Involvement of doxorubicin-induced Fas expression in the antitumor effect of doxorubicin on Lewis lung carcinoma in vivo
Involvement of doxorubicin-induced Fas expression in the antitumor effect of doxorubicin on Lewis lung carcinoma in vivo
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DOI：
10.1016/j.intimp.2004.09.032
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发表时间：
2005-02-01
影响因子：
5.6
通讯作者：
Ishizuka, M
中科院分区：
文献类型：
--
作者：
Yoshimoto, Y;Kawada, M;Ishizuka, M
Fas表达缺陷是谣言免疫逃避的机制之一。几种抗肿瘤药物。如多柔比星（DOX）在体外可增加肿瘤细胞中Fas的表达并使细胞对Fas介导的凋亡敏感。然而，Fas在体内表达的意义尚不清楚。因此，我们使用缺乏功能性Fas配体（FasL）的C57 BL/6-gld小鼠中的刘易斯肺癌（3LL）细胞的同基因肿瘤模型来检查Fas表达对DOX的抗肿瘤效果的作用。体外，抗Fas激动性抗体。乔2。在不存在DOX的情况下不降低3LL细胞的活细胞数，而在存在DOX的情况下显著降低细胞活力。以相同剂量单独用DOX处理不诱导细胞死亡。流式细胞术分析Fas表达显示，3LL细胞仅表达少量Fas，但用DOX处理细胞可增加细胞表面Fas的表达。当从携带3LL的C57 BL/6小鼠制备脾T细胞时，脾T细胞比未处理的3LL细胞显著地更多地杀死DOX预处理的3LL细胞。在同系模型中，DOX对野生型C57 BL/6小鼠和Fas缺陷型C57 BL/6-lpr小鼠的3LL实体瘤生长均有抑制作用，但对C57 BL/6-gld小鼠的抑制作用不明显。表明宿主Fas与肿瘤Fas之间的相互作用参与了DOX的抗肿瘤作用。此外。DOX治疗后，实体瘤中Fas表达增加。这些结果提示，DOX的抗肿瘤作用部分是通过Fas表达和宿主免疫防御来实现的。(C)2004 Elsevier B.V保留所有权利。
Deficiency of Fas expression is one of mechanisms involved in the immune evasion by rumors. Several antitumor drugs. such as doxorubicin (DOX) increase Fas expression in tumor cells and sensitize the cells to Fas-mediated apoptosis to vitro. However, the significance of the Fas expression in vivo is still unclear. Therefore, we examined a role of Fas expression on antitumor effect of DOX using a syngeneic tumor model of Lewis lung carcinoma (3LL) cells in C57BL/6-gld mice that lack functional Fas ligand (FasL). In vitro, anti-Fas agonistic antibody. Jo2. did not decrease a viable cell number of 3LL cells in the absence of DOX, whereas it significantly reduced the cell viability in the presence of DOX. The treatment with DOX alone at the same dose did not induce cell death. Flowcytometric analysis of Fas expression revealed that 3LL cells expressed only a marginal amount of Fas, but the treatment of the cells with DOX increased the expression of Fas in the cell surface. When splenic T cells were prepared from 3LL-bearing C57BL/6 mice, the splenic T cells significantly killed DOX-pretreated 3LL cells more than untreated 3LL cells. In the syngeneic models, DOX inhibited growth of 3LL solid tumor both in wild-type C57BL/6 mice and in Fas-deficient C57BL/6-lpr mice, but it failed in C57BL/6-gld mice. suggesting that the interaction between host Fast, and tumor Fas is involved in the antitumor effect of DOX. Furthermore. Fas expression was increased in the solid tumor by the treatment of DOX These results suggest that the antitumor effect of DOX is partly exerted by the Fas expression and host immune defense. (C) 2004 Elsevier B.V All rights reserved.