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Augmentation of the Antimetastatic Effect of Anticoagulant Drugs by Immunostimulation in Mice

Biological Therapeutics Branch, Biological Response Modifiers Program, Division of Cancer Treatment, National Cancer Institute-Frederick Cancer Research Facility, Frederick, Maryland 21701

The effect of anticoagulant drugs on formation of experimental tumor metastases after i.v. inoculation of BL6 melanoma or Lewis lung carcinoma (3LL) cells was studied in mice with stimulated or depressed natural killer (NK) cell activity.

When mice were treated with anticoagulants (warfarin or heparin) or when NK cell activity was stimulated by polyinosinic-polycytidylic acid, significant antimetastatic effects were observed; these effects were substantially augmented when the treatments were combined. However, when NK reactivity of mice was suppressed by anti-asialo G_M1 serum or cyclophosphamide, the antimetastatic effects of warfarin and heparin were diminished or completely abrogated.

In some experiments, the anticoagulants had a partial effect in mice treated with cyclophosphamide or anti-asialo G_M1 serum and reduced at least to control levels the number of metastases in these mice. This limited antimetastatic effect of the anticoagulants was mostly due to the action of residual NK cells, since it was completely abrogated in mice whose NK cell activity was more completely suppressed by two injections of anti-asialo G_M1 serum. In addition, the low NK reactivity of 3-week-old C57BL/6 or beige mice was sufficient to support the antimetastatic effects of the anticoagulants, effects that completely disappeared after these mice were treated with anti-asialo G_M1 serum. Augmentation or abrogation of the antimetastatic effects of heparin after polyinosinic-polycytidylic acid or anti-asialo G_M1 treatments, respectively, was observed in athymic nude and allogeneic BALB/c mice that received i.v. injections of B16F1 melanoma cells, indicating that the antimetastatic effects of anticoagulants depend on the presence of active NK rather than T-cells. Furthermore, adoptive transfer of NK-competent but not NK-depleted syngeneic spleen cells restored the antimetastatic effect of heparin in cyclophosphamide-treated mice. Warfarin treatment increased the elimination of radiolabeled BL6 melanoma cells from the lungs of normal mice, and the rate of tumor cell elimination was further potentiated when NK cell activity was stimulated by polyinosinic-polycytidylic acid. In contrast, after anti-asialo G_M1 treatment, warfarin had no effect on the survival of i.v. administered tumor cells. Covering of YAC-1 or 3LL tumor cells with fibrin after in vitro exposure with fibrinogen and thrombin substantially protected them from the in vitro cytotoxic action of NK or lymphokine-activated killer cells.

Thus, fibrin deposition on tumor cells during their migration in the blood could protect them from elimination by NK or other cytotoxic cells. Anticoagulant drugs might prevent fibrin coating of the tumor cells and increase efficiency of tumor cell elimination by immune effector cells.

¹ To whom requests for reprints should be addressed. Present address: Pittsburgh Cancer Institute, 230 Lothrop Street, Pittsburgh, PA 15213.

Received 3/14/86. Revised 9/17/86. Revised 10/28/86. Accepted 10/30/86.

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