogens could abrogate removal of damaged cells via inhibition of the apopwtic processes and, in conjunction w1th a simultaneously occurring prolifemtive stimulus. could promote formation of preneoplastic and neoplastic lesions. Indeed, a commonly observed feature of non-genotoxic compounds tested at high concenlrations in carcinogenicity bioassays is lhe concurrent cytotoxicity and/or cell proliferation along with hyperplasia in the tissues that finally develop tumors. 1t i5 the aim of !:his short overview to delineate the mechanisms by which non-genotoxic renal carcinogens induce the …

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