Adipose Tissue-derived Mesenchymal Stem Cells Expressing Prodrug-converting Enzyme Inhibit Human Prostate Tumor Growth
Adipose Tissue-derived Mesenchymal Stem Cells Expressing Prodrug-converting Enzyme Inhibit Human Prostate Tumor Growth
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DOI：
10.1038/mt.2009.237
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发表时间：
2010-01-01
影响因子：
12.4
通讯作者：
Altaner, Cestmir
中科院分区：
文献类型：
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作者：
Cavarretta, Ilaria T.;Altanerova, Veronika;Altaner, Cestmir
人脂肪组织源性间充质干细胞 (AT-MSC) 被设计为表达自杀基因胞嘧啶脱氨酶::尿嘧啶磷酸核糖基转移酶 (CD::UPRT)，能够将相对无毒的 5-氟胞嘧啶 (5-FC) 转化为剧毒的抗肿瘤药物 5-氟尿嘧啶 (5-FU)，并且能够跟踪并植入肿瘤和微转移，使这些细胞成为有吸引力的工具直接在肿瘤块内激活前药。在这项研究中，我们测试了这些治疗细胞在前列腺癌（PC）治疗中作为前药激活酶的细胞载体的可行性和功效。在体外迁移实验中，我们表明治疗性 AT-MSC 迁移到所有测试的前列腺细胞系中。在一项临床前试验研究中，我们观察到，将人骨转移性 PC 细胞与转导的 AT-MSC 共同注射到用 5-FC 治疗的裸鼠体内，以剂量依赖性方式诱导肿瘤完全消退，甚至不允许肿瘤形成。更重要的是，我们还证明了治疗细胞在静脉内给药后可有效显着抑制 PC 肿瘤生长，这是基因导向酶前药疗法任何临床应用的关键条件。
The ability of human adipose tissue-derived-mesenchymal stem cells (AT-MSCs), engineered to express the suicide gene cytosine deaminase:: uracil phosphoribosyltransferase (CD::UPRT), to convert the relatively nontoxic 5-fluorocytosine (5-FC) into the highly toxic antitumor 5-fluorouracil (5-FU) together with their ability to track and engraft into tumors and micrometastases makes these cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we tested the feasibility and efficacy of these therapeutic cells to function as cellular vehicles of prodrug-activating enzymes in prostate cancer (PC) therapy. In in vitro migration experiments we have shown that therapeutic AT-MSCs migrated to all the prostate cell lines tested. In a pilot preclinical study, we observed that coinjections of human bone metastatic PC cells along with the transduced AT-MSCs into nude mice treated with 5-FC induced a complete tumor regression in a dose dependent manner or did not even allow the establishment of the tumor. More importantly, we also demonstrated that the therapeutic cells were effective in significantly inhibiting PC tumor growth after intravenous administration that is a key requisite for any clinical application of gene-directed enzyme prodrug therapies.