Guo Hong Liang, Wolfe Darren, Epperly Michael W, Huang Shaohua, Liu Kaihong, Glorioso Joseph C, Greenberger Joel, Blumberg David
Radiation Oncology, University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, PA 15261, USA.
J Gastrointest Surg. 2003 Feb;7(2):229-35; discussion 235-6. doi: 10.1016/s1091-255x(02)00186-5.
Small bowel toxicity represents a major dose-limiting side effect of radiation treatment for many malignancies. We examined the effects of overexpressing human manganese superoxide dismutase (MnSOD) in the small intestine in mice to prevent radiation enteritis. Mice were treated with the human MnSOD gene delivered enterally using a nontoxic, replication-defective herpes simplex virus (HSV)-1-based vector. HSV vectors containing the human MnSOD transgene and green fluorescent protein (GFP) transgene, or GFP transgene alone, were constructed and injected intraluminally into a 2cm length of small intestine of C3H/HeNsd mice. Total body irradiation of 15 Gy was delivered to mice inoculated 24 hours earlier with either HSV-MnSOD (10(3) to 10(8) plaque-forming units), control HSV-GFP, or no vector. At 24 or 72 hours after irradiation, mice were killed and villi areas were measured from appropriate segments of the small intestine. Control irradiated mice showed a decreased villi area of 82% by day 3 after irradiation, whereas treatment of mice with HSV-MnSOD 10(8) plaque-forming units led to only a 16% decrease in villi area (P < 0.001) before radiation. Similar findings were seen on day 3 and were associated with a significant (P < 0.001) preservation of enteric protein content in HSV-MnSOD-treated mice. A dose-dependent effect of MnSOD in preventing radiation-induced small bowel injury was evident. These data demonstrate that overexpression of human MnSOD via a replication-defective herpes viral vector is an efficacious method of protecting the small intestine from ionizing radiation damage.
小肠毒性是许多恶性肿瘤放射治疗的主要剂量限制性副作用。我们研究了在小鼠小肠中过表达人锰超氧化物歧化酶（MnSOD）以预防放射性肠炎的效果。使用无毒、复制缺陷型单纯疱疹病毒1型（HSV-1）载体经肠道递送人MnSOD基因来处理小鼠。构建了包含人MnSOD转基因和绿色荧光蛋白（GFP）转基因的HSV载体，或仅含GFP转基因的载体，并将其腔内注射到C3H/HeNsd小鼠2厘米长的小肠段中。对24小时前接种了HSV-MnSOD（10³至10⁸空斑形成单位）、对照HSV-GFP或未接种载体（即无载体）的小鼠进行15 Gy的全身照射。照射后24或72小时，处死小鼠并测量小肠相应节段的绒毛面积。对照照射小鼠在照射后第3天绒毛面积减少了82%，而用10⁸空斑形成单位的HSV-MnSOD处理小鼠，在照射前绒毛面积仅减少了16%（P<0.001）。在第3天观察到类似结果，且与HSV-MnSOD处理小鼠肠道蛋白质含量的显著保留（P<0.001）相关。MnSOD在预防辐射诱导的小肠损伤方面具有明显的剂量依赖性效应。这些数据表明，通过复制缺陷型疱疹病毒载体过表达人MnSOD是保护小肠免受电离辐射损伤的有效方法。
