Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I.
J-107088 [6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carb azo le-5,7(6H)-dione] is a new derivative of NB-506, an indolocarbazole antitumor agent. J-107088 induced single-strand DNA cleavage only in the presence of topoisomerase I (top1) more effectively than NB-506 or camptothecin. The preferable sequences of the DNA cleaved by J-107088 were C/T / G as in the case of NB-506. This base-preference of J-107088 in top1-mediated cleavage was different from that of camptothecin, which was T / G/A. top1 poisons stabilize the complex between DNA and top1 (cleavable complex). This cleavable complex is released on addition of a high concentration of monovalent cation or removal of top1 poisons. The complex induced by J-107088 was quite stable; it was scarcely released on the addition of NaCl or dilution of J-107088, contrary to the case with camptothecin and NB-506. J-107088-inducing complexes were also stable in cultured cells, when the compound was added to the culture medium. These unique in vitro activities of J-107088 on top1 that differed from those of camptothecin and NB-506 may be relevant to its more potent in vivo antitumor efficacy in a human tumor xenographted nude mouse model.
Yoshinari
T
T
Banyu Tsukuba Research Institute and Merck Research Laboratories, Japan.
Ohkubo
M
M
Fukasawa
K
K
Egashira
S
S
Hara
Y
Y
Matsumoto
M
M
Nakai
K
K
Arakawa
H
H
Morishima
H
H
Nishimura
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D007211:Indoles; D051379:Mice; D012965:Sodium Chloride / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005960:Glucosides; D007211:Indoles; C092476:NB 506; D059004:Topoisomerase I Inhibitors; C121395:edotecarin; D012965:Sodium Chloride; D004247:DNA