Induction of a heat-stable topoisomerase II-DNA cleavable complex by nonintercalative terpenoides, terpentecin and clerocidin.
Terpentecin and clerocidin, microbial terpenoides, have been known to be potent antitumor antibiotics. However, the critical biochemical target of these terpenoides has not been identified. Our present studies, using purified mammalian topoisomerase II, have shown that terpentecin and clerocidin induce topoisomerase II-mediated DNA cleavage in vitro with comparable potency to that of demethylepipodophyllotoxin ethylidene-beta-D-glucoside. These terpenoides produced a similar DNA cleavage pattern which is distinctly different from those generated in the presence of the known topoisomerase poisons, demethylepipodophyllotoxin ethylidene-beta-D-glucoside and 4'-(9-acridinylamino)methanesulfon-m-anisidide. Brief heating at 65 degrees C, which abolishes completely the cleavable complex with demethylepipodophyllotoxin ethylidene-beta-D-glucoside, of the reaction mixture containing these terpenoides resulted in slight reduction in DNA cleavage. Thus, differently from other topoisomerase II-active antitumor agents, terpentecin and clerocidin induce formation of a cleavable complex which is stable for heat or salt treatments. The lack of significant DNA binding or intercalation activity of terpentecin and clerocidin suggests that topoisomerase II is a cellular target for these drugs.
Kawada
S
S
Tokyo Research Laboratories, Kyowa Hakko Co., Ltd., Japan.
Yamashita
Y
Y
Fujii
N
N
Nakano
H
H
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000502:physiology*; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006358:Hot Temperature; D013713:Teniposide / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004224:Diterpenes; C047785:terpentecin; D005047:Etoposide; C039027:clerocidin; D004247:DNA; D013713:Teniposide; D004250:DNA Topoisomerases, Type II