위암에서 ex vivo Model 을 이용한 MMP - 9 에 대한 Gabexate Mesylate IC50의 응용 : 예후인자 및 치료대상 선정기준

Abstract

Purpose: Among the many biological characteristics of cancer, matrix metalloproteinases (MMPs) are essential for tumor invasion and metastasis. The correction of the imbalance between MMPs and tissue inhibitors of matrix metalloproteinase (TIMP) has been suggested as a possible goal for the control of invasive phenotype of the cancer. To test the possible inhibition of MMP-9 in ex vivo model and the selection of the patients who are sensitive to MMP inhibitory (MMPI) treatment, we evaluated IC50 of the gabexate mesylate (Foy) against MMP-9 and compared them to the clinical parameters and patients survivals. Materials and Methods: Thirty-four paired normal and gastric cancer tissues were tested for the IC50 of the gabexate mesylate. MMP-9 activity was measured by zymography. Results: MMP-9 expression (percent of sample band density to control band) (p=0.04) and IC50 (p=0.02) of cancer tissues were significantly higher than those of normal tissues. Cancer tissue IC50 was higher than that of normal tissues in cases when the tumor mass diameter was longer than 5 cm (p=0.03) as well as in higher T-stage (p=0.04), lymph node metastasis (p=0.04) and in advanced stages (p=0.04). There was a tendency of increased IC50 of diffuse and mixed type than that of intestinal type (diffuse & mixed: 11.0±20.8 mg/ml, intestinal: 2.7±3.9 mg/ml; p 0.07), in spite of no difference in MMP-9 expression (diffuse & mixed: 40.3+49.2%, intestinal: 51.0±58.0%). In early gastric cancer (EGC), there was no difference in IC50 between normal and cancer tissues whereas cancer tissue IC50 was higher than that of normal tissue in advanced gastric cancer (p 0.02). There was a tendency of increment of ICo in cancer tissues of advanced gastric cancer than that of EGC whereas no difference was found in MMP-9 expression between these types of cancers. Poor prognosis was found in high IC50 patients in curatively resected patients (p=0.04). In multivariate analysis, high IC50 was suggested as a possible independent prognostic factor. Conclusion: We could differentiate the high risk patients using IC50 of gabexate mesylate in ex vivo model. This model can be applied in detecting patients with poor prognosis and patients who can have a possible benefit with MMPI treatment.