Nakajima Takako Eguchi, Yanagihara Kazuyoshi, Takigahira Misato, Yasunaga Masahiro, Kato Ken, Hamaguchi Tetsuya, Yamada Yasuhide, Shimada Yasuhiro, Mihara Keichiro, Ochiya Takahiro, Matsumura Yasuhiro
Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Cancer Res. 2008 Nov 15;68(22):9318-22. doi: 10.1158/0008-5472.CAN-08-2822.
7-Ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity. Moreover, we have reported the strong antitumor activity of NK012 (i.e., SN-38-releasing polymeric micelles) against human cancer xenografts compared with CPT-11. Here, we investigated the advantages of NK012 over CPT-11 treatment in mouse models of gastric cancer with peritoneal dissemination. NK012 or CPT-11 was i.v. administered thrice every 4 days at their respective maximum tolerable doses (NK012, 30 mg/kg/day; CPT-11, 67 mg/kg/day) to mice receiving orthotopic transplants of gastric cancer cell lines (44As3Luc and 58As1mLuc) transfected with the luciferase gene (n = 5). Antitumor effect was evaluated using the photon counting technique. SN-38 concentration in gastric tumors and peritoneal nodules was examined by high-performance liquid chromatography (HPLC) 1, 24, and 72 hours after each drug injection. NK012 or CPT-11 distribution in these tumors was evaluated using a fluorescence microscope on the same schedule. In both models, the antitumor activity of NK012 was superior to that of CPT-11. High concentrations of SN-38 released from NK012 were detected in gastric tumors and peritoneal nodules up to 72 hours by HPLC. Only a slight conversion from CPT-11 to SN-38 was observed from 1 to 24 hours. Fluorescence originating from NK012 was detected up to 72 hours, whereas that from CPT-11 disappeared until 24 hours. NK012 also showed antitumor activity against peritoneal nodules. Thus, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent.
7-乙基-10-羟基喜树碱（SN-38）是盐酸伊立替康（CPT-11）的活性代谢产物，具有强大的抗肿瘤活性。此外，我们已经报道了NK012（即释放SN-38的聚合物胶束）与人癌异种移植瘤相比，对CPT-11具有更强的抗肿瘤活性。在此，我们研究了在胃癌腹膜播散小鼠模型中，NK012相对于CPT-11治疗的优势。将NK012或CPT-11以各自的最大耐受剂量（NK012，30mg/kg/天；CPT-11，67mg/kg/天）每4天静脉注射三次，给药对象为接受了转染荧光素酶基因的胃癌细胞系（44As3Luc和58As1mLuc）原位移植的小鼠（n = 5）。使用光子计数技术评估抗肿瘤效果。在每次药物注射后1、24和72小时，通过高效液相色谱（HPLC）检测胃肿瘤和腹膜结节中的SN-38浓度。按照相同的时间表，使用荧光显微镜评估NK012或CPT-11在这些肿瘤中的分布。在两种模型中，NK012的抗肿瘤活性均优于CPT-11。通过HPLC在胃肿瘤和腹膜结节中检测到，直至72小时，NK012释放出高浓度的SN-38。在1至24小时内，仅观察到CPT-11向SN-38的轻微转化。直至72小时都能检测到源自NK012的荧光，而源自CPT-11的荧光在24小时时消失。NK012对腹膜结节也显示出抗肿瘤活性。因此，由于SN-38的抗肿瘤活性具有时间依赖性，NK012显示出增强的分布并延长了SN-38的释放，可能是癌症治疗的理想选择。
