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 Balosso, J. Articles by Favaudon, V. Search for Related Content PubMed PubMed Citation Articles by Balosso, J. Articles by Favaudon, V.

Additive and Supraadditive Interaction between Ionizing Radiation and Pazelliptine, a DNA Topoisomerase Inhibitor, in Chinese Hamster V-79 Fibroblasts¹

Unité 219 INSERM, Institut Curie-Biologie, Labs. 110–112, Centre Universitaire, 91405 Orsay Cedex, France

The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with -ray irradiation was investigated using Chinese hamster V-79 cells in culture. -ray irradiation and drug treatment (1-h drug exposure) were applied at 1-h intervals for partial DNA damage recovery in growth medium. Isobologram analysis of the clonogenic potential gave evidence of supraadditive interaction in the radiation drug sequence with 10% survival as an endpoint. No synergistic potentiation was observed at higher survival or as pazelliptine was applied first. Pazelliptine abolished the low-dose shoulder characteristic of asynchronous cell response to -rays. Although rejoining of radiation-induced DNA strand breaks was completed at the time of drug exposure, pazelliptine brought about a larger amount of DNA strand breaks in preirradiated than in nonirradiated cells.

The time and dose dependencies of DNA strand break formation and repair with radiation and/or pazelliptine were analyzed by neutral and alkaline filter elution. Pazelliptine in the micromolar range showed the same pattern of double-stranded cleavable complex formation as expected of a DNA topoisomerase II-targeting agent. At a low concentration of pazelliptine, however, protein-concealed breaks were mostly in the form of single-stranded adducts. Such single-stranded complexes have been reported to occur with some topoisomerase II-targeting drugs; their properties are also reminiscent of those induced by the topoisomerase I poison, camptothecin. It is proposed that topoisomerase poisoning interacts with the repair of radiation-induced lesions.

¹ This work was supported by a research fellowship from the Centre Hospitalier Universitaire de Montpellier to J. B., by financial aid from the Institut National de la Santé et de la Recherche Médicale, and by a grant (No. 89-21-5) from the Institut Curie.

² Present address: Service de Radiothérapie, Hôpital Tenon, 4 Rue de la Chine, 75970 Paris Cedex 20, France.

³ To whom requests for reprints should be addressed.

Received 11/21/90. Accepted 4/ 2/91.

This article has been cited by other articles:

				C. Godon, F. P. Cordelieres, D. Biard, N. Giocanti, F. Megnin-Chanet, J. Hall, and V. Favaudon PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility Nucleic Acids Res., August 1, 2008; 36(13): 4454 - 4464. [Abstract] [Full Text] [PDF]

				G. Noel, C. Godon, M. Fernet, N. Giocanti, F. Megnin-Chanet, and V. Favaudon Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol. Cancer Ther., March 1, 2006; 5(3): 564 - 574. [Abstract] [Full Text] [PDF]

				C. Reis, N. Giocanti, C. Hennequin, F. Megnin-Chanet, M. Fernet, R. Filomenko, A. Bettaieb, E. Solary, and V. Favaudon A role for PKC{zeta} in potentiation of the topoisomerase II activity and etoposide cytotoxicity by wortmannin Mol. Cancer Ther., October 1, 2005; 4(10): 1457 - 1464. [Abstract] [Full Text] [PDF]

				S. MIYAMOTO, T. T. HUANG, S. WUERZBERGER-DAVIS, W. G. BORNMANN, J. J. PINK, C. TAGLIARINO, T. J. KINSELLA, and D. A. BOOTHMAN Cellular and Molecular Responses to Topoisomerase I Poisons: Exploiting Synergy for Improved Radiotherapy Ann. N.Y. Acad. Sci., December 1, 2000; 922(1): 274 - 292. [Abstract] [Full Text] [PDF]