You Mi-Hyeon, Kim Wang-Joon, Shim Wooyoung, Lee Sang-Rim, Lee Gwang, Choi Sangdun, Kim Dae-Yong, Kim Yong Man, Kim Hyunsoo, Han Sang-Uk
Department of Veterinary Pathology, Seoul National University, Seoul, Korea.
J Gastroenterol Hepatol. 2009 Aug;24(8):1393-400. doi: 10.1111/j.1440-1746.2009.05862.x. Epub 2009 May 28.
Stem cell transplantation offers potential gene therapy for brain tumors. However, this approach has received little attention as a treatment for gastrointestinal tumors. In the present study, we explored the possibility of human bone marrow-derived mesenchymal stem cells (hMSC) producing cytosine deaminase (CD), followed by systemic 5-fluorocytosine (5-FC) administration, showing an antitumor effect on a mouse gastric cancer xenograft.
We first explored the ability of hMSC, coated with fluorescent dye, to migrate to human gastric cancer MKN45 cells in vitro and in vivo. We then used hMSC in which a gene expressed the prodrug-activating enzyme CD, which can convert the prodrug 5-FC into the cytotoxic agent 5-fluorouracil (5-FU), and further investigated the potential of these cells to deliver the CD gene and to reduce tumor growth in nude mice. The migratory capacity of hMSC was confirmed by an in vitro migration assay, as well as in an in vivo model of nude mice bearing subcutaneous tumors of MKN45 cells when hMSC were injected.
The migration ability of hMSC towards MKN45 cells was confirmed by migration assay. Effective conversion of 5-FC to 5-FU by hMSC transfected with the CD gene (CD-hMSC) showed therapeutic anticancer potential in a MKN45 cell co-culture system, as confirmed by thin layer chromatography. Nude mice bearing MKN45 tumors were intravenously injected with CD-hMSC, followed by systemic 5-FC treatment (500 mg/kg/day) for 7 days. Tumor volumes and weights of mice injected with CD-hMSC decreased significantly after treatment with 5-FC. However, the 5-FC-treated group without CD-hMSC injection showed neither a decrease in tumor volume nor bodyweight loss.
The CD-hMSC system showed anticancer therapeutic potential, and minimized the side-effects of 5-FU.
干细胞移植为脑肿瘤提供了潜在的基因治疗方法。然而，作为胃肠道肿瘤的一种治疗方法，这种方法很少受到关注。在本研究中，我们探讨了人骨髓间充质干细胞（hMSC）产生胞嘧啶脱氨酶（CD）的可能性，随后全身给予5-氟胞嘧啶（5-FC），对小鼠胃癌异种移植瘤显示出抗肿瘤作用。
我们首先研究了用荧光染料包被的hMSC在体外和体内迁移至人胃癌MKN45细胞的能力。然后，我们使用表达前药激活酶CD的hMSC，该酶可将前药5-FC转化为细胞毒性剂5-氟尿嘧啶（5-FU），并进一步研究这些细胞传递CD基因和减少裸鼠肿瘤生长的潜力。通过体外迁移试验以及在注射hMSC的携带MKN45细胞皮下肿瘤的裸鼠体内模型中证实了hMSC的迁移能力。
通过迁移试验证实了hMSC向MKN45细胞的迁移能力。经薄层色谱法证实，用CD基因转染的hMSC（CD-hMSC）将5-FC有效转化为5-FU，在MKN45细胞共培养系统中显示出治疗性抗癌潜力。给携带MKN45肿瘤的裸鼠静脉注射CD-hMSC，随后全身给予5-FC治疗（500mg/kg/天），持续7天。用5-FC治疗后，注射CD-hMSC的小鼠的肿瘤体积和重量显著降低。然而，未注射CD-hMSC的5-FC治疗组既未出现肿瘤体积减小，也未出现体重减轻。
CD-hMSC系统显示出抗癌治疗潜力，并将5-FU的副作用降至最低。
