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Mutagenicity and cyto toxicity of 5 anti tumor ellipticines in mammalian cells and their structure activity relationships in salmonella



Mutagenicity and cyto toxicity of 5 anti tumor ellipticines in mammalian cells and their structure activity relationships in salmonella



Cancer Research 43(8): 3544-3552



The mutagenicity and cytotoxicity of 5 antitumor compounds (ellipticines) were investigated in the Chinese hamster ovary cell [CHO] hypoxanthine-guanine phosphoribosyltransferase assay and in 6 strains of Salmonella. All 5 compounds (ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, 9-aminoellipticine and 2-methyl-9-hydroxyellipticinium) were cytotoxic and mutagenic in the CHO 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 3 compounds appear to cause frame-shift mutations by both intercalation and covalent bonding with DNA; thus, these are classified as reactive intercalators. 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 CHO 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. That the ellipticines are mutagenic in mammalian cells suggests that these antitumor agents may be carcinogenic.

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