N. SAITO1, T. Uwagawa1, H. Shiba1, R. Hamura1, N. Takada1, H. Sugano1, T. Horiuchi1, Y. Shirai1, T. Ohashi1, K. Yanaga1, K. Yanaga1 1Jikei University School Of Medicine,Department Of Surgery,Minato-ku, TOKYO, Japan
Introduction: Liver metastasis is a significant clinical problem early after resection of pancreatic cancer. Kocherization during early phase of the operation for pancreatic cancer prohibits the use of no-touch isolation, when tumor cells may dislodge, implant and settle in the liver through the portal vein. Matrix metalloproteinase (MMP)-2/9 degrades basement membrane and makes the tumor more susceptible to infiltration. FUT 175, a serine protease inhibitor, is known to inhibit MMP-2/9 by suppressing the NF-kB signal. Therefore, we hypothesized that preoperative treatment by FUT 175 may prevent hepatic metastasis and prolong postoperative survival of patients with post-resectional pancreatic cancer.
Methods: In vitro, we used a mouse pancreatic cancer cell line (PAN02). Between control and FUT 175 treatment groups, cell viability was examined by MTT assay, and the levels of cytoplasm MMP-2/9 were evaluated by Western blotting. Furthermore, activation levels of MMP-2/9 in supernatant of cultured cells were investigated by gelatin zymography. In vivo, 1´106 PAN02 cells were injected into the spleen of the mouse (C57BL6) to produce liver metastases. In treatment group, PAN02 cells were treated with FUT 175, as compared to vehicle alone in control group. The volume of liver metastasis was assessed by MRI once a week. After sacrifice, metastatic tumors were evaluated by various assays. Also, survival rates were compared.
Results: FUT 175 did not suppress the viability of PAN02 cells for the first 24 h of treatment (p>0.05). However, the levels of cytoplasmic MMP-2/9 were down-regulated by FUT 175 after 24 h of treatment. In vivo, for control group, all animals died within 7 weeks after injection (n=10), for which MRI revealed rapid growth of metastatic tumors. On the contrary, the tumor growth rates of treatment group were very slow, and 4 of 10 animals (40%) were alive for over 7 weeks.
Conclusion: Because of suppression of the level of MMP-2/9 in vitro and prolonged survival of liver metastasis of pancreatic cancer in mice, FUT 175 may prevent liver recurrence after pancreatectomy.