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 Kaufmann, S. H. Search for Related Content PubMed PubMed Citation Articles by Kaufmann, S. H.

Antagonism between Camptothecin and Topoisomerase II-directed Chemotherapeutic Agents in a Human Leukemia Cell Line¹

Oncology Center, Johns Hopkins Hospital, and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

To search for possible synergy between topoisomerase (topo) II-directed chemotherapeutic agents and topo I-directed agents, HL-60 human progranulocytic leukemia cells were incubated with etoposide in the absence or presence of camptothecin (CPT). Treatment of HL-60 cells for 1 h with 15–20 µM etoposide resulted in the death of 99–99.9% of the cells as assessed by colony formation in soft agar. Unexpectedly, simultaneous incubation with 1 µM CPT increased the survival of etoposide-treated cells as much as 30-fold. Inhibition of etoposide cytotoxicity was observed at CPT concentrations as low as 0.01 µM and was one-half maximal at 0.1 µM. CPT also antagonized the cytotoxicity of 4'-(9-acridinylamino)methanesulfon-M-anisidide and daunorubicin, two structurally unrelated topo II-directed agents. Topotecan, a CPT analogue currently undergoing Phase I clinical trials, had a similar effect. Studies using an alkaline unwinding assay (to measure DNA strand breaks) and Western blotting (to assess formation of covalent adducts involving topo II) revealed that CPT did not alter the ability of etoposide to stabilize topo II-DNA adducts. CPT is a potent inhibitor of both DNA and RNA synthesis. To further assess the mechanism by which CPT diminished the cytotoxicity of topo II-directed agents, inhibitors of DNA synthesis or RNA synthesis were substituted for CPT. Aphidicolin, an inhibitor of replicative DNA polymerases, enhanced the survival of etoposide-treated HL-60 cells <3-fold. In contrast, inhibitors of RNA synthesis (cordycepin or 5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole) enhanced the survival of etoposide-treated HL-60 cells as much as 20-fold. The potential biological and therapeutic implications of these results are discussed.

¹ Supported in part by Grant CA50435 from the NIH and a grant from the American Cancer Society.

Received 5/25/90. Accepted 11/29/90.

This article has been cited by other articles:

				L. Catley, Y.-T. Tai, R. Shringarpure, R. Burger, M. T. Son, K. Podar, P. Tassone, D. Chauhan, T. Hideshima, L. Denis, et al. Proteasomal Degradation of Topoisomerase I Is Preceded by c-Jun NH2-Terminal Kinase Activation, Fas Up-Regulation, and Poly(ADP-Ribose) Polymerase Cleavage in SN38-Mediated Cytotoxicity against Multiple Myeloma Cancer Res., December 1, 2004; 64(23): 8746 - 8753. [Abstract] [Full Text] [PDF]

				A. Ardizzoni Topotecan in the Treatment of Recurrent Small Cell Lung Cancer: An Update Oncologist, December 1, 2004; 9(suppl_6): 4 - 13. [Abstract] [Full Text] [PDF]

				M. O. Christensen, R. M. Krokowski, H. U. Barthelmes, R. Hock, F. Boege, and C. Mielke Distinct Effects of Topoisomerase I and RNA Polymerase I Inhibitors Suggest a Dual Mechanism of Nucleolar/Nucleoplasmic Partitioning of Topoisomerase I J. Biol. Chem., May 21, 2004; 279(21): 21873 - 21882. [Abstract] [Full Text] [PDF]

				E. J. Licitra, V. Vyas, K. Nelson, R. Musanti, S. Beers, C. Thomas, E. Poplin, S. Smith, Y. Lin, Larry. J. Schaaf, et al. Phase I Evaluation of Sequential Topoisomerase Targeting with Irinotecan/Cisplatin Followed by Etoposide in Patients with Advanced Malignancy Clin. Cancer Res., May 1, 2003; 9(5): 1673 - 1679. [Abstract] [Full Text] [PDF]

				A. Ardizzoni, C. Manegold, C. Debruyne, R. Gaafar, E. Buchholz, E. F. Smit, P. Lianes, G. ten Velde, L. Bosquee, C. Legrand, et al. European Organization for Research and Treatment of Cancer (EORTC) 08957 Phase II Study of Topotecan in Combination with Cisplatin as Second-Line Treatment of Refractory and Sensitive Small Cell Lung Cancer Clin. Cancer Res., January 1, 2003; 9(1): 143 - 150. [Abstract] [Full Text] [PDF]

				C. Twelves, M. Campone, B. Coudert, M. Van den Bent, M. de Jonge, C. Dittrich, R. Rampling, R. Sorio, D. Lacombe, C. de Balincourt, et al. Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme Ann. Onc., May 1, 2002; 13(5): 777 - 780. [Abstract] [Full Text] [PDF]

				J. H. Schiller, S. Adak, D. Cella, R. F. DeVore III, and D. H. Johnson Topotecan Versus Observation After Cisplatin Plus Etoposide in Extensive-Stage Small-Cell Lung Cancer: E7593--A Phase III Trial of the Eastern Cooperative Oncology Group J. Clin. Oncol., April 15, 2001; 19(8): 2114 - 2122. [Abstract] [Full Text] [PDF]

				M. L. Rothenberg Irinotecan (CPT-11): Recent Developments and Future Directions-Colorectal Cancer and Beyond Oncologist, February 1, 2001; 6(1): 66 - 80. [Abstract] [Full Text]

				C. Erlichman, S. A. Boerner, C. G. Hallgren, R. Spieker, X.-Y. Wang, C. D. James, G. L. Scheffer, M. Maliepaard, D. D. Ross, K. C. Bible, et al. The HER Tyrosine Kinase Inhibitor CI1033 Enhances Cytotoxicity of 7-Ethyl-10-hydroxycamptothecin and Topotecan by Inhibiting Breast Cancer Resistance Protein-mediated Drug Efflux Cancer Res., January 1, 2001; 61(2): 739 - 748. [Abstract] [Full Text]

				M. Fujishiro, T. Shinkai, M. Fukuda, T. Tamura, Y. Ohe, H. Kunitoh, Y. Nishiwaki, I. Sekine, H. Fukuda, and N. Saijo Phase I Study of a Weekly Infusion of Irinotecan Hydrochloride (CPT-11) and a 14-day Continuous Infusion of Etoposide in Patients with Lung Cancer: JCOG Trial 9408 Jpn. J. Clin. Oncol., November 1, 2000; 30(11): 487 - 493. [Abstract] [Full Text] [PDF]

				R van Gijn, R. Lendfers, J. Schellens, A Bult, and J. Beijnen Dual topoisomerase I/II inhibitors Journal of Oncology Pharmacy Practice, September 1, 2000; 6(3): 92 - 108. [Abstract] [PDF]

				K. C. Bible, R. H. Bible Jr., T. J. Kottke, P. A. Svingen, K. Xu, Y.-P. Pang, E. Hajdu, and S. H. Kaufmann Flavopiridol Binds to Duplex DNA Cancer Res., May 1, 2000; 60(9): 2419 - 2428. [Abstract] [Full Text]

				M. Fujishiro, T. Shinkai, M. Fukuda, T. Tamura, Y. Ohe, H. Kunitoh, H. Nishiwaki, I. Sekine, Y. Matsuno, M. Niimi, et al. Phase I Study of a Weekly Infusion of Irinotecan Hydrochloride (CPT-11) and a 14-day Continuous Infusion of Etoposide in Patients with Lung Cancer: Japan Clinical Oncology Group 9408 Jpn. J. Clin. Oncol., March 1, 2000; 30(3): 122 - 127. [Abstract] [Full Text] [PDF]

				J. Thompson, E. O. George, C. A. Poquette, P. J. Cheshire, L. B. Richmond, S. S. N. de Graaf, M. Ma, C. F. Stewart, and P. J. Houghton Synergy of Topotecan in Combination with Vincristine for Treatment of Pediatric Solid Tumor Xenografts Clin. Cancer Res., November 1, 1999; 5(11): 3617 - 3631. [Abstract] [Full Text] [PDF]

				L. M. Martins, P. W. Mesner, T. J. Kottke, G. S. Basi, S. Sinha, J. S. Tung, P. A. Svingen, B. J. Madden, A. Takahashi, D. J. McCormick, et al. Comparison of Caspase Activation and Subcellular Localization in HL-60 and K562 Cells Undergoing Etoposide-Induced Apoptosis Blood, December 1, 1997; 90(11): 4283 - 4296. [Abstract] [Full Text] [PDF]

				W. A. Cliby, K. A. Lewis, K. K. Lilly, and S. H. Kaufmann S Phase and G2 Arrests Induced by Topoisomerase I Poisons Are Dependent on ATR Kinase Function J. Biol. Chem., January 4, 2002; 277(2): 1599 - 1606. [Abstract] [Full Text] [PDF]