Genetic toxicology profile of the new antineoplastic drug mitoxantrone in the mammalian test systems.
As part of safety evaluation and drug development, 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]-ethyl]amino]-9,10-anthracenedione dihydrochloride (mitoxantrone, NSC 301739, CL 232,315, Novantrone) was tested in the mammalian test systems to determine its mutagenic potential. Mitoxantrone produced significant clastogenic effect in bone marrow of rats treated for 5 days at greater than or equal to 0.5 mg/kg i.p. It produced apparent increases in DNA repair in the rat hepatocyte UDS (unscheduled DNA synthesis) test and increased SCEs (sister chromatid exchanges) in CHO cells and mutant frequencies in mouse lymphoma assay. In the cell transformation test using C3H/10T 1/2 cl 8 cells, mitoxantrone did not produce significant increases in type II or type III transformed foci. In the dominant lethal test in rats, mitoxantrone administered 2 mg/kg/d i.p. affected matings of treated males, however, total implantations as well as early deaths resulting from matings with surviving males were unaffected. These results show the potential of mitoxantrone to produce genetic activity in vitro and in the somatic cells in vivo but inability of the drug to cause morphological transformation in vitro or genotoxic effect in the germinal cells in vivo. The biological significance of findings such as above is uncertain. Examination of genetic end-points such as chromosomal assays in rodents on life time studies which are currently being completed will delineate the significance, if any, of these findings.
D000818:Animals; D001711:Biotransformation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects; D005799:Genes, Dominant / Q000187:drug effects; D005804:Genes, Lethal / Q000187:drug effects; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D008942:Mitoxantrone / Q000378:metabolism / Q000633:toxicity*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012854:Sister Chromatid Exchange / Q000187:drug effects
D009153:Mutagens; D004247:DNA; D008942:Mitoxantrone