Bewirkt der hoch-selektive Matrix-Metalloproteinase-Inhibitor RO 28-2653 über eine Reduktion der Matrix-Metalloproteinasen −2 und −9 eine Verminderung des Tumorwachstums und der Lebermetastasierung beim duktalen Pankreaskarzinom im Syrischen Hamster?

Abstract

Background: Matrix metalloproteinases (MMP) are proteolytic enzymes which play an important role in the process of tumor growth and metastasis. Therapeutic effects of matrix metalloproteinase inhibitors (MMPI) on carcinogenesis were observed in several carcinomas. Therefore we evaluated the effect of matrix metalloproteinase inhibitor (MMPI) RO 28-2653 on the incidence of liver metastases and the concentrations of MMP 2 and MMP 9 in ductal pancreatic adenocarcinoma in Syrian hamster. Material and Methods: 130 male Syrian hamsters were randomised into 8 groups (gr. 1–3: n = 15, gr. 4–8: n = 17). In Gr.4–8 ductal pancreatic adenocarcinoma was induced for 10 weeks by weekly subcutaneous injection of 10mg N-nitrosobis-2-oxopropylamin (BOP)/kg body weight, while Gr.1–3 received 0,5 ml sodium chloride 0,9 %. Gr.1 and 4 had free access to a standard diet, Gr. 2, 3 and 5–8 received a diet rich in polyunsaturated fatty acids. Oral therapy started after 16 weeks: Gr.3 and 6: 60 mg Eudragit (vehicle of MMPI)/kg body weight/day; Gr.7 and 8: 40 mg respectively 120 mg RO 28-2653/kg body weight/day; Gr.1, 2, 4 and 5: Ø therapy. After 30 weeks all hamsters were sacrificed and histopathologically examined. Additionally concentrations of MMP 2 and 9 were measured in non-metastatic liver and liver metastases. Results: Concentrations of MMP-2 and MMP-9 in liver metastases were decreased by high and low dose therapy with MMPI. Furthermore the incidence of liver metastases was significantly decreased by low dose therapy with RO 28-2653. Conclusion: Low dose therapy with RO 28-2653 showed a decreased incidence of liver metastasis due to a reduction of MMP 2 and MMP 9 concentration in this animal model.