Cytotoxicity as a mechanism of carcinogenesis

Some of our previous results had shown that certain relatively weak carcinogens induced DNA single-strand breaks in rat hepatocytes but only with concomitant cytotoxicity. Stronger carcinogens usually induced breaks at relatively nontoxic concentrations. These observations led us to propose that chronic toxicity may be weakly carcinogenic through a cell-mediated mechanism without the necessity for a compound to directly attack DNA. The proposed mechanism is that one of a cell's responses to sublethal toxicity is to release the contents of some, but not all, of its lysosomes. Since lysosomes contain DNA hydrolases, these could enter the nucleus and induce single- and double-strand breaks in the DNA. Such DNA damage could lead to a malignant phenotype by a variety of mechanisms in those cells that survive. Some initial support for this hypothesis comes from our observation that hypotonic shock causes single-strand breaks in the DNA of mouse L1210 cells and that these breaks can be repaired.