This Article Full Text 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 Kanzawa, F. Articles by Nishio, K. Search for Related Content PubMed PubMed Citation Articles by Kanzawa, F. Articles by Nishio, K.

In Vitro Synergistic Interactions between the Cisplatin Analogue Nedaplatin and the DNA Topoisomerase I Inhibitor Irinotecan and the Mechanism of this Interaction¹

Pharmacology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan [F. Ka., F. Ko., Y. K., T. N., Y. T., H. F., K. N.]; Radiation Oncology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan [N. S.]; and Discovery Research Laboratories, Shionogi & Co., Ltd., Osaka 553-0002, Japan [T. Y.]

Among the numerous clinical regimens used in combination chemotherapy, synergy is particularly marked in combinations containing cisplatin (CDDP). However, the clinical use of CDDP is sometimes limited due to its nephrotoxicity. Nedaplatin (NDP) is a second-generation platinum complex with reduced nephrotoxicity that may substitute for CDDP or even surpass it for use in combination with other drugs. We investigated the effects of combinations of NDP and other anticancer drugs on the growth of human small cell lung cancer cells (SBC-3) and non-small cell lung cancer cells (PC-14) using a three-dimensional analysis model. Among the combinations tested, the combination of NDP and irinotecan (CPT-11) showed the most marked synergistic interaction, and the synergism has also been observed against PC-14 cells. With regard to treatment schedule, a remarkable synergistic interaction was produced by concurrent exposure to NDP and CPT-11. On the other hand, sequential exposure to the two drugs led only to additivity. To analyze the interaction between the drugs, the effect of NDP on the 7-ethyl-1-hydroxy-CPT (the active form of CPT-11)-induced inhibitory effect on DNA topoisomerase I was examined. The topoisomerase I-inhibitory effect of 7-ethyl-1-hydroxy-CPT was enhanced 10-fold in the presence of NDP at microgram/milliliter concentrations. These biochemical interactions might be responsible for the synergistic interaction between NDP and CPT-11. These results suggest that the combination of NDP with CPT-11 may be clinically useful for the chemotherapy of lung cancer.

This article has been cited by other articles:

				L. D. Mayer and A. S. Janoff Optimizing Combination Chemotherapy by Controlling Drug Ratios Mol. Interv., August 1, 2007; 7(4): 216 - 223. [Abstract] [Full Text] [PDF]

				L. D. Mayer, T. O. Harasym, P. G. Tardi, N. L. Harasym, C. R. Shew, S. A. Johnstone, E. C. Ramsay, M. B. Bally, and A. S. Janoff Ratiometric dosing of anticancer drug combinations: Controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol. Cancer Ther., July 1, 2006; 5(7): 1854 - 1863. [Abstract] [Full Text] [PDF]

				B. W. Cooper, G. J. Veal, T. Radivoyevitch, M. J. Tilby, H. J. Meyerson, H. M. Lazarus, O. N. Koc, R. J. Creger, G. Pearson, G. M. Nowell, et al. A Phase I and Pharmacodynamic Study of Fludarabine, Carboplatin, and Topotecan in Patients With Relapsed, Refractory, or High-Risk Acute Leukemia Clin. Cancer Res., October 15, 2004; 10(20): 6830 - 6839. [Abstract] [Full Text] [PDF]