Enhancement of antitumor radiation efficacy and consistent induction of the abscopal effect in mice by ECI301, an active variant of macrophage inflammatory protein-1α
Enhancement of antitumor radiation efficacy and consistent induction of the abscopal effect in mice by ECI301, an active variant of macrophage inflammatory protein-1α
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DOI：
10.1158/1078-0432.ccr-07-4485
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发表时间：
2008-02-15
影响因子：
11.5
通讯作者：
Kanegasaki, Shiro
中科院分区：
文献类型：
--
作者：
Shiraishi, Kenshiro;Ishiwata, Yoshiro;Kanegasaki, Shiro
目的：研究静脉注射阿司匹林是否有效。在局部肿瘤部位照射后给予趋化因子可以通过白细胞募集来防止残留的和远处未照射的肿瘤细胞的生长。在右侧或两侧。右侧局部照射ECI301后，静脉注射人巨噬细胞炎性蛋白-1α变异体。结果：在荷瘤BALB/c小鼠中，6GyECI301连续3~5d每天重复给药2 mg/只，可延长小鼠生存期，且无明显毒性反应，约半数小鼠肿瘤完全消失。局部照射后每周给药三次的ECI301也导致了显著的抗肿瘤放射疗效，尽管效果较差。ECI301还抑制其他同基因移植瘤的生长，包括甲基纤维肉瘤(BALB/c)和Lewis肺癌(C57BL/6)。重要的是，非辐射部位的肿瘤生长受到抑制，表明ECI301增强了辐射的非局域效应。在BALB/c和C57BL/6小鼠中观察到的这种异常效应与肿瘤类型无关。白细胞耗竭实验显示CD8+、CD4+淋巴细胞和NK1.1细胞参与其中。结论：静脉注射能显著抑制照射部位肿瘤的生长，彻底消除肿瘤，并一致地诱导肿瘤的异常效应。ECI301的管理。本研究结果可能为肿瘤治疗提供一个新的概念，即局部照射后给予趋化因子，从而为晚期转移癌的治疗提供新的治疗方法。
Purpose: We studied whether i.v. administration of a chemokine after local tumor site irradiation could prevent remaining, as well as distant, nonirradiated tumor cell growth by leukocyte recruitment.Experimental Design: Tumors were implanted s.c. in the right or both flanks. After local irradiation at the right flank, ECI301, a human macrophage inflammatory protein-1 alpha variant was injected i.v. Tumor volumes were measured every 3 days after treatment.Results: In Colon26 adenocarcinoma-bearing BALB/c mice, repeated daily administration (over 3-5 consecutive days) of 2 mu g per mouse ECI301 after local irradiation of 6 Gy prolonged survival without significant toxicity, and in about half of the treated mice, the tumor was completely eradicated. Three weekly administrations of ECI301 after local irradiation also led to significant, although less effective, antitumor radiation efficacy. ECI301 also inhibited growth of other syngenic tumor grafts, including MethA fibrosarcoma (BALB/c) and Lewis lung carcinoma (C57BL/6). Importantly, tumor growth at the nonirradiated site was inhibited, indicating that ECI301 potentiated the abscopal effect of radiation. This abscopal effect observed in BALB/c and C57BL/6 mice was tumor-type independent. Leukocyte depletion studies suggest that CD8+ and CD4+ lymphocytes and NK1.1 cells were involved.Conclusions: Marked inhibition of tumor growth at the irradiated site, with complete tumor eradication and consistent induction of the abscopal effect, was potentiated by i.v. administration of ECI301. The results of this study may offer a new concept for cancer therapy, namely chemokine administration after local irradiation, leading to development of novel therapeutics for the treatment of advanced metastatic cancer.