Genotoxicity of the antitumor antibiotic CC-1065.
CC-1065, a very potent antitumor antibiotic, is active against several animal tumors, and against human tumors in the cloning assay at doses 50-1000 times lower than other agents such as adriamycin. It binds and alkylates DNA, and inhibits DNA synthesis, suggesting a potential for genotoxicity. Therefore, the genotoxic effects of CC-1065 were tested in several assay systems. CC-1065 was weakly mutagenic in the Ames Salmonella mutation assay (strain TA100) without S9 activation, but lacked mutagenic activity in TA98 with or without activation. CC-1065 was a very potent mutagen in the Salmonella forward mutation assay (induction of 8-azaguanine resistance), increasing the mutation frequency 19-fold over background at 0.1 ng/ml without activation. In mammalian (V79) cells it was a very potent mutagen without activation, increasing the mutation frequency 20-fold over background a 0.5 ng/ml. CC-1065 induced chromosome aberrations in V79 cells at very low (less than 0.1 ng/ml) doses, making this assay the most sensitive. CC-1065 increased the induction of micronuclei in rats 10- to 20-fold over the background at 200 and 400 micrograms/kg, but not at 100 micrograms/kg. CC-1065 failed to cause DNA breaks or DNA--protein cross-links as measured by the DNA damage/alkaline elution assay.
Harbach
P R
PR
Department of Pathology, Upjohn Company, Kalamazoo, MI 49001.
Trzos
R J
RJ
Mazurek
J H
JH
Zimmer
D M
DM
Petzold
G L
GL
Bhuyan
B K
BK
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations; D004247:DNA / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000633:toxicity*; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013866:Thioguanine / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D009153:Mutagens; C018782:CC 1065; D004247:DNA; D013866:Thioguanine