Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy
Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy
复制标题
DOI：
10.1158/1535-7163.mct-05-0423
复制
发表时间：
2006-03-01
影响因子：
5.7
通讯作者：
Altura, RA
中科院分区：
文献类型：
--
作者：
Caldas, H;Jaynes, FO;Altura, RA
生存素是一种抗凋亡蛋白，在恶性肿瘤细胞中高度表达，对细胞毒疗法具有抗性。颗粒酶B是一种有效的细胞毒性蛋白质，其在有害刺激（包括外来入侵物）后从哺乳动物自然杀伤细胞和CTL释放。在这里，我们利用这两种功能不同的分子的特性，创造了一种分子试剂，特异性激活肿瘤细胞内的颗粒酶B。我们设计了Survivin和颗粒酶B诱导的凋亡（佐贺），其由Survivin基因启动子与活性颗粒酶B的编码序列的融合组成。在用佐贺DNA转染的培养的人肿瘤细胞中，颗粒酶B快速表达并导致显著的肿瘤细胞死亡。在体内，携带人卵巢肿瘤的小鼠对佐贺治疗具有统计学显著的临床应答，其在用佐贺和紫杉醇联合治疗后被放大。在3周治疗试验完成时，SAGA治疗组15只动物中有3只没有疾病，另外8只动物的肿瘤不可触及，仅在手术切除时检测到。相比之下，对照组和仅紫杉醇治疗组的15只动物中有15只在治疗结束时患有肿瘤。在20只动物中的19只中，用佐贺与或不与紫杉醇一起治疗也防止了疾病传播。这些结果有力地表明，佐贺有可能成为一个有效的药物治疗原发性和复发性人卵巢癌。
Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural killer cells and CTLs following noxious stimuli, including foreign invaders. Here, we took advantage of the properties of these two functionally divergent molecules to create a molecular agent that specifically activates Granzyme B within tumor cells. We designed Survivin and Granzyme B-induced apoptosis (SAGA), which consists of a fusion of the Survivin gene promoter to the coding sequence of active Granzyme B. In cultured human tumor cells transfected with SAGA DNA, Granzyme B is rapidly expressed and results in significant tumor cell death. In vivo, mice harboring human ovarian tumors had statistically significant clinical responses to SAGA treatment that were magnified following combination therapy with SAGA and paclitaxel. At the completion of a 3-week therapeutic trial, 3 of 15 animals were free of disease in the SAGA-treated group, and an additional eight animals had tumors that were nonpalpable and only detected on surgical resection. In contrast, 15 of 15 animals in the control and paclitaxel-only-treated groups had tumors at end of therapy. Treatment with SAGA with or without paclitaxel also prevented disease dissemination in 19 of 20 animals. These results strongly suggest that SAGA has the potential to be a potent agent for the treatment of primary and recurrent human ovarian carcinoma.