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Vol. 53, Issue 2, 213-220, February 1998

S16020-2, a New Highly Cytotoxic Antitumor Olivacine Derivative: DNA Interaction and DNA Topoisomerase II Inhibition

Sandrine Le Mée, Alain Pierré, Judith Markovits, Ghanem Atassi, Alain Jacquemin-Sablon, and Jean-Marie Saucier

Unité de Recherche Associée au Centre National de la Recherche Scientifique 147, Institut Gustave Roussy, 94805 Villejuif Cedex, France (S.L.M., J.M., A.J.-S., J.-M.S.), and Institut de Recherches Servier, Division de Cancérologie Expérimentale, 92150 Suresnes, France (A.P., G.A.)

S16020-2 (NSC-659687) is a new olivacine derivative that is highly cytotoxic in vitro and displays remarkable antitumor activity against various experimental tumors, especially some solid tumor models. Its antitumor activity is notably higher than that of 2-methyl-9-hydroxy-ellipticinium (NMHE) and comparable to that of doxorubicin HCl, although with a different tumor specificity. S16020-2 is being tested in phase I clinical trials. A study of the interaction of S16020-2 with DNA showed that it binds through intercalation between adjacent DNA base pairs, inducing an unwinding of 10° of the double helix. Its DNA affinity is approximately equal to that of NMHE and decreases as a function of the salt concentration, indicating a significant electrostatic contribution to the overall binding free energy. S16020-2 did not interfere with the catalytic cycle of DNA topoisomerase I but stimulated DNA topoisomerase II-mediated DNA cleavage via a strictly ATP-dependent mechanism. The interactions of S16020-2 and NMHE with DNA topoisomerase II in vitro are very similar. Both drugs have the same DNA sequence specificity of cleavage and the same biphasic dose-effect response, and neither drug inhibited the rate of DNA religation. In contrast with these observations, in in vivo experiments, S16020-2 was able to induce topoisomerase II-mediated DNA strand breaks at concentrations 500-fold lower than NMHE. We conclude that DNA topoisomerase II most likely is the cellular target involved in the mechanism of cytotoxicity of S16020-2. Its higher biological activity and potency to induce cellular DNA cleavage suggest the involvement of as-yet-unidentified cellular factors.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics