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0026-895X/97/020269-08$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 51:269-276 (1997).

Correlation between the Formation of Cleavable Complex with Topoisomerase I and Growth-Inhibitory Activity for Saintopin-Type Antibiotics

Noboru Fujii, Yoshinori Yamashita, Tamio Mizukami, and Hirofumi Nakano

Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 3-6-6 Asahimachi, Machida, Tokyo 194, Japan

New saintopin-type antibiotics (e.g., saintopin, saintopin E, UCE1022, UCE6) with a naphthacene-dione structure have been discovered through our mechanistically oriented screening using purified mammalian DNA topoisomerases. Saintopin is a dual inducer of topoisomerase I- and topoisomerase II-mediated DNA cleavages in a cell-free system using purified enzymes, whereas others induced topoisomerase I- but not topoisomerase II-mediated DNA cleavage. The order of topoisomerase I-mediated DNA cleavage activity at lower concentrations (<1 µM) was UCE6 > saintopin > saintopin E > UCE1022. The DNA cleavage-intensity patterns induced by these antibiotics with topoisomerase I were identical, indicating that saintopin-type antibiotics have a similar DNA sequence selectivity in stabilization of the cleavable complex with topoisomerase I. Increases in protein/DNA complexes were observed in saintopin-type antibiotic-treated HeLa S3 cells using the potassium/sodium dodecyl sulfate precipitation method. Brief heating of these drugs-treated cells at 65° for 10 min resulted in a rapid reduction in the number of protein/DNA complexes. Immunoblot analysis using antibody against human topoisomerase I or II revealed that the protein linked to DNA in saintopin-type antibiotic-treated cells is most likely topoisomerase I. These results suggest that saintopin-type antibiotics interfere with topoisomerase I in cells by trapping reversible topoisomerase I/DNA cleavable complexes. The formation of topoisomerase I/DNA complexes by saintopin-type antibiotics correlates well with their growth-inhibitory activities, suggesting that topoisomerase I can be the principal target of these antibiotics.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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