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Mutagenicity and Cytotoxicity of Five Antitumor Ellipticines in Mammalian Cells and Their Structure-Activity Relationships in Salmonella¹

University of Tennessee-Oak Ridge Graduate School of Biomedical Sciences [D. M. D.] and Biology Division, Oak Ridge National Laboratory [A. W. H.], Oak Ridge, Tennessee 37830, and Laboratoire de Pharmacologie et de Toxicologie Fondamentales du C.N.R.S., 205 route de Narbonne, 31400 Toulouse Cedex, France [S. C., C. P., P. L.]

The mutagenicity and cytotoxicity of five antitumor compounds (ellipticines) were investigated in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay and in six strains of Salmonella. All five compounds (ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, 9-aminoellipticine, and 2-methyl-9-hydroxyellipticinium) were cytotoxic and mutagenic in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay in the presence or absence of Aroclor 1254-induced rat liver S9, and all except the last compound were mutagenic in Salmonella. Based on the reversion pattern obtained in various frame-shift and DNA repair-proficient (uvrB⁺) or -deficient (uvrB) strains of Salmonella in the presence or absence of S9, the first three compounds appear to cause frameshift mutations by both intercalation and covalent bonding with DNA; thus, these are classified as reactive intercalators. However, 9-aminoellipticine intercalates only weakly and may instead exert its mutagenic activity primarily (or exclusively) by forming a covalent adduct with DNA. Compared to the published antitumor data obtained in mice, the results in Salmonella and Chinese hamster ovary cells suggest that the ability of ellipticine, 9-methoxyellipticine, and 9-hydroxyellipticine to intercalate with DNA, induce frame-shift mutations, and cause cell killing is associated with and may be the basis for their antitumor activity. The observation that the ellipticines are mutagenic in mammalian cells suggests that these antitumor agents may be carcinogenic.

¹ Research sponsored jointly by Coordinating Council for Cancer Research, Villejuif, France, and New York, N. Y.; and Office of Health and Environmental Research, United States Department of Energy, under Contract W-7405-eng-26 with the Union Carbide Corporation.

² Postdoctoral Investigator, supported by Subcontract 3322 from the Biology Division of Oak Ridge National Laboratory to the University of Tennessee. Present address: National Toxicology Program, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, N. C. 27709.

Received 11/17/82. Accepted 4/26/83.

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