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.
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.


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 10mg 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.


CONCLUSIONS
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.
Kilian
M
M
Clinic of General, Visceral, Vascular and Thoracic Surgery, Charité Campus Mitte, Universitätsmedizin in Berlin, Schumannstr. 20/21, 10117 Berlin, Germany. isletcell@aol.com
Gregor
J I
JI
Heukamp
I
I
Hanel
M
M
Ahlgrimm
M
M
Schimke
I
I
Kristiansen
G
G
Ommer
A
A
Walz
M K
MK
Jacobi
C A
CA
Wenger
F A
FA
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D021441:Carcinoma, Pancreatic Ductal / Q000139:chemically induced / Q000201:enzymology / Q000556:secondary*; D006224:Cricetinae; D004195:Disease Models, Animal; D008113:Liver Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D061965:Matrix Metalloproteinase Inhibitors; D008647:Mesocricetus; D009602:Nitrosamines / Q000633:toxicity; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D010879:Piperazines / Q000008:administration & dosage*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage*
D002273:Carcinogens; D061965:Matrix Metalloproteinase Inhibitors; D009602:Nitrosamines; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; C453902:Ro 28-2653; C013622:nitrosobis(2-oxopropyl)amine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9