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Production of Protein-associated DNA Breaks by 10-[Diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline in Cultured L1210 Cells and in Isolated Nuclei: Comparison with Other Topoisomerase II Inhibitors

Sanofi Recherche [V. P., A. P.], 195 route d'Espagne, 31035 Toulouse Cedex, France; Laboratory of Molecular Pharmacology [Y. P.], Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20892; and Sanofi Recherche [P. G.], rue du Professeur Blayac, 34082 Montpellier, France

10-[3-Diethylaminopropylamino]6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline (PZE) is an ellipticine derivative currently in clinical trials. PZE has been postulated to produce cellular DNA lesions by an uncommon mechanism. PZE-induced DNA damage was further investigated in L1210 cells in culture. PZE was highly cytotoxic for these cells (90% inhibitory concentration = 3.1 µM). The effects of PZE on cellular DNA were studied first by alkaline sucrose sedimentation, in comparison with those of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). Like m-AMSA, PZE induced DNA strand breaks which were detected without a proteolytic treatment of the cell lysate. This result rules out the existence of covalent protein bridges sealing DNA termini at the break sites. PZE was less active than m-AMSA. DNA fragmentation was maximum at 5 µM and was lower at higher concentrations. The DNA effects of PZE were also studied by alkaline elution, and compared with those of Adriamycin and m-AMSA. Like Adriamycin, PZE induced single-strand breaks (SSBs) in a bell-shaped manner with respect to drug concentration. The maximum SSB frequency [1784 ± 370 (SEM) rad equivalents)] was obtained at 16 µM. The kinetics of SSB reversion after drug removal was slower than in the case of m-AMSA. Similar bell-shaped curves were obtained for PZE-induced double-strand breaks and DNA-protein cross-links. PZE induced more double-strand breaks per SSB than did m-AMSA. However, as in the case of m-AMSA, PZE induced equal SSB and DNA-protein cross-link frequencies. These results suggest that PZE induces DNA breaks by inhibiting topoisomerase II as do other antitumor intercalators.

¹ Supported by a grant from the Ministere de la Recherche et de l'Enseignement Supérieur. Present address: Laboratoire de Pharmacologie et de Toxicologie Fondamentales du CNRS, 205 route de Narbonne, 31078 Toulouse, France. To whom requests for reprints should be addressed.

² Present address: Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France.

Received 9/22/87. Revised 12/ 1/87. Accepted 12/14/87.

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