Nozaki Masako, Yoshikawa Masanobu, Ishitani Kunihiko, Kobayashi Hiroyuki, Houkin Kiyohiro, Imai Kohzoh, Ito Yoichiro, Muraki Takamura
Department of Clinical Pharmacology, Tokai University School of Medicine, Kanagawa, Japan.
Keio J Med. 2010;59(1):10-8. doi: 10.2302/kjm.59.10.
We explored the possibility of the cysteinyl leukotriene receptor antagonists, pranlukast and montelukast, preventing tumor cell migration through both cerebral and peripheral capillaries. To study tumor cell migration through brain capillaries, male Fisher rats were cannulated via the cisterna magna under pentobarbital anesthesia. RCN9 cells labeled with a fluorescent marker PKH67 were intravenously administered following arachidonic acid administration into the subarachnoid space, and specimens of the central nervous system were collected every 30 min for 8 h. Arachidonic acid increased the fluid volume with elevated white blood cell and RCN9 cell counts. When given 2 h before arachidonic acid administration, pranlukast, but not montelukast, reduced the fluid volume and inhibited white blood cell and RCN9 cell extravasation through the brain capillary. In addition, a Lewis lung carcinoma metastasis model in mice was used to study the inhibitory effect of pranlu kast and montelukast against cancer cell extravasation through general capillaries. When mice were given food containing either pranlukast or montelukast, immediately after paw amputation, tumor metastasis was prevented by both drugs, and their survival was prolonged. These results show that pranlukast can inhibit tumor cell migration through both the brain and peripheral capillaries, whereas montelukast inhibits tumor cell migration only in the peripheral capillaries.
我们探究了半胱氨酰白三烯受体拮抗剂普仑司特和孟鲁司特通过脑毛细血管和外周毛细血管阻止肿瘤细胞迁移的可能性。为研究肿瘤细胞通过脑毛细血管的迁移情况，在戊巴比妥麻醉下，经枕大池对雄性Fisher大鼠进行插管。在向蛛网膜下腔注射花生四烯酸后，静脉注射用荧光标记物PKH67标记的RCN9细胞，每30分钟收集一次中枢神经系统标本，共收集8小时。花生四烯酸使液体量增加，白细胞和RCN9细胞计数升高。在花生四烯酸给药前2小时给予普仑司特（而非孟鲁司特），可减少液体量，并抑制白细胞和RCN9细胞通过脑毛细血管的渗出。此外，利用小鼠Lewis肺癌转移模型研究普仑司特和孟鲁司特对癌细胞通过全身毛细血管渗出的抑制作用。在小鼠爪子截肢后立即给予含普仑司特或孟鲁司特的食物，两种药物均可预防肿瘤转移，并延长其生存期。这些结果表明，普仑司特可抑制肿瘤细胞通过脑毛细血管和外周毛细血管的迁移，而孟鲁司特仅抑制肿瘤细胞在外周毛细血管的迁移。
