The use of structure-activity relationships and markers of cell toxicity to detect non-genotoxic carcinogens

In contrast to the situation for genotoxic carcinogens, few in vitro tests exist that can detect early markers of the events thought to be associated with non-genotoxic carcinogenesis. Also, comparatively little is known about the quantitative structure-activity relationships (Q)SARs of these agents. This review discusses published SAR studies conducted on non-genotoxic carcinogens, in relation to the use of several markers of in vitro cell toxicity (inhibition of gap-junctional intercellular communication, inhibition of tubulin polymerization, modulation of apoptosis and induction of cell proliferation), which are used as endpoints for screening this class of carcinogen. Much of the work has involved the identification of new biophores (substructural features of molecules associated with toxicity), as well as other structural features, which are thought to predispose the chemicals to ligand binding with specific target molecules acting as possible receptors (e.g. protein kinase C, the oestrogen, peroxisome-proliferator and tubulin protein receptors), implicated in the mechanism of toxicity involved. It is concluded that (a) there is an urgent need for more information on (Q)SARs for non-genotoxic carcinogens; (b) this information should be acquired by using several different approaches in a variety of laboratories; and (c) such research should proceed together with more studies on the mechanisms of cell toxicity caused by these chemicals, including the identification and characterisation of further specific receptors involved in mediating the various types of cell toxicity associated with this type of carcinogenesis. (C) 2000 Elsevier Science Ltd. All rights reserved.