Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I

Cancer Res. 1999 Sep 1;59(17):4271-5.

Abstract

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carbazoles / pharmacology*
  • Cell Line
  • DNA / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Glucosides / pharmacology*
  • Humans
  • Indoles*
  • Mice
  • Sodium Chloride / pharmacology
  • Topoisomerase I Inhibitors*

Substances

  • Antineoplastic Agents
  • Carbazoles
  • Enzyme Inhibitors
  • Glucosides
  • Indoles
  • NB 506
  • Topoisomerase I Inhibitors
  • edotecarin
  • Sodium Chloride
  • DNA