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Differential Effects of Ellipticine and AZA-Analogue Derivatives on Cell Cycle Progression and Survival of BALB/c 3T3 Cells Released from Serum Starvation or Thymidine Double Block¹

Laboratoire de Pharmacologie Expérimentale (U. 107 INSERM), Centre Hayem [M-J. V., F. P., M-P. G., C-J. L.] and Groupe de Pharmacologie Clinique des Agents Anti-Cancéreux [F. C.], Hópital Saint-Louis, 2 Place du Docteur Fournier, 75475-Paris Cédex 10 France, and Unité de Biochimie et Enzymologie (U. 140 INSERM and L. A. 147 CNRS) [J-Y. C.], Institut Gustave Roussy, 94800-Villejuif, France

10-[Diethylaminopropylamino]-6-methyl-⁵H-pyrido[3',4':4,5] pyrrolo[2,3-g]isoquinoline (BD-40) (NSC-327471D) is an azaellipticine derivative with a promising antitumor activity (M. Marty, C. Jasmin, P. Pouillard, C. Gisselbrecht, G. Gouvenia, and H. Magdalainat, 17th Annual Meeting of the American Society of Clinical Oncology, C-108, 1981) and less toxicity than ellipticine. We have compared the effects of ellipticine, several of its analogues, and two aza-analogue ellipticine derivatives (BD-40 and BR-1376) on cell cycle progression of BALB/c 3T3 mouse cells under different growth conditions. Both drug series were found to stop cell growth and block cells in G₂ phase in exponentially growing cultures and cultures released from a thymidine double block. Long-term viability of these cells was completely suppressed after a short exposure to the drugs. In contrast, while ellipticine and its derivatives caused identical effects in cells recovering from serum starvation, BD-40 and BR-1376 did not block cells in G₂ phase and did not prevent the completion of the first division round occurring after serum addition to quiescent cells. This transient refractory state was accompanied by a total conservation of long-term viability of these cells at least for the next 6 h following serum and drug addition. This lack of effect was not related to an impaired drug uptake by cells recovering from serum starvation or by a dramatic change in drug distribution inside the cells. These results indicate that the nitrogen substitution in the ellipticine heterocycle is an important if not unique feature for the particular effect of the aza-analogues of ellipticine. Furthermore, they suggest that, in contrast to ellipticine derivatives, these compounds require an activation step before exhibiting cytotoxicity.

¹ Supported by the Centre National de la Recherche Scientifique and l'Association pour la Recherche contre le Cancer, Villejuif, France (Contract 3119).

² To whom requests for reprints should be addressed.

Received 12/26/84. Revised 4/ 9/85. Accepted 4/15/85.