Fukuda M, Nishio K, Kanzawa F, Ogasawara H, Ishida T, Arioka H, Bojanowski K, Oka M, Saijo N
Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Cancer Res. 1996 Feb 15;56(4):789-93.
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-(beta-D- glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-di one (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 microM) 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 microM) was reduced by NB-506 (10 nM) exposure. On the other hand, a higher concentration of CDDP (150 microM) 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.
靶向拓扑异构酶I的抗癌药物，如7-乙基-10-[4-(1-哌啶基)-1-哌啶基]羰氧基-喜树碱（CPT-11）和6-N-甲酰氨基-12,13-二氢-1,11-二羟基-13-(β-D-吡喃葡萄糖基)-5H-吲哚[2,3-a]吡咯[3,4-c]咔唑-5,7(6H)-二酮（NB-506）已被研发出来，并显示出对多种癌症的强大抗肿瘤活性。我们研究了这些药物与顺铂（CDDP）的相互作用以及它们之间协同作用的生化机制。使用等效线图法分析了药物在人小细胞肺癌细胞SBC-3中的相互作用。CDDP与NB-506、CPT-11以及CPT-11的活性代谢产物7-乙基-10-羟基-CPT（SN-38）的组合显示出协同作用。使用碱性洗脱试验分析了细胞上DNA链间交联（ICL）的形成，与单独使用CDDP相比，同时暴露于CDDP（1.5微摩尔）和NB-506（10纳摩尔）时观察到ICL增加。暴露于NB-506（10纳摩尔）可降低由3小时暴露于CDDP（1.5微摩尔）诱导的ICL形成后的DNA修复。另一方面,较高浓度的CDDP（150微摩尔）增强了通过超螺旋大肠杆菌DNA松弛测定的NB-506和SN-38的拓扑异构酶I抑制活性。这些生物学相互作用可能导致CDDP与NB-506或SN-38之间的协同相互作用。拓扑异构酶I抑制剂和顺铂可能是癌症化疗的关键方案，值得进一步研究。
