SYNERGISM BETWEEN CISPLATIN AND TOPOISOMERASE-I INHIBITORS, NB-506 AND SN-38, IN HUMAN SMALL-CELL LUNG-CANCER CELLS

Topoisomerase I-targeting anticancer agents such as (1-piperidyl)-1-pi peridyl]carbonyloxy-camptothecin (CPT-11) and 6-N-formylamino-12, indo lo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506) have been deve loped and show strong antitumor activity against various cancers. We e xamined the interaction of these drugs and cisplatin (CDDP), and bioch emical mechanisms of synergism between them. Interaction of drugs in h uman small cell lung cancer cells, SBC-3, was analyzed using the isobo logram method. Combinations of CDDP with NB-506, CPT-11, and an active metabolite of CPT-11, 7-ethyl-10-hydroxy-CPT (SN-38), shelved synergi stic effects. Formation of DNA interstrand cross-links (TCLs) on the c ells was analyzed using an alkaline elution assay and increased ICLs w ere observed by simultaneous exposure to CDDP (1.5 mu M) and NB-506 (1 0 nM) compared with that in response to CDDP alone. DNA repair after I CL formation induced by 3-h exposure to CDDP (1.5 mu M) was reduced by NB-506 (10 nM) exposure. On the other hand, a higher concentration of CDDP (150 mu M) enhanced the topoisomerase I inhibitory activity of N B-506 and SN-38 determined by relaxation of supercoiled Escherichia co li DNA. These biological interactions might result in synergistic inte ractions between CDDP and NB-506 or SN-38. Topoisomerase I inhibitors and CDDP may be a key regimen for cancer chemotherapy and merit furthe r examination.