Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene.

R L Stickle, M W Epperly, E Klein, J A Bray, J S Greenberger
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引用次数: 81

Abstract

Esophagitis is a major toxicity of radiation therapy for nonsmall-cell lung cancer. Intraesophageal injection of manganese superoxide dismutase (MnSOD) plasmid/liposome complexes (1 mg of the pRK5-MnSOD plasmid containing the human MnSOD transgene in a 0.15 ml volume of lipofectin) before irradiation was carried out to attempt to prevent irradiation esophagitis. In control noninjected male C3H/HeNsd mice, esophagitis was induced by single fraction 3,500 cGy irradiation. Histopathology at 4 days revealed vacuole formation in squamous lining cells, separation of the squamous layer from the underlying muscle layer, ulceration at 7 days, and dehydration and death by 30 days. MnSOD plasmid/liposome complex-injected mice showed transcription of the human MnSOD transgene message in esophageal squamous lining cells by nested reverse transcriptase-polymerase chain reaction (RT-PCR) increased MnSOD biochemical activity 24 h after injection, decreased vacuole formation at day 4 (P < 0.001) after 3,500 cGy thoracic irradiation, and improved survival (P = 0.0009). In contrast, groups of mice receiving LacZ (bacterial beta-galactosidase gene) plasmid/liposome complexes or liposomes containing no DNA before 3,500 cGy irradiation showed an unaltered irradiation histopathology and decreased survival. Mice receiving intraesophageal MnSOD plasmid/liposomes followed 8 h later by human equivalent doses of Taxol (1.4 mg/kg) and carboplatin (2.5 mg/kg), then 15 h later 3,300 cGy irradiation, showed increased survival, compared with irradiated control or LacZ plasmid/liposome groups. Thus, overexpression of the human MnSOD transgene in the esophagus can prevent irradiation-induced esophagitis in the mouse model.

质粒/脂质体递送人锰超氧化物歧化酶转基因预防辐照诱导的食管炎。
食管炎是非小细胞肺癌放射治疗的主要毒性。在辐照前食管内注射锰超氧化物歧化酶(MnSOD)质粒/脂质体复合物(含人MnSOD转基因pRK5-MnSOD质粒1 mg,体积为0.15 ml脂质体),试图预防辐照性食管炎。对照组未注射C3H/HeNsd雄性小鼠,单组分3500 cGy辐照诱导食管炎。第4天的组织病理学显示鳞状衬细胞形成液泡,鳞状层从下层肌肉层分离,第7天溃疡,第30天脱水死亡。注射MnSOD质粒/脂质体复合物的小鼠,通过巢式逆转录聚合酶链反应(RT-PCR)在食管鳞衬细胞中转录人MnSOD转基因信息,在注射24 h后MnSOD生化活性升高,在3500 cGy胸部照射后第4天空泡形成减少(P < 0.001),生存率提高(P = 0.0009)。相比之下,在3500 cGy辐照前接受LacZ(细菌β -半乳糖苷酶基因)质粒/脂质体复合物或不含DNA的脂质体的小鼠组,其辐照组织病理学未发生改变,但存活率下降。与对照组或LacZ质粒/脂质体组相比,接受食道内MnSOD质粒/脂质体治疗的小鼠在8小时后接受人体等量紫杉醇(1.4 mg/kg)和卡铂(2.5 mg/kg)的照射,15小时后接受3,300 cGy的照射。由此可见,在小鼠模型中,过表达人MnSOD转基因在食管中可以预防辐照性食管炎。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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