This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Esnault, C. Articles by Pecq, J. B. L. Search for Related Content PubMed PubMed Citation Articles by Esnault, C. Articles by Pecq, J. B. L.

Effects of New Antitumor Bifunctional Intercalators Derived from 7H-Pyridocarbazole on Sensitive and Resistant L1210 Cells¹

Laboratoire de Pharmacologie Moléculaire (Centre National de la Recherche Scientifique LA 147, Institut National de la Santé et de la Recherche Médicale U 140), Institut Gustave Roussy, 94805 Villejulf Cedex [C. E., A. J-S., J. B. L.], and Département de Chimie Organique, ERA 613 du Centre National de la Recherche Scientifique et U 266 de l'Institut National de la Santé et de la Recherche Médicale, Unité d'Enseignement et de Recherche des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75006 Paris [B. P. R.], France

The antitumor properties of 7H-pyridocarbazole dimers, a new series of bifunctional intercalators, have recently been described (Pelaprat, D., Delbarre, A., Le Guen, I., Roques, B. P., and Le Pecq, J. B. J. Med. Chem., 23: 1336–1343, 1980; and Roques, B. P., Pelaprat, D., Le Guen, I., Porcher, G., Gosse, C., and Le Pecq, J. B. Biochem. Pharmacol., 28: 1811–1815, 1979). In order to study the mechanism of action of these compounds, an L1210 subline was made resistant to one dimer (NSC 335153; ditercalinium). Selection of resistant cells was based on an in vitro-in vivo procedure as follows. Ascitic cells were taken from a leukemic mouse and incubated in vitro with the dimer for 1 hr. They were then injected into mice. After the development of the ascites, L1210 cells were collected and the process was repeated 13 times, until establishment of the resistance. Cloned resistant cells have maintained their resistance for 18 months of in vitro culture. The effects of two dimers (NSC 335153 and NSC 335154) on cell viability, growth, colony formation, and cell cycle progression were investigated on parental and resistant L1210 cells. The cross-resistance of these two L1210 cell lines to several cytotoxic agents was estimated. Several observations indicate that the mechanism of action of these dimers might be different from that of monointercalating agents: (a) these drugs induce a delayed toxicity (growth arrest occurring five generations after drug exposure) in sensitive but not in resistant cells; (b) cells exposed to the dimers arrested almost randomly in all phases of the cell cycle, whereas the corresponding monomer provokes a block in the G₂ + M phase. Resistant cells were cross-resistant to 7H-pyridocarbazole monomer, Adriamycin, and vincristine but not to 6H-pyridocarbazole monomer derivatives, actinomycin D, and methotrexate.

¹ Supported in part by grants from Université P. M. Curie (Paris VI, UER Biochimie), Association pour la Recherche sur le Cancer, and Fondation pour la Recherche Médicale Française.

² To whom requests for reprints should be addressed, at the Institute Gustave Roussy, 53 rue Camille Desmoulins, 94805 Villejuif Cedex, France.

Received 2/28/84. Accepted 6/22/84.

This article has been cited by other articles:

				T. Berge, N. S. Jenkins, R. B. Hopkirk, M. J. Waring, J. M. Edwardson, and R. M. Henderson Structural perturbations in DNA caused by bis-intercalation of ditercalinium visualised by atomic force microscopy Nucleic Acids Res., July 1, 2002; 30(13): 2980 - 2986. [Abstract] [Full Text] [PDF]