Quantitative structure-activity carcinogenicity

Benigni R, Giuliani A. Quantitative structure-activity relationship (QSAR) studies of mutagens and carcinogens. Med Res Rev 1996 16 267-84. 

We have developed a quantitative structure-activity model for the variations in potency among the nitrosamines and, more recently, a related model for the variation in target organ for a smaller set of nitrosamines. We are currently developing a model for interspecies variation in susceptibility toward carcinogenic nitrosamines. The model for organ selectivity requires terms for the parent nitrosamine as well as for the hypothesized metabolites while the model for potency variations contains terms only for the unmetabolized parent compound. 

There appears now to be ample evidence that the variations in carcinogenicity among the nitrosamines are systematically and rationally related to structure and that several Indices of carcinogenic potency can be used as indices of biological response for the generation of quantitative structure-activity models (11-17). 

The Danish EPA has developed an advisory list for self-classification of dangerous substances including 20 624 substances. The substances have been identified by means of QSAR models (Quantitative Structure-Activity Relationship) as having acute oral toxicity, sensitization, mutagenicity, carcinogenicity, and/or danger to the aquatic environment. 

Although traditional octanol/water distribution coefficients are still widely used in quantitative structure-activity relationships (QSAR) and in ADME/ pharmacokinetic (PK) studies, alternatives have been proposed. To cover the variability in biophysical characteristics of different membrane types, a set of four solvents has been suggested - sometimes called the critical quartet [49-51], The 1,2-dichloroethane (DCE)/water system has been promoted as a good alternative to alkane/water due to its far better dissolution properties [50, 51], but it may be used only rarely due to its carcinogenic properties. 

A hierarchical approach. In Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens, Benigni, R., Ed., CRC Press, Boca Raton, FL, 2003, pp. 207-234. 

Patlewicz, G., Rodford, R. and Walker, J.D. (2003) Quantitative structure-activity relationships for predicting mutagenicity and carcinogenicity. Environ. Toxicol. Chem., 22 (8),... 

Benigni, R., Andreoli, C. and Giuliani, A. (1989) Quantitative structure—activity relationships principles and applications to mutagenicity and carcinogenicity. Mutat. Res., 221, 197—216. 

Blake BW, Enslein K, Gombar VK, et al. 1990. Salmonella mutagenicity and rodent carcinogenicity quantitative structure-activity relationships. Mutat Res 241(3) 261-271. 

A.H. Morales et al., Quantitative structure activity relationship for the computational prediction of nitrocompounds carcinogenicity. Toxicology 220, 51-62 (2006)... 

Croisy, and P.C. Jacquignon. A quantitative structure-activity analysis of the mutagenic and carcinogenic... 

Benigni, R., Giuliani, A., Franke, R., and Gruska, A., Quantitative structure-activity relationships of mutagenic and carcinogenic aromatic amines, Chem. Rev., 100, 3697-3714, 2000. 

R. Benigni, C. Andreoli, and A. Giuliani, in QSAR Quantitative Structure-Activity Relationships in Drug Design, J. L. Fauchere, Ed., Alan R. Liss, New York, 1989. Structure-Activity Studies of Chemical Carcinogens in Non-generic Sets of Compounds. 

Apart from toxicity tests involving the use of live animals, there are other ways of evaluating the toxic properties of chemicals that stem from an understanding of their mode of action. For example, the Ames test aids in the identification of substances that act as carcinogens or mutagens in mammals. Also, the study of the relationship between structure and toxicity (i.e., quantitative structure-activity relationships or QSARs) can provide support for the identification of toxic substances. These approaches will become more viable as molecular mechanisms of toxicity become better known, and they can lead to an understanding of the molecular characteristics that cause a chemical to interact adversely with cellular macromolecules. 

Lewis DF, Ioannides C, Parke DV. A quantitative structure-activity relationship (QSAR) study of mutagenicity in several series of organic chemicals likely to be activated by cytochrome P450 enzymes. Teratogen Carcinogen Mutagen 2003 (Suppl)l 187-93. 

Niculescu-Duvaz I, Craescu T, Tugulea M, Croisy A, Jacquignon PC. A quantitative structure-activity analysis of the mutagenic and carcinogenic action of 43 structurally related heterocyclic compounds. Carcinogenesis 1981 2 269-75. 

Franke R, Gruska A, Giuliani A, Benigni R. Prediction of rodent carcinogenicity of aromatic amines A quantitative structure-activity relationships model. Carcinogenesis 2001 22 1561-71. 

Singh AK. Development of quantitative structure-activity relationship (QSAR) models for predicting risk of exposure from carcinogens in animals. Cancer Invest 2001 19 611-20. 

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