Kanzawa F, Koizumi F, Koh Y, Nakamura T, Tatsumi Y, Fukumoto H, Saijo N, Yoshioka T, Nishio K
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Clin Cancer Res. 2001 Jan;7(1):202-9.
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.
在联合化疗中使用的众多临床方案中，协同作用在含顺铂（CDDP）的联合方案中尤为显著。然而，由于其肾毒性，CDDP的临床应用有时会受到限制。奈达铂（NDP）是一种肾毒性降低的第二代铂类复合物，可替代CDDP，甚至在与其他药物联合使用时效果更佳。我们使用三维分析模型研究了NDP与其他抗癌药物联合使用对人小细胞肺癌细胞（SBC - 3）和非小细胞肺癌细胞（PC - 14）生长的影响。在所测试的联合方案中，NDP与伊立替康（CPT - 11）的联合显示出最显著的协同相互作用，并且在PC - 14细胞中也观察到了这种协同作用。关于治疗方案，同时暴露于NDP和CPT - 11会产生显著的协同相互作用。另一方面，两种药物序贯暴露仅导致相加作用。为了分析药物之间的相互作用，研究了NDP对7 - 乙基 - 1 - 羟基 - CPT（CPT - 11的活性形式）诱导的对DNA拓扑异构酶I的抑制作用的影响。在微克/毫升浓度的NDP存在下，7 - 乙基 - 1 - 羟基 - CPT对拓扑异构酶I的抑制作用增强了10倍。这些生化相互作用可能是NDP与CPT - 11之间协同相互作用的原因。这些结果表明，NDP与CPT - 11联合使用可能对肺癌化疗具有临床应用价值。
