Antimetastatic effects of heparin and warfarin was demonstrated against various tumor cell lines Bl6Fl0, BL6 melanoma cells, Lewis lung carcinoma (3LL), Madison lung carcinoma M109. The antimetastatic effects of the anticoagulant agents can be enhanced by stimulation of the host NK reactivity by poly I:C treatment. In contrast, depression of NK cell function by cyclophosphamide (Cy) or anti-asialo GMI serum abrograted the antimetastatic effects of heparin or warfarin. In some experiments, this abrogation was partially due to the effect of the residual NK cells surviving after l injection of Cy or anti-asialo GMl serum. Antimetastatic effects of the anticoagulants completely disappeared after 2 treatments with Cy or antiserum. Since young (3 weeks old) C57BL/6 or beige mice have some NK reactivity, the heparin and warfarin exerted the antimetastatic activity in these mice which disappeared after one injection of anti-asialo GM1 serum. The importance of NK cells in the antimetatic effects of the anticoagulant drugs supports by the fact that restoration of NK reactivity of Cy treated mice after adoptive transfer normal spleen cells associated with the restoration of the antimetastatic effects of heparin. However, spleen cells of mice with depleted NK function after anti-asialo GM1 treatment failed to reconstitute NK reactivity of the recipient mice as well as the antimetastatic activity of heparin. These results indicate that fibrin coagulation on the tumor cells may be one of the mechanisms responsible for the in vivo tumor cell protection. Anticoagulant drugs make tumor cells more vulnurable to the destruction by NK (or other cytotoxic) cells. These data shed new light on the understanding of the mechanisms of the antimetastatic effects of the anticoagulant drugs and the in vivo role of natural cell-mediated immunity.
