Bacterial and mammalian cell mutagenesis, sister‐chromatid exchange, and mouse lung adenoma bioassay with the antineoplastic acridine derivative amsacrine
作者:
FelixA. de la Iglesia,
JamesE. Fitzgerald,
EdwardJ. McGuire,
Sang‐Nam Kim,
CarlL. Heifetz,
GaryD. Stoner,
期刊:
Journal of Toxicology and Environmental Health
(Taylor Available online 1984)
卷期:
Volume 14,
issue 5-6
页码: 667-681
ISSN:0098-4108
年代: 1984
DOI:10.1080/15287398409530616
出版商: Taylor & Francis Group
数据来源: Taylor
摘要:
Amsacrine is a DNA intercalating agent with antineoplastic properties in lymphopro‐liferative disorders. This report describes a group of short‐term tests with multiple endpoints to characterize the mutagenic and carcinogenic properties of this drug. In vitro studies included bacterial and mammalian cell mutagenesis, and slster‐chromatid exchange and chromosome aberrations in mammalian cells. In vivo, mice were given amsacrine for 7 wk at 2, 5, and 10 mg/kg and were observed for an additional 17 wk. The standard bacterial assay revealed cytotoxicity at 2000 and 5000 μg/plate in the pre‐incubation assay. No significant increase in revertants occurred in Salmonella strains, except for TA1537 in the activation phase. Amsacrine at 4.0 μg/ml was cytotoxic to V‐79 cells in the cell mutation assay, and at lower dose levels was a direct‐acting mutagen for the HGPRT locus. Sister‐chromatid exchange rate of Chinese hamster ovary cells was increased more than twofold at 2 μg/ml without metabolic activation. Cell anomalies included changes in metaphase cell kinetics and chromosome damage. Mice in the lung adenoma bioassay failed to show increased numbers of tumors, while indicating lack of tolerance and survival beyond 5 mg/kg. The results indicate clear genotoxicity to mammalian cell systems with a spectrum of changes from point mutation and SCE induction to cell‐cycle alterations, irrespective of exogenous metabolic activation. These results corroborate previous findings in animal and human cell systems in vitro. The reduction of genotoxicity in bacterial assays after exogenous metabolic activation may suggest some detoxification, and the magnitude of effects observed in mammalian cells indicates that exogenous metabolic activation is not required to manifest amsacrine's activity. The lack of tumor‐inducing potential in mice may be attributed to strong cytotoxic effects in this species, or to an insensitivity of the target organ, or to assay systems that may mask the carcinogenic potential.
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