Heritable and cancer risks of exposures to anticancer drugs: inter-species comparisons of covalent deoxyribonucleic acid-binding agents.
In the past years, several methodologies were developed for potency ranking of genotoxic carcinogens and germ cell mutagens. In this paper, we analyzed six sub-classes of covalent deoxyribonucleic acid (DNA) binding antineoplastic drugs comprising a total of 37 chemicals and, in addition, four alkyl-epoxides, using four approaches for the ranking of genotoxic agents on a potency scale: the EPA/IARC genetic activity profile (GAP) database, the ICPEMC agent score system, and the analysis of qualitative and quantitative structure-activity and activity-activity relationships (SARs, AARs) between types of DNA modifications and genotoxic endpoints. Considerations of SARs and AARs focused entirely on in vivo data for mutagenicity in male germ cells (mouse, Drosophila), carcinogenicity (TD50s) and acute toxicity (LD50s) in rodents, whereas the former two approaches combined the entire database on in vivo and in vitro mutagenicity tests. The analysis shows that the understanding and prediction of rank positions of individual genotoxic agents requires information on their mechanism of action. Based on SARs and AARs, the covalent DNA binding antineoplastic drugs can be divided into three categories. Category 1 comprises mono-functional alkylating agents that primarily react with N7 and N3 moieties of purines in DNA. Efficient DNA repair is the major protective mechanism for their low and often not measurable genotoxic effects in repair-competent germ cells, and the need of high exposure doses for tumor induction in rodents. Due to cell type related differences in the efficiency of DNA repair, a strong target cell specificity in various species regarding the potency of these agents for adverse effects is found. Three of the four evaluation systems rank category 1 agents lower than those of the other two categories. Category 2 type mutagens produce O-alkyl adducts in DNA in addition to N-alkyl adducts. In general, certain O-alkyl DNA adducts appear to be slowly repaired, or even not at all, which make this kind of agents potent carcinogens and germ cell mutagens. Especially the inefficient repair of O-alkyl-pyrimidines causes the high mutational response of cells to these agents. Agents of this category give high potency scores in all four expert systems. The major determinant for the high rank positions on any scale of genotoxic of category 3 agents is their ability to induce primarily structural chromosomal changes. These agents are able to cross-link DNA. Their high intrinsic genotoxic potency appears to be related to the number of DNA cross-links per target dose unit they can induce. A confounding factor among category 3 agents is that often the genotoxic endpoints occur close to or at toxic levels, and that the width of the mutagenic dose range, i.e., the dose area between the lowest observed effect level and the LD50, is smaller (usually no more than 1 logarithmic unit) than for chemicals of the other two categories. For all three categories of genotoxic agents, strong correlations are observed between their carcinogenic potency, acute toxicity and germ cell specificity.
Leiden University Medical Centre, Dept. Radiation Genetics and Chemical Mutagenesis, MGC, Wassenaarseweg 72, 2300 RA Leiden, Netherlands. vogel@rullf2.medfac.leidenuniv.nl
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Vogel
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Barbin
M J
MJ
Nivard
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Stack
M D
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Waters
P H
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Lohman
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D015197:Carcinogenicity Tests / Q000379:methods / Q000706:statistics & numerical data; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D003432:Cross-Linking Reagents; D004247:DNA / Q000378:metabolism*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005796:Genes / Q000187:drug effects; D005854:Germ Cells / Q000187:drug effects; D006801:Humans; D007928:Lethal Dose 50; D008540:Meiosis / Q000187:drug effects; D009152:Mutagenicity Tests / Q000379:methods / Q000706:statistics & numerical data; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000139:chemically induced; D011237:Predictive Value of Tests; D018570:Risk Assessment; D013045:Species Specificity
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004247:DNA