Abstract C183: Antitumor efficacy of PEG-Hirudin (LU 87981), administered three times weekly, in an orthotopic AsPC-1 pancreas carcinoma model
Authors: Esser Norbert , Fiedler Ulrike , Graeser Ralph , Yu Tony , Mueller Iris , Schaechtele Christoph 
Published: June 2012

Background: Since anticoagulants could be shown as promising novel therapeutics in oncology, direct thrombin inhibitors like recombinant Hirudin (Revasc©/desirudin) were assessed in a preclinical orthotopic AsPC-1 mouse model in vivo. The challenges of desirudin for the treatment of cancer are its complex pharmacodynamics and a short half life (mean elimination half-life of 2–3h), requiring at least twice daily subcutaneous administration of the drug. PEG-Hirudin, the conjugate of recombinant Hirudin with two molecules of polyethylene glycol (PEG)-5000 represents a potential alternative to Revasc© with a longer half-life and more stable plasma levels. In order to test this compound, the pancreatic cancer cell line, AsPC-1 was chosen, for which preliminary results with Revasc© were available. AsPC-1 cells implanted orthotopically into the mouse pancreas reflect hallmarks of the human disease such as early invasion of the surrounding pancreatic tissue and the formation of metastases in the spleen and liver as well as the peritoneum.

Material and Methods: Luciferase expressing AsPC-1 cells were orthotopically implanted into mouse pancrei. The growth of the tumors was followed via bioluminescence measurements (whole body imaging). 13 days after surgery, 12 animals each were randomized into 5 treatment groups according to their bioluminescence signal. Group 1 served as vehicle control receiving 100µl saline solution three times weekly s.c. from day 15 to day 38. The application scheme was comparable to treatment groups receiving 1mg/kg (group 3), 3 mg/kg (group 4) and 0.3mg/kg (group 5) PEG-Hirudin three times weekly s.c. starting at day 15. The animals of group 2 received Gemcitabin at 240mg/kg administered i.v. once weekly starting at day 15. 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).

Results: PEG-Hirudin was well tolerated, no bleeding at the injection site or other side effects could be observed. Only one animal of group 4 was found dead during the study, all other animals reached the end of the study. Gemcitabin, did not affect tumor growth according to in vivo bioluminescence imaging, whereas PEG-Hirudin at 1 and 3 mg reduced the increase of the bioluminescence signal during the treatment period significantly. Once the animals were sacrificed and tumor sizes measured, treatment with PEG-Hirudin at 1 and 3 mg/kg showed significant reduction of the average primary tumor size (Group 3: *p= 0.0129, Group 4:**p=0.0015). The positive control, Gemcitabin showed as well a significant antitumor efficacy (***p=0.0002). The differing results of in vivo imaging and primary tumor sizes are reflecting the different efficacy of the test items on primary tumor and peritoneal metastases.

Conclusion: The results presented here suggest a promising anti-tumoral efficacy of the PEG-Hirudin compound. Due to its extended half-life and the resulting relaxation of the application scheme, PEG-Hirudin is a promising alternative to Revasc© (desirudin) in oncology.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C183.