Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice
Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice
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DOI：
10.1002/jgm.1239
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发表时间：
2008-10-01
影响因子：
3.5
通讯作者：
Altaner, Cestmir
中科院分区：
文献类型：
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作者：
Kucerova, Lucia;Matuskova, Miroslava;Altaner, Cestmir
背景以前，我们验证了人脂肪组织来源的间充质干细胞(AT-MSC)作为基因导向的酶前体药物分子化疗的细胞载体的能力。酵母融合胞嘧啶脱氨酶：表达AT-MSC的尿嘧啶磷酸核糖转移酶(CDY-AT-MSC)联合系统性5-氟胞嘧啶(5FC)显著抑制人结肠癌移植瘤的生长。目的检测CDY-AT-MSC/5FC在体外和体内对其他肿瘤细胞的杀伤作用。方法体外直接和间接共培养法检测CDY-AT-MSC/5FC对一组人肿瘤细胞系的增殖抑制作用。结果扩增的CDY-AT-MSC在体外对人黑色素瘤、胶质母细胞瘤、结肠癌、乳腺癌和膀胱癌仍表现出较强的旁观者细胞毒作用。CDY-AT-MSC/5FC与2%的CDY-AT-MSC/5FC直接共培养时，对黑色素瘤A375细胞的抑制率最高(91%)。进一步评价CDY-AT-MSC/5FC系统对裸鼠黑色素瘤A375移植瘤的治疗作用。在体内，20%CDY-AT-MSC/5FC与肿瘤细胞共注射可使肿瘤完全消退。结论CDY-AT-MSC靶向于皮下黑色素瘤的能力为选择性原位生产细胞毒剂提供了可能。我们的数据进一步证明了AT-MSC作为一种细胞载体的有益的生物学特性，用于分子化疗的酶/前药治疗方法。版权所有(C)2008 John Wiley&Sons，Ltd.
Background previously, we validated capability of human adipose tissue-derived mesenchymal stem cells (AT-MSC) to serve as cellular vehicles for gene-directed enzyme prodrug molecular chemotherapy. Yeast fusion cytosine deaminase: uracil phosphoribosyltransferase expressing AT-MSC (CDy-AT-MSC) combined with systemic 5-fluorocytosine (5FC) significantly inhibited growth Of human colon cancer xenografts. We aimed to determine the cytotoxic efficiency to other tumour cells both in vitro and in vivo.Methods CDy-AT-MSC/5FC-rnediated proliferation inhibition against a panel of human turnout cells lines was evaluated in direct and indirect cocultures in vitro. Antitumour effect was tested on immunodeficient mouse model in vivo.Results Although culture expansion of CDy-AT-MSC sensitized these cells to 5FC mediated suicide effect, expanded CDy-AT-MSC/5FC still exhibited strong bystander cytotoxic effect towards human melanoma, glioblastoma, colon, breast and bladder carcinoma in vitro. Most efficient inhibition (91%) was observed in melanoma A375 cell line when directly cocultured with 2% of therapeutic cells CDy-AT-MSC/5FC. The therapeutic paradigm of the CDy-AT-MSC/5FC system was further evaluated on melanoma A375 xenografts on nude mice in vivo. Complete regression in 89% of tumours was achieved when 20% CDy-AT-MSC/5FC were co-injected along with tumour cells. More importantly, systemic CDy-AT-MSC administration resulted in therapeutic cell homing into subcutaneous melanoma and mediated turnout growth inhibition.Conclusions CDy-AT-MSC capability of targeting subcutaneous melanoma offers a possibility to selectively produce cytotoxic agent in situ. Our data further demonstrate beneficial biological properties of AT-MSC as a cellular vehicle for enzyme/prodrug therapy approach to molecular chemotherapy. Copyright (C) 2008 John Wiley & Sons, Ltd.