The Experimental Research for Analysis and Treatment of Invasion of Ora Cancer. (Inhibitory effects regarding MMP production as target.)

口腔癌侵袭分析及治疗的实验研究。

• 批准号: 11671987
• 负责人: NISHIYAMA Akiyoshi
• 金额: $ 1.86万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671987/
• 关键词: MMP; Invasion; MMP Inhibitor; Orthotopic implantation; 口腔癌; MMP阻害剤; 転移

Invasion and metastasis are the most important and complex factors determining cancer treatment. Many studies have shown that some matrix metalloproteinases (MMPs) play essential roles in tumor metastasis and invasion. Recently, some MMP inhibitors have been developed and would be expected to limit the tumor growth and formation of metastasis. MMI-166, is a newly developed MMPs inhibitor that can be administered orally and has a more potent and selective inhibitory activit of MMP-2 and MMP-9, both related to tumor invasion and metastasis. We examined the effect of MMP inhibitor, MMI-166, in an experimental tongue cancer model in nude mice using human oral cancer cells.Experimental tongue cancer model was obtained by the injection of human oral cancer cell line, HSC-3 producing MMP-2 and MMP-9, into the tongue of nude mice. From the same day, MMI-166 (1.8 mg/mouse/day) was orally administered once a day for 12 days. The control group received normal saline solution instead of MMI-166. The tumor size was evaluated by the method described by Kikuchi et al. and the mode of invasion was determined by histological evaluation.The MMI-166 treated animals presented tumors 60% smaller than the MMI-166-untreated group. Histological examination of the tongue of the untreated group revealed that tumor aggressively invaded into the surrounding muscle and blood vessels. On the other hand, MMI-166 inhibited the invasion of cancer cells and no infiltrating cells were observed in the tumor margins. MMI-166 did not inhibit the growth of HSC-3 cancer cells in vitro. These results suggested that the inhibitory activity of MMI-166 for the tumor growth at tongue should be due to the inhibition of matrix metalloproteinases but the direct anticancer activity.The anti-cancer drug without cytotoxic effects MMI-166 is potentially effective for the treatment of human oral cancer.

侵袭和转移是决定癌症治疗的最重要和最复杂的因素。许多研究表明，一些基质金属蛋白酶（MMPs）在肿瘤的转移和侵袭中起重要作用。最近，已经开发了一些MMP抑制剂，并且预期其将限制肿瘤生长和转移的形成。MMI-166是一种新型的MMPs抑制剂，口服给药后对与肿瘤侵袭和转移相关的MMP-2和MMP-9具有更强的抑制活性和选择性。本研究采用人口腔癌细胞株HSC-3，经舌内注射MMP-2和MMP-9，建立裸鼠实验性舌癌模型，观察MMP抑制剂MMI-166对裸鼠实验性舌癌的影响。从同一天开始，每天一次经口给予MMI-166（1.8 mg/小鼠/天），持续12天。对照组接受生理盐水溶液代替MMI-166。通过菊池等人描述的方法评价肿瘤大小，并通过组织学评价确定侵袭模式。未治疗组的舌组织学检查显示肿瘤侵袭周围的肌肉和血管。另一方面，MMI-166抑制癌细胞的侵袭，并且在肿瘤边缘中没有观察到浸润细胞。MMI-166在体外对HSC-3癌细胞的生长无抑制作用。提示MMI-166对舌部肿瘤生长的抑制作用可能是通过抑制基质金属蛋白酶而不是直接的抗癌作用，MMI-166是一种无细胞毒性的抗癌药物，对口腔癌有潜在的治疗作用。