Mutagenicity and cytotoxicity of five antitumor ellipticines in mammalian cells and their structure-activity relationships in Salmonella

Journal Article · Mon Aug 01 00:00:00 EDT 1983 · Cancer Res.; (United States)

OSTI ID:5748461

DeMarini, D M; Cros, S; Paoletti, C; Lecointe, P; Hsie, A W

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/sup +/) 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.

• Research Organization: Univ. of Tennessee-Oak Ridge Graduate School of Biomedical Sciences
• DOE Contract Number: W-7405-ENG-26
• OSTI ID: 5748461
• Journal Information: Cancer Res.; (United States), Journal Name: Cancer Res.; (United States) Vol. 43; ISSN CNREA
• Country of Publication: United States
• Language: English

Related Subjects

560301* -- Chemicals Metabolism & Toxicology-- Cells-- (-1987)
560302 -- Chemicals Metabolism & Toxicology-- Microorganisms-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMALS
ANTINEOPLASTIC DRUGS
BACTERIA
CARCINOGEN SCREENING
CELL KILLING
CHEMICAL BONDS
CHO CELLS
COVALENCE
DATA
DNA REPLICATION
DRUGS
ENZYME ACTIVITY
EXPERIMENTAL DATA
HAMSTERS
INFORMATION
MAMMALS
METABOLIC ACTIVATION
MICROORGANISMS
MUTAGEN SCREENING
MUTAGENESIS
MUTANTS
NUCLEIC ACID REPLICATION
NUMERICAL DATA
REVERTANTS
RODENTS
SALMONELLA
SCREENING
STRUCTURE-ACTIVITY RELATIONSHIPS
TOXICITY
VERTEBRATES