METHODS FOR PREDICTING CARCINOGENIC HAZARDS - NEW OPPORTUNITIES COMING FROM RECENT DEVELOPMENTS IN MOLECULAR ONCOLOGY AND SAR STUDIES

Without epidemiological evidence, and prior to either short-term tests of genotoxicity or long-term tests of carcinogenicity in rodents, an initial level of information about the carcinogenic hazard of a chemic al that perhaps has been designed on paper, but never synthesized, can be provided by structure-activity relationship (SAR) studies. Herein, we have reviewed the interesting strategies developed by human expert s and/or computerized approaches for the identification of structural alerts that can denote the possible presence of a carcinogenic hazard in a novel molecule. At a higher level of information, immediately bel ow epidemiological evidence, we have discussed carcinogenicity experim ents performed in new types of genetically engineered small rodents. I f a dominant oncogene is already mutated, or if an allele of a recessi ve oncogene is inactivated, we have a model animal with (n-1) stages i n the process of carcinogenesis. Both genotoxic and receptor-mediated carcinogens can induce cancers in 20-40% of the time required for clas sical murine strains. We have described the first interesting results obtained using these new artificial animal models for carcinogenicity studies. We have also briefly discussed other types of engineered mice (lac operon transgenic mice) that are especially suitable for detecti ng mutagenic effects in a broad spectrum of organs and tissues and tha t can help to establish mechanistic correlations between mutations and cancer frequencies in specific target organs. Finally, we have review ed two complementary methods that, while obviously also feasible in ro dents, an especially suitable for biomonitoring studies. We have illus trated some of the advantages and drawbacks related to the detection o f DNA adducts in target and surrogate tissues using the P-32-DNA postl abeling technique, and we have discussed the possibility of biomonitor ing mutations in different human target organs using a molecular techn ique that combines the activity of restriction enzymes with polymerase chain reaction (RFLP/PCR). Prediction of carcinogenic hazard and biom onitoring are very wide-ranging areas of investigation. We have theref ore selected five different subfields for which we felt that interesti ng innovations have been introduced in the last few years. We have mod e no attempt to systematically cover the entire area: such an endeavor would have produced a book instead of a review article. (C) 1997 Else vier Science B.V.