Antitumor Effect of NK012, a 7-Ethyl-10-Hydroxycamptothecin-Incorporating Polymeric Micelle, on U87MG Orthotopic Glioblastoma in Mice Compared with Irinotecan Hydrochloride in Combination with Bevacizumab
Antitumor Effect of NK012, a 7-Ethyl-10-Hydroxycamptothecin-Incorporating Polymeric Micelle, on U87MG Orthotopic Glioblastoma in Mice Compared with Irinotecan Hydrochloride in Combination with Bevacizumab
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DOI：
10.1158/1078-0432.ccr-09-2393
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发表时间：
2010-01-15
影响因子：
11.5
通讯作者：
Matsumura, Yasuhiro
中科院分区：
文献类型：
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作者：
Kuroda, Jun-ichiro;Kuratsu, Jun-ichi;Matsumura, Yasuhiro
目的：为了阐明与盐酸伊立替康（CPT-11）与贝伐单抗的组合疗法相比，贝伐单抗对携带U87 MG胶质母细胞瘤原位异种移植物的小鼠中的NK 012疗法的影响，实验设计：在有或没有贝伐单抗的情况下，每4天静脉内施用3次7-乙基-10-羟基喜树碱（SN-38）当量剂量的NK 012，每4天3次。CPT-11以66.7 mg/kg每4天静脉给药3次，或CPT-11以40 mg/kg/d连续5天给药，伴或不伴贝伐珠单抗。在每个实验中，每4天腹膜内给予贝伐珠单抗6次。通过生物发光成像、组织病理学评价和免疫组织化学评价体内抗肿瘤作用。结果：CPT-11与贝伐单抗联合用药的抗肿瘤活性明显高于CPT-11单药治疗（P < 0.05），生存期明显延长（P < 0.05）。然而，NK 012单药治疗和NK 012与贝伐珠单抗联合治疗之间没有差异。NK 012与贝伐珠单抗联合用药后，肿瘤组织中释放的游离SN-38浓度降低（P = 0.027）。NK 012单药治疗或NK 012与贝伐单抗联合治疗显示出比CPT-11与贝伐单抗联合治疗的任何给药方法更强的抗肿瘤活性和更长的生存期（P < 0.05）。用NK 012治疗的原位肿瘤显示肿瘤细胞减少和Ki-67指数降低（P < 0.001）。结论：本研究使用小鼠原位胶质母细胞瘤模型，可能需要在进行药物临床试验之前对NK 012进行进一步的临床前评价，因为NK 012单一疗法的抗肿瘤活性上级于CPT-11与贝伐单抗的组合疗法。Clin Cancer Res; 16（2）; 521-9.（C）2010年AACR。
Purpose: To clarify the effect of bevacizumab on NK012 therapy in mice bearing U87MG glioblastoma orthotopic xenografts in comparison with the combination therapy of irinotecan hydrochloride (CPT-11) with bevacizumab.Experimental Design: NK012 at 7-ethyl-10-hydroxycamptothecin (SN-38) equivalent dose of 30 mg/kg was administered intravenously three times every 4 days with or without bevacizumab. CPT-11 at 66.7 mg/kg was administered intravenously three times every 4 days or CPT-11 at 40 mg/kg/d over 5 consecutive days with or without bevacizumab. Bevacizumab was administered intraperitoneally six times every 4 days in each experiment. In vivo antitumor effects were evaluated by bioluminescence imaging, histopathologic evaluation, and immunohistochemistry. To evaluate interaction with bevacizumab, free SN-38 concentration in tumor tissues was examined by high-performance liquid chromatography.Results: CPT-11 in combination with bevacizumab showed significantly more potent antitumor activity and longer survival than CPT-11 monotherapy (P < 0.05). However, there was no difference between NK012 monotherapy and NK012 in combination with bevacizumab. Concentration of free SN-38 released from NK012 in tumor tissue decreased in combination with bevacizumab (P = 0.027). NK012 monotherapy or NK012 with bevacizumab showed potent antitumor activity and longer survival than any dosing method of CPT-11 in combination with bevacizumab (P < 0.05). Orthotopic tumors treated with NK012 showed decreased tumor cellularity and lower Ki-67 index (P < 0.001) relative to those treated with CPT-11/bevacizumab.Conclusions: The present study using orthotopic glioblastoma model in mice may warrant further preclinical evaluation of NK012 before conducting the clinical trial of the drug, because the antitumor activity of NK012 monotherapy was superior to the combination therapy of CPT-11 with bevacizumab. Clin Cancer Res; 16(2); 521-9. (C)2010 AACR.