Induction of topoisomerase I-mediated DNA cleavage by a new indolocarbazole, ED-110.
ED-110 is a new semisynthetic antitumor agent derived from a novel indolocarbazole antibiotic, BE-13793C, produced by an actinomycete. ED-110 induced topoisomerase I-mediated DNA cleavage in vitro as strongly as camptothecin, whereas topoisomerase II-mediated DNA cleavage was not induced by this agent. Exposure of P388 cells to ED-110 caused a typical topoisomerase toxicity, i.e.: formation of cleavable complexes; inhibition of nucleotide synthesis rather than protein synthesis; and cell cycle arrest in G2. ED-110 inhibited the growth of P388 cells, with a 50% growth-inhibitory concentration of 44 nM. ED-110 is distinguished from camptothecin by its very different structure and its ability to intercalate into double-stranded DNA. These results suggest that ED-110 has potential as a novel antitumor agent targeting topoisomerase I.
Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Japan.
T
T
Yoshinari
A
A
Yamada
D
D
Uemura
K
K
Nomura
H
H
Arakawa
K
K
Kojiri
E
E
Yoshida
H
H
Suda
A
A
Okura
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004278:DNA, Superhelical / Q000378:metabolism; D004790:Enzyme Induction; D005434:Flow Cytometry; D005960:Glucosides / Q000378:metabolism / Q000494:pharmacology*; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D005960:Glucosides; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C078870:ED 110; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II