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Physicochemical and Pharmacological Properties of the Antitumor Ellipticine Derivative 2-(Diethylamino-2-ethyl)9-hydroxy Ellipticinium-Chloride, HCl¹

Laboratoire de Biochimie Enzymologie, INSERM U 140, CNRS LA 147, Institut Gustave-Roussy, Villejuif [C. A., E. V., J-M. S., C. P.]; SANOFI Recherche, Route d'Espagne, Toulouse [A. P., P. G., O. P., C. C., B. V.]; and Laboratoire de Pharmacologie et Toxicologie Fondamentales du CNRS, 205 route de Narbonne, Toulouse [S. C.], France

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro.

DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain.

From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque.

The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.

¹ This work was supported in part by Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique.

² To whom requests for reprints should be addressed, at either Laboratoire de Biochimie Enzymologie, INSERM U 140, Institut Gustave Roussy, rue Camille Desmoulins, 94800 Villejuif, France, (C. A.) or SANOFI Recherche, 195, route d'Espagne, 31078 Toulouse, France (A. P.).

Received 11/14/86. Revised 7/21/87. Accepted 8/24/87.

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