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Synergism between Cisplatin and Topoisomerase I Inhibitors, NB-506 and SN-38, in Human Small Cell Lung Cancer Cells¹

Medical Oncology, National Cancer Center Hospital [M. F., N. S.] and Pharmacology Division, National Cancer Center Research Institute [K. N., F. K., H. O., T. I., H. A., K. B., N. S.], Tsukiji 5-1-1, Chuo-ku, Tokyo 104, and The Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, [M. F., M. O.], Japan

Topoisomerase I-targeting anticancer agents such as 7-ethyl-10-[4-(1-piperidyl)-1-piperidyl]carbonyloxy-camptothecin (CPT-11) and 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(ß-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506) have been developed and show strong antitumor activity against various cancers. We examined the interaction of these drugs and cisplatin (CDDP), and biochemical mechanisms of synergism between them. Interaction of drugs in human small cell lung cancer cells, SBC-3, was analyzed using the isobologram method. Combinations of CDDP with NB-506, CPT-11, and an active metabolite of CPT-11, 7-ethyl-10-hydroxy-CPT (SN-38), showed synergistic effects. Formation of DNA interstrand cross-links (ICLs) on the cells was analyzed using an alkaline elution assay and increased ICLs were observed by simultaneous exposure to CDDP (1.5 µM) and NB-506 (10 nM) compared with that in response to CDDP alone. DNA repair after ICL formation induced by 3-h exposure to CDDP (1.5 µM) was reduced by NB-506 (10 nM) exposure. On the other hand, a higher concentration of CDDP (150 µM) enhanced the topoisomerase I inhibitory activity of NB-506 and SN-38 determined by relaxation of supercoiled Escherichia coli DNA. These biological interactions might result in synergistic interactions between CDDP and NB-506 or SN-38. Topoisomerase I inhibitors and CDDP may be a key regimen for cancer chemotherapy and merit further examination.

¹ This work was supported in part by Grants-in-Aid for Cancer Research and from the Second Term Comprehensive 10-Year Strategy for Cancer Control, the Ministry of Health and Welfare, the Ministry of Education Science of Japan, a trust fund, the Adult Disease Memorial Foundation, and the Bristol-Myers Squibb Foundation.

² To whom requests for reprints should be addressed. Phone: 81-3-3542-2511; Fax: 81-3-3542-1886.

Received 8/14/95. Accepted 12/ 6/95.

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