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 Pommier, Y. Articles by Kohn, K. W. Search for Related Content PubMed PubMed Citation Articles by Pommier, Y. Articles by Kohn, K. W.

Reduced Formation of Protein-associated DNA Strand Breaks in Chinese Hamster Cells Resistant to Topoisomerase II Inhibitors

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205

DNA intercalating drugs and the epipodophyllotoxins etoposide and teniposide interfere with the action of mammalian DNA topoisomerase II by trapping an intermediate complex of the enzyme covalently linked to the 5'-termini of DNA breaks. This effect can be observed in intact cells by alkaline elution measurement of protein-associated DNA strand breaks. To assess the cytotoxic role of this effect, we have studied a subline of DC3F Chinese hamster lung cells selected for resistance to the intercalating agent 9-hydroxyellipticine. This subline (DC3F/9-OHE) was cross-resistant to other intercalators as well as to etoposide. Resistance to Adriamycin was associated with reduced uptake. However, resistance to 4'-(9-acridinylamino)methanesulfon-m-aniside and 2-methyl-9-hydroxyellipticinium was observed in the absence of changes in drug uptake, suggesting a second mode of resistance. DC3F/9-OHE cells formed fewer protein-associated DNA strand breaks in response to 4'-(9-acridinylamino)methanesulfon-m-aniside, 2-methyl-9-hydroxyellipticinium, or etoposide than did the sensitive parental cells. The same was true for isolated nuclei from these cells, which is consistent with a mode of resistance unrelated to drug uptake through the plasma membrane. These data suggest that resistance to DNA topoisomerase II inhibitors exhibited by DC3F/9-OHE cells is due in part to a modification of topoisomerase II activity.

¹ To whom requests for reprints should be addressed, at Building 37, Room 5A19, National Institutes of Health, Bethesda, MD 20205.

² Present address: Department of Chemotherapy Research, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Drive, Houston, TX 77030.

³ Present address: Laboratoire d'Enzymologie, Institut Gustave Roussy, 94800 Villejuif, France.

Received 7/16/85. Revised 10/18/85. Accepted 10/21/85.

This article has been cited by other articles:

				S. Le Mée, F. Chaminade, C. Delaporte, J. Markovits, J.-M. Saucier, and A. Jacquemin-Sablon Cellular Resistance to the Antitumor DNA Topoisomerase II Inhibitor S16020-2: Importance of the N-[2(Dimethylamino)ethyl]carbamoyl Side Chain Mol. Pharmacol., October 1, 2000; 58(4): 709 - 718. [Abstract] [Full Text]

				T. Khelifa, B. Rene, S. L. Mee, B. Lambert, J.-M. Saucier, J. Markovits, H. Jacquemin-Sablon, and A. Jacquemin-Sablon Transfection of 9-Hydroxyellipticine-resistant Chinese Hamster Fibroblasts with Human Topoisomerase II{{alpha}} cDNA: Selective Restoration of the Sensitivity to DNA Religation Inhibitors Cancer Res., October 1, 1999; 59(19): 4927 - 4936. [Abstract] [Full Text] [PDF]

				S. Le Mée, A. Pierré, J. Markovits, G. Atassi, A. Jacquemin-Sablon, and J.-M. Saucier S16020-2, a New Highly Cytotoxic Antitumor Olivacine Derivative: DNA Interaction and DNA Topoisomerase II Inhibition Mol. Pharmacol., February 1, 1998; 53(2): 213 - 220. [Abstract] [Full Text]

				S.-W. Ng, J. P. Eder, L. E. Schnipper, and V. T. W. Chan Molecular Cloning and Characterization of the Promoter for the Chinese Hamster DNA Topoisomerase IIalpha Gene J. Biol. Chem., October 27, 1995; 270(43): 25850 - 25858. [Abstract] [Full Text] [PDF]