Tumorigenicity in vivo and induction of mutagenesis and DNA repair in vitro by aclacinomycin A and marcellomycin: structure-activity relationship and predictive value of short-term tests.
The genotoxicity of two new anthracycline antitumor antibiotics, aclacinomycin A and marcellomycin, which are potent cytostatic agents similar to Adriamycin and daunomycin, was investigated in various assays. In contrast to Adriamycin and daunomycin, both agents were devoid of mutagenic activity in the Salmonella-microsome assay as well as in a mammalian cell assay using V79 Chinese hamster cells. In primary rat hepatocytes, aclacinomycin A was active in inducing unscheduled DNA synthesis, whereas marcellomycin was not. After single i.v. doses of the 10% lethal dose, marcellomycin (15 mg/kg) did induce mammary tumors in female Sprague-Dawley rats, whereas aclacinomycin A (15 mg/kg) proved to be nontumorigenic. In conjunction with previous data, these results indicate that: (a) cytostatic and genotoxic properties of anthracyclines can be clearly separated; (b) alkylation of the primary amino group of their sugar moieties can abolish or greatly reduce mutagenic activity; and (c) poor correlations in some instances must be anticipated between in vivo tumorigenicity and activity in in vitro short-term tests as well as among different short-term tests.
D015250:Aclarubicin; D000818:Animals; D018943:Anthracyclines; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic; D002273:Carcinogens; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair; D004353:Drug Evaluation, Preclinical; D008168:Lung; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D009279:Naphthacenes / Q000633:toxicity; D009374:Neoplasms, Experimental / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D002273:Carcinogens; D009153:Mutagens; D009279:Naphthacenes; C015338:marcellomycin; D015250:Aclarubicin