Abstract C187: Antitumoral efficacy of the novel thrombin inhibitor Revasc©/Desirudin in an orthotopic metastatic AsPC-1 pancreas tumor model
Authors: Esser Norbert , Fiedler Ulrike , Graeser Ralph , Yu Tony , Mueller Iris , Schaechtele Christoph 
Published: June 2012

Abstract
Background: Thrombo-embolism is one of the most common secondary diseases in cancer patients and is the second leading cause of death of these patients. In pancreatic cancer patients, thrombosis occurs more frequently than in other cancer patients. Thus anticoagulants are widely used in cancer therapies mainly to prevent the development of thrombo-embolisms. However there is increasing evidence that anticoagulants have also antitumoral and anti-angiogenic effects. The aim of this study was to evaluate the anti-tumoral, anti-metastatic and anti-angiogenic efficacy of the novel anticoagulant Revasc© a recombinant hirudin and direct thrombin inhibitor, in an orthotopic mouse model of pancreatic cancer.
Material and Methods: To evaluate the anti-tumoral, anti-metastatic and anti-angogenic efficacy of Revasc©, luciferase labeled pancreatic AsPC-1-tumor cells were orthotopically implanted into the pancreas of NMRI nude mice. After onset of tumor growth, mice were randomized into six groups. Group 1 received vehicle control (0.9% NaCl) twice daily, Group 2 received Gemcitabine (240 mg/kg) once weekly; Group 3 received Revasc at a concentration of 1 mg/kg twice daily, Group 4 received Revasc© at a concentration of 3 mg/kg twice daily, Group 5 received Revasc© at a concentration of 10 mg/kg daily and Group 6 received a combination therapy of twice daily 10 mg/kg Revasc© plus a weekly dose of 240 mg/kg Gemcitabine. At the end of the study, tumor weight and volume were determined and luciferase activity was monitored in the primary tumor and selected organs (spleen, liver, stomach, intestine, lung and inguinal lymph nodes). In addition, microvessel densities and vessel maturation was determined by immunohistochemisty.
Results: In general, Revasc© was very well tolerated. The primary tumor weight was significantly reduced in the groups receiving Revasc© at a concentration of 3 mg/kg and 10 mg/kg as well as in the control group treated with Gemcitabine. The combination of Gemcitabine and Revasc©, however, did not show any additive effect. No significant reduction of metastasis could be observed in the Revasc© Groups, whereas Gemcitabine efficiently inhibited metastasis into the lung. However, Revasc© showed a significant anti-angiogenic potential at the lowest concentration of 1mg/kg, corroborating findings of other groups showing that thrombin inhibition acts anti-angiogenic.
Conclusion: Taken together the study showed that Revasc© has an anti-tumoral and a mild anti-angiogenic effect. The data suggest that Revasc© has a potential to be used for the treatment of patients with pancreatic cancers; primarily to prevent thromboembolism but secondarly also to inhibit tumor growth. It remains to be shown if Revasc will lead to a solid anti-tumoral effect in patients and if the relatively short mean elimination half life of Revasc© (2–3 h) will allow to identify a convenient dosing scheme. Alternatively a pegylated hirudin derivative (PEG-hirudin) which has a longer half life and which has proven to have a very efficient antitumoral activity could be of high therapeutic interest.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C187.