Effect of Warfarin, Warfarin Enantiomers and Defibrase on Lewis Lung Carcinoma Metastasis Growth in Mice

Abstract

The Lewis Lung Carcinoma (3LL) is a spontaneously metastasizing tumor, the development of which is eccompanied by marked hemostatic changes. Acceleration of labelled fibrinogen turnover and fibrin accumulation at the tumor and metastasis sites have been observed in 3LL bearing mice. Both the number and the weight of lung metastases were significantly lower in mice anti-coagulated with racemic sodium warfarin during the whole tumor development period (prothrombin complex activity around 20%). This treatment had less effect on the primary tumor. The anti-metastatic effect was slightly greater with larger doses of warfarin, which lowered the prothrombin complex activity to less than 5%. Continuous anticoagulation also protected the animals from pulmonary growth of blood-borne tumor emboli following intravenous injection of 3LL cells. This effect appeared to be closely associated with the anticoagulant activity of warfarin; indeed experiments performed with the resolved warfarin enantiomers showed that R-warfarin had virtually no anticlotting activity in mice and did not modify the metastatic growth of 3LL cells; the opposite was true for S-warfarin.Lung metastasis growth was increased in mice kept defibrinogenated during the whole period of tumor development by treatment with batrcxobin; in contrast, in mice kept defibrinated only during the period of metastasis growth, with or without surgical removal of the primary tumor, metastasis formation was slightly decreased. This suggests that fibrin may play different roles in various phases of metastaticspreading of the same tumor.