Krassikova Lyudmila S, Karshieva Saida S, Cheglakov Ivan B, Belyavsky Alexander V
Pushchino State Institute of Natural Sciences, Pushchino, Russia.
Engelhardt Institute of Molecular Biology RAS, Moscow, Russia.
J Gene Med. 2016 Sep;18(9):220-33. doi: 10.1002/jgm.2894.
The combination of stem cell-based gene therapy with chemotherapy comprises an advantageous strategy that results in a reduction of system toxicity effects and an improvement in the general efficacy of treatment. In the present study, we estimated the efficacy of adipose tissue-derived mesenchymal stem cells (AT-MSCs) expressing cytosine deaminase (CDA) combined with lysomustine chemotherapy in mice bearing late stage Lewis lung carcinoma (LLC).
Adipose tissue-derived mesenchymal stem cells were transfected with non-insert plasmid construct transiently expressing fused cytosine deaminase-uracil phosphoribosyltransferase protein (CDA/UPRT) or the same construct fused with Herpes Simplex Virus Type1 tegument protein VP22 (CDA/UPRT/VP22). Systemic administration of 5-fluorocytosine (5FC) and lysomustine was implemented after a single intratumoral injection of transfected AT-MSCs.
We demonstrated that direct intratumoral transplantation of AT-MSCs expressing CDA/UPRT or CDA/UPRT/VP22 followed by systemic administration of 5FC resulted in a significant tumor growth inhibition. There was a 56% reduction in tumor volume in mice treated by AT-MSCs-CDA/UPRT + 5FC or with AT-MSCs-CDA/UPRT/VP22 + 5FC compared to control animals grafted with lung carcinoma alone. Transplantation of AT-MSCs-CDA/UPRT + 5FC and AT-MSCs-CDA/UPRT/VP22 + 5FC prolonged the life span of mice bearing LLC by 27% and 31%, respectively. Co-administration of lysomustine and AT-MSCs-CDA/UPRT + 5FC led to tumor growth inhibition (by 86%) and life span extension (by 60%) compared to the control group.
Our data indicate that a combination CDA/UPRT-expressing AT-MSCs with lysomustine has a superior antitumor effect in the murine lung carcinoma model compared to monotherapies with transfected AT-MSCs or lysomustine alone, possibly because of a synergistic effect of the combination therapy. Copyright © 2016 John Wiley & Sons, Ltd.
基于干细胞的基因治疗与化疗相结合是一种具有优势的策略，可减少全身毒性作用并提高总体治疗效果。在本研究中，我们评估了表达胞嘧啶脱氨酶（CDA）的脂肪组织来源间充质干细胞（AT-MSCs）与溶肉瘤素化疗联合应用于晚期Lewis肺癌（LLC）小鼠的疗效。
用瞬时表达融合胞嘧啶脱氨酶-尿嘧啶磷酸核糖转移酶蛋白（CDA/UPRT）的非插入性质粒构建体或与单纯疱疹病毒1型被膜蛋白VP22融合的相同构建体（CDA/UPRT/VP22）转染脂肪组织来源间充质干细胞。在瘤内单次注射转染后的AT-MSCs后，进行5-氟胞嘧啶（5FC）和溶肉瘤素的全身给药。
我们证明，表达CDA/UPRT或CDA/UPRT/VP22的AT-MSCs直接瘤内移植，随后全身给予5FC，可显著抑制肿瘤生长。与仅移植肺癌的对照动物相比，接受AT-MSCs-CDA/UPRT + 5FC或AT-MSCs-CDA/UPRT/VP22 + 5FC治疗的小鼠肿瘤体积减少了56%。移植AT-MSCs-CDA/UPRT + 5FC和AT-MSCs-CDA/UPRT/VP22 + 5FC分别使荷LLC小鼠的寿命延长了27%和31%。与对照组相比，溶肉瘤素与AT-MSCs-CDA/UPRT + 5FC联合给药导致肿瘤生长抑制（86%）和寿命延长（60%）。
我们的数据表明，与单独使用转染的AT-MSCs或溶肉瘤素的单一疗法相比，表达CDA/UPRT的AT-MSCs与溶肉瘤素联合在小鼠肺癌模型中具有更强的抗肿瘤作用，这可能是由于联合治疗的协同效应。版权所有© 2016约翰威立父子有限公司。
