NOVEL ANTITUMOR INDOLOCARBAZOLE COMPOUND -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 dolo[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 mu M but not the cleavage by topoisomerase II at 300 mu M. It also caused single-strand DNA breakage in intact c ells at 0.08 mu M and more. Unlike the known topoisomerase I inhibitor camptothecin, NB-506 intercalated with DNA. However, the binding affi nity to DNA and the inhibition against DNA polymerase alpha and RNA po ly merase II were marginal compared with those of Adriamycin or actino mycin D. NB-506 inhibited the growth of various tumor cell lines at tw o micromoles or less, and its cytotoxicity was found to be cell Line s elective. This selective cytotoxicity of NB-506 was not fully explaine d by the differences in topoisomerase I activity in these cell Lines, but there was some relationship between the amount of NB-506 accumulat ed in these cell lines and its cytotoxicity toward them. In conclusion , NB-506 is a potent topoisomerase I poison, acting selectively on tum or cell lines accumulating NB-506.