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 chemical 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 experts 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 below epidemiological evidence, we have discussed carcinogenicity experiments performed in new types of genetically engineered small rodents. If a dominant oncogene is already mutated, or if an allele of a recessive oncogene is inactivated, we have a model animal with (n-1) stages in the process of carcinogenesis. Both genotoxic and receptor-mediated carcinogens can induce cancers in 20-40% of the time required for classical 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 detecting mutagenic effects in a broad spectrum of organs and tissues and that can help to establish mechanistic correlations between mutations and cancer frequencies in specific target organs. Finally, we have reviewed two complementary methods that, while obviously also feasible in rodents, are especially suitable for biomonitoring studies. We have illustrated some of the advantages and drawbacks related to the detection of DNA adducts in target and surrogate tissues using the 32P-DNA postlabeling technique, and we have discussed the possibility of biomonitoring mutations in different human target organs using a molecular technique that combines the activity of restriction enzymes with polymerase chain reaction (RFLP/PCR). Prediction of carcinogenic hazard and biomonitoring are very wide-ranging areas of investigation. We have therefore selected five different subfields for which we felt that interesting innovations have been introduced in the last few years. We have made no attempt to systematically cover the entire area: such an endeavor would have produced a book instead of a review article.
Taningher
M
M
National Institute for Cancer Research, Laboratory of Experimental Oncology, University of Genoa, Italy.
Malacarne
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D
Mancuso
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Peluso
M
M
Pescarolo
M P
MP
Parodi
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D000818:Animals; D030801:Animals, Genetically Modified; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis; D001330:Electronic Data Processing; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D013329:Structure-Activity Relationship
D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens