Novel antitumor indolocarbazole compound 6-N-formylamino-12,13-dihydro-1,11- dihydroxy-13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4- c]carbazole-5,7(6H)-dione (NB-506): induction of topoisomerase I-mediated DNA cleavage and mechanisms of cell line-selective cytotoxicity.
A new indolocarbazole antitumor agent, NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H- indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione], enhanced the DNA cleavage catalyzed by HeLa S3 topoisomerase I at 0.01 microM but not the cleavage by topoisomerase II at 300 microM. It also caused single-strand DNA breakage in intact cells at 0.08 microM and more. Unlike the known topoisomerase I inhibitor camptothecin, NB-506 intercalated with DNA. However, the binding affinity to DNA and the inhibition against DNA polymerase alpha and RNA polymerase II were marginal compared with those of Adriamycin or actinomycin D. NB-506 inhibited the growth of various tumor cell lines at two micromoles or less, and its cytotoxicity was found to be cell line selective. This selective cytotoxicity of NB-506 was not fully explained by the differences in topoisomerase I activity in these cell lines, but there was some relationship between the amount of NB-506 accumulated in these cell lines and its cytotoxicity toward them. In conclusion, NB-506 is a potent topoisomerase I poison, acting selectively on tumor cell lines accumulating NB-506.
Yoshinari
T
T
Banyu Tsukuba Research Institute, Tsukuba, Japan.
Matsumoto
M
M
Arakawa
H
H
Okada
H
H
Noguchi
K
K
Suda
H
H
Okura
A
A
Nishimura
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; C092476:NB 506; D047428:Protein Kinase Inhibitors; D004247:DNA; D012321:DNA-Directed RNA Polymerases; D004264:DNA Topoisomerases, Type I