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Intercalation into DNA Is Not Required for Inhibition of Topoisomerase I by Indolocarbazole Antitumor Agents¹

Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret and Institut National de la Santé et de la Recherche Médicale U-524, IRCL, Lille 59045, France [C. B., L. D.]; Laboratoire de Chimie Macromoléculaire et Chimie Physique, Université de Liège, Liège 4000, Belgium [P. C., C. H.]; and Banyu Tsukuba Research Institute, Okubo, Tsukuba 300-26, Japan [K. F., S. N., T. Y.]

The DNA-intercalating antitumor drug NB-506 is a potent topoisomerase poison currently undergoing phase I/II clinical trials. It contains a planar indolocarbazole chromophore substituted with a glucose residue. Up until now, it was thought that intercalation of the drug into DNA was essential for the stabilization of topoisomerase I-DNA covalent complexes. But, in the present study, we show that a regio-isomeric form of NB-506 has lost its capacity to intercalate into DNA, but remains an extremely potent topoisomerase I poison. The new analogue contains two hydroxyl groups at positions 2,10 instead of positions 1,11 in NB-506. The relocation of the two OH groups reduces considerably the strength of binding to DNA and prevents the drug from intercalating into the DNA double helix. However, the topoisomerase I inhibition capacity of the new analogue remains very high. The two drug isomers are equally potent at maintaining the integrity of the topoisomerase I-DNA covalent complexes, but stimulate cleavage at different sites on DNA. NB-506 stabilizes topoisomerase I preferentially at sites having a pyrimidine (T or C) and a G on the 5' and 3' sides of the cleaved bond, respectively. The 2,10-isomer induces topoisomerase I-mediated cleavage only at TG sites and, thus, behaves exactly as the reference topoisomerase I poison camptothecin. Finally, cytotoxicity measurements performed with a panel of murine and human cancer cell lines reveal that the newly designed drug is considerably (up to 100-fold) more toxic to tumor cells than the parent drug NB-506. We conclude that the DNA-binding and topoisomerase I poisoning activities of NB-506 can be viewed as two separate mechanisms.

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