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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Comparative structure-genotoxicity study of three aminoanthraquinone drugs and doxorubicin.

Two aminoanthraquinone analogs 1,4-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (HAQ) and 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino]-9,10-anthracenedione (DHAQ) have been shown to possess similar therapeutic activities against experimental tumors but different toxicities to the animals. In this study, the genotoxic effects of these two drugs and a new analog, 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino]-9,10-anthracenedione diacetate, were analyzed by using mammalian cell cytogenetic assays (chromosome breakage and sister chromatid exchanges) as well as bacterial mutagenesis assays. The experimental therapeutic activities of these drugs in vivo correlated well with their in vitro genetic toxicities as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Discrepancies were observed between results obtained from cytogenic assays and those from mutagenesis assays. Whereas DHAQ was most active in cytogenetic studies, Adriamycin was most mutagenic or toxic. HAQ was least active cytogenetically, and this activity was not changed appreciably in the presence of metabolic enzymes. However, it was metabolically activated to a bacterial mutagen. Our studies suggest that the cytogenetic and mutagenesis assays may be sensitive to the activities of different agents and of different moieties of the same agent. The application of short-term in vitro assays to identify the chemical structures responsible for genetic toxicity and for therapeutic activities in vivo may lead to the better understanding of drug activities and to the development of more effective drugs.[1]

References

  1. Comparative structure-genotoxicity study of three aminoanthraquinone drugs and doxorubicin. Au, W.W., Butler, M.A., Matney, T.S., Loo, T.L. Cancer Res. (1981) [Pubmed]
 
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