Antitumor Effect of SN-38-Releasing Polymeric Micelles, NK012, on Spontaneous Peritoneal Metastases from Orthotopic Gastric Cancer in Mice Compared with Irinotecan
Antitumor Effect of SN-38-Releasing Polymeric Micelles, NK012, on Spontaneous Peritoneal Metastases from Orthotopic Gastric Cancer in Mice Compared with Irinotecan
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DOI：
10.1158/0008-5472.can-08-2822
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Matsumura, Yasuhiro
中科院分区：
文献类型：
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作者：
Nakajima, Takako Eguchi;Yanagihara, Kazuyoshi;Matsumura, Yasuhiro
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，具有较强的抗肿瘤活性。此外，我们已经报道了NK 012的强抗肿瘤活性（即，SN-38-释放聚合物胶束）与CPT-11相比对人癌症异种移植物的作用。在这里，我们研究了NK 012在腹膜转移的胃癌小鼠模型中治疗CPT-11的优势。对接受荧光素酶基因转染的胃癌细胞系（44 As 3Luc和58 As 1 mLuc）原位移植的小鼠（n= 5），以各自的最大耐受剂量（NK 012，30 mg/kg/天; CPT-11，67 mg/kg/天）每4天静脉注射NK 012或CPT-11 3次。采用光子计数法评价其抗肿瘤作用。在每次药物注射后1、24和72小时，通过高效液相色谱法（HPLC）检查胃肿瘤和腹膜结节中的SN-38浓度。使用荧光显微镜按照相同的时间表评价NK 012或CPT-11在这些肿瘤中的分布。在两种模型中，NK 012的抗肿瘤活性均上级CPT-11。通过HPLC在胃肿瘤和腹膜结节中检测到高浓度的从NK 012释放的SN-38，长达72小时。从1至24小时，仅观察到CPT-11轻微转化为SN-38。在72小时内检测到源自NK 012的荧光，而源自CPT-11的荧光直到24小时才消失。NK 012还显示出对腹膜结节的抗肿瘤活性。因此，表现出增强的分布和延长的SN-38释放的NK 012对于癌症治疗可能是理想的，因为SN-38的抗肿瘤活性是时间依赖性的。[Cancer Res 2008;68（22）：9318-22]
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 I 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. [Cancer Res 2008;68(22):9318-22]