Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model

被引：39

作者：

Graepler, Florian ^{[1
]}

Lemken, Marie-Luise ^{[1
]}

Wybranietz, Wolfgang A. ^{[1
]}

Schmidt, Ulrike ^{[1
]}

Smirnow, Irina ^{[1
]}

Gross, Christine D. ^{[1
]}

Spiegel, Martin ^{[1
]}

Schenk, Andrea ^{[1
]}

Graf, Hansjoerg ^{[2
]}

Lauer, Ulrike A. ^{[2
]}

Vonthein, Reinhard ^{[3
]}

Gregor, Michael ^{[1
]}

Armeanu, Sorin ^{[1
]}

Bitzer, Michael ^{[1
]}

Lauer, Ulrich M. ^{[1
]}

机构：

[1] Univ Clin Tubingen, Dept Internal Med 1, D-72076 Tubingen, Germany

[2] Univ Clin Tubingen, Sect Expt Radiol, D-72076 Tubingen, Germany

[3] Univ Clin Tubingen, Dept Med Biometry, D-72076 Tubingen, Germany

来源：

WORLD JOURNAL OF GASTROENTEROLOGY | 2005年 / 11卷 / 44期

关键词：

YCD/YUPRT fusion; Cytosine deaminase; GDEPT; Suicide gene therapy; Hepatoma therapy;

D O I：

10.3748/wjg.v11.i44.6910

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

AIM: To investigate the effects of catalytically superior gene-directed enzyme prodrug therapy systems on a rat hepatoma model. METHODS: To increase hepatoma cell chemosensitivity for the prodrug 5-fluorocytosine (5-FC), we generated a chimeric bifunctional SuperCD suicide gene, a fusion of the yeast cytosine deaminase (YCD) and the yeast uracil phosphoribosyltransferase (YUPRT) gene. RESULTS: In vitro stably transduced Morris rat hepatoma cells (MH) expressing the bifunctional SuperCD suicide gene (MH SuperCD) showed a clearly marked enhancement in cell killing when incubated with 5-FC as compared with MH cells stably expressing YCD solely (MH YCD) or the cytosine deaminase gene of bacterial origin (MH BCD), respectively. In vivo, MH SuperCD tumors implanted both subcutaneously as well as orthotopically into the livers of syngeneic ACI rats demonstrated significant tumor regressions (P < 0.01) under both high dose as well as low dose systemic 5-FC application, whereas MH tumors without transgene expression (MH naive) showed rapid progression. For the first time, an order of in vivo suicide gene effectiveness (SuperCD >> YCD >> BCD >>> negative control) was defined as a result of a direct in vivo comparison of all three suicide genes. CONCLUSION: Bifunctional SuperCD suicide gene expression is highly effective in a rat hepatoma model, thereby significantly improving both the therapeutic index and the efficacy of hepatocellular carcinoma killing by fluorocytosine. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

引用

页码：6910 / 6919

页数：10

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