Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: Inhibition of matrix metalloproteinases in pancreatic cancer

Abstract

Background

Matrix metalloproteinases (MMP) are proteolytic enzymes which degrade the extracellular matrix and therefore play an important role in metastasis. However, the impact of MMP inhibitors (MMPI) on pancreatic cancer is still unclear. Thus we evaluated the influence of selective MMPI Ro 28-2653 on the incidence of liver metastases and the concentration of MMP-2 and MMP-9 in ductal pancreatic adenocarcinoma in Syrian hamster.

Material and methods

One hundred and thirty male Syrian hamsters were randomised into 8 groups (Gr.1–3: $n=15$, Gr.4–8: $n=17$). Pancreatic cancer was induced by weekly subcutaneous injection of 10 mg N-nitrosobis-2-oxopropylamin (BOP)/kg body weight (Gr.4–8) while healthy control 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, which increases liver metastasis in this model. In week 17 oral therapy started: Gr.3 and 6: 60 mg Eudragit/kg body weight/d (vehicle of MMPI), Gr.7 and 8: 40 mg, respectively, 120 mg RO 28-2653/kg body weight/d; Gr.1, 2, 4, 5: no therapy. After 30 weeks all hamsters were sacrificed and histopathologically examined. Additionally concentrations of MMP-2 and MMP-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 reduced by low-dose therapy with Ro 28-2653.

Conclusion

Low-dose therapy with Ro 28-2653 decreased liver metastasis due to an inhibition of MMP-2 and MMP-9 concentration in ductal pancreatic cancer.

Introduction

Pancreatic cancer is the fifth leading cause for death of malignancies in Europe and the USA [1], [2] with a median survival time less than 6 months [3], [4], [5], [6]. Even after resection survival rates are low because of local recurrence and hepatic metastasis. Although several predispositional factors for pancreatic cancer like tobacco or alcohol have been identified, the pathomechanism of carcinogenesis is still unclear [4], [5], [6], [7].

However, the structure of the basement membrane is supposed to play an important role in liver metastasis. Thus matrix metalloproteinases (MMP) [8], a group of calcium-depending secreted and membrane-bound zinc-endopeptidases (gelatinases, collagenases, stromelysins and membrane-bound matrix metalloproteinases), have a central position in the degradation of the extra cellular matrix (ECM) including tissue remodelling, inflammatory cell invasion, organogenesis, angiogenesis, wound healing, bone resorption, trophoblast invasion and adipogenesis [9]. Accordingly MMP are also involved in the process of carcinogenesis due to a destruction of tissue integrity, metastatic spread and entry to blood and lymphatic systems. However, the balance of degrading processes and inactivity of MMP is controlled by four tissue inhibitors of metalloproteinases (TIMP). Moreover secreted pro-MMP have to be converted into active enzymes by proteolyses. Thus Gelatinase A (MMP 2) and B (MMP 9) degrade type-IV collagen, the major component of the basement membrane. Since MMP-2 and MMP-9 are overexpressed in ductal pancreatic cancer [10], [11], [12], [13], we evaluated the impact of synthetic MMPI RO 28-2653 with a high specifity towards MMP-2 and MMP-9 on the incidence of liver metastasis in a model of ductal pancreatic carcinoma in Syrian hamster [14], [15], [16], [17].