PO-34 - Optimal doses of tinzaparin to reduce both cancer-associated thrombosis and tumor growth in a mouse model of ectopic pancreatic syngeneic tumor
Résumé
In clinical studies, thromboprophylaxis with low-molecular-weight heparins (LMWHs) has been demonstrated to reduce the risk of venous thromboembolism and to improve outcomes in cancer patients. Moreover, preclinical models have previously suggested that LMWHs may also offer additional benefits through direct antitumor properties. However, the optimal doses of LMWHs that may prevent both cancer-related thrombosis and tumor development are yet unknown.
The goal of this study was to determine the optimal doses of tinzaparin that may prevent both cancer-related thrombosis and tumor development in a syngeneic ectopic model of pancreatic cancer.
The optimal doses of tinzaparin to generate a plasma anti-Xa activity >0.2IU/mL were determined in vivo following injection into wild type mice.The syngeneic ectopic model of cancer was induced in wild-type mice using the mouse pancreatic cancer cell line Panc02. Mice were injected daily with 200, 300IU/kg or 400IU/kg, or placebo from day 8 to 25 following tumor induction. Kinetics of thrombus formation and fibrin generation were determined in real time by digital real time intravital microscopy in mice bearing a tumor treated with tinzaparin or placebo. The growth of the tumor and the bleeding times were measured and compared in the different groups of mice.
Plasma anti-Xa levels <0.2IU/mL were observed with tinzaparin doses ranging from 0 to 150IU/kg, whereas plasma anti-Xa activities >0.2IU/mL were obtained with >200IU/kg tinzaparin doses. At day 25 following tumor induction, the kinetics of thrombosis were not affected in mice treated with daily 200IU/kg tinzaparin compared to controls whereas it was strongly affected in mice treated with daily 300 and 400IU/kg tinzaparin. Interestingly, a significant decrease in tumor growth was observed in mice treated with 200, 300 and 400IU/kg tinzaparin in comparison to controls, with no significant difference between these groups. Bleeding times were similar to control mice in mice treated with 200IU/kg tinzaparin, but significantly increased in mice treated with 300IU/kg and 400IU/kg tinzaparin.
At the dose of 200IU/kg, tinzaparin treatment significantly inhibits tumor growth but did not affect the thrombotic phenotype in mice developing a cancer. When 300 and 400IU/kg dose are used, tinzaparin treatment decreases both cancer-related thrombotic phenotype and tumor growth, but at the price of a significant increase in the bleeding time.