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Covalent Binding of Elliptinium Acetate (NSC 264137) to Nucleic Acids of L1210 Cells in Culture¹

Laboratoire de Pharmacologie et de Toxicologie Fondamentales du CNRS, 205, route de Narbonne, 31400 Toulouse [B. D., B. M.], and Laboratoire de Biochimie Enzymologie, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex [C. A.], France

Elliptinium acetate (9-OH-NME; Celiptium) is an antineoplastic agent currently used in the treatment of metastatic breast cancer and is known to intercalate into DNA. Previous studies have demonstrated that this molecule can be oxidized, yielding a reactive electrophilic form, which is able to bind covalently to a nucleophilic biological molecule.

In this work, we evidenced a covalent binding of this drug to nucleic acids of L1210 cells in culture. A high performance liquid chromatography technique allowed us to distinguish between reversible and nonreversible interaction and to determine the binding ratio (r_b) of covalently bound elliptinium versus bases of nucleic acids extracted from cells. After an 8-h incubation of L1210 cells with 0.1 µM elliptinium (the dose corresponding to the 50% inhibitory dose), we obtained 2.4 x 10^-6 and 3.4 x 10^-6 as the r_b for RNA and DNA, respectively. The kinetics of binding was also studied. The dose-response relationship obtained is linear in a concentration range of 0.025 to 0.5 µM 9-OH-NME. Furthermore, we demonstrated that the covalent binding of 9-OH-NME to DNA is not repaired during a period of 40 h (during this period, the cell population has undergone two doublings). The nonhydroxylated and non-antitumoral derivative of 9-OH-NME, N²-methylellipticinium, is 20 to 30 times less active in terms of covalent binding to nucleic acids, compared to the antitumor compound 9-OH-NME. The implication of the covalent binding of 9-OH-NME is discussed with respect to its mechanism of action.

¹ The Association pour la Recherche sur le Cancer (ARC, Villejuif) is acknowledged for a grant. Financial support was also donated by Sanofi (Paris).

² To whom requests for reprints should be addressed.

Received 9/19/85. Revised 3/14/86. Accepted 4/15/86.