Hyoudou Kenji, Nishikawa Makiya, Kobayashi Yuki, Kuramoto Yukari, Yamashita Fumiyoshi, Hashida Mitsuru
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Clin Exp Metastasis. 2006;23(5-6):269-78. doi: 10.1007/s10585-006-9036-8. Epub 2006 Nov 3.
Hydrogen peroxide may aggravate the peritoneal dissemination of tumor cells by activating the expression of a variety of genes. In this study, we used pegylated catalase (PEG-catalase) to examine whether prolonged retention of catalase activity within the peritoneal cavity is effective in inhibiting peritoneal dissemination in mouse models. Murine B16-BL6 cells or colon 26 cells labeled with firefly luciferase gene were inoculated intraperitoneally into syngeneic mice. Compared with unmodified catalase, PEG-catalase was retained in the peritoneal cavity for a long period after intraperitoneal injection. A single injection of PEG-catalase just before tumor inoculation significantly reduced the number of the tumor cells at 1 and 7 days. The changes in the expression of molecules involved in the metastasis were evaluated by real time quantitative PCR analysis. Inoculation of the tumor cells increased the expression of intercellular adhesion molecule (ICAM)-1 in the greater omentum, which was inhibited by PEG-catalase. An injection of PEG-catalase at 3 days after tumor inoculation also reduced the number of the tumor cells, suggesting that processes other than the adhesion of tumor cells to peritoneal organs are also inhibited. Daily doses of PEG-catalase significantly prolonged the survival time of tumor-bearing mice. These results indicate that intraperitoneal injection of PEG-catalase inhibits the multiple processes of peritoneal dissemination of tumor cells by scavenging hydrogen peroxide in the peritoneal cavity.
过氧化氢可能通过激活多种基因的表达来加剧肿瘤细胞的腹膜播散。在本研究中，我们使用聚乙二醇化过氧化氢酶（PEG-过氧化氢酶）来检测在小鼠模型中，过氧化氢酶活性在腹腔内的长期保留是否能有效抑制腹膜播散。将用萤火虫荧光素酶基因标记的小鼠B16-BL6细胞或结肠26细胞腹腔接种到同基因小鼠体内。与未修饰的过氧化氢酶相比，PEG-过氧化氢酶腹腔注射后在腹腔内长期留存。在肿瘤接种前单次注射PEG-过氧化氢酶可在第1天和第7天显著减少肿瘤细胞数量。通过实时定量PCR分析评估转移相关分子表达的变化。肿瘤细胞接种增加了大网膜中细胞间黏附分子（ICAM）-1的表达，而PEG-过氧化氢酶可抑制这一表达。在肿瘤接种后第3天注射PEG-过氧化氢酶也减少了肿瘤细胞数量，这表明除肿瘤细胞与腹膜器官的黏附过程外的其他过程也受到了抑制。每日注射PEG-过氧化氢酶可显著延长荷瘤小鼠的生存时间。这些结果表明，腹腔注射PEG-过氧化氢酶可通过清除腹腔内的过氧化氢来抑制肿瘤细胞腹膜播散的多个过程。
