The interaction between metastasizing tumor cells and the hemostatic system of the host has been implicated in successful tumor cell dissemination. Prostacyclin (PGI2) decreases metastasis from tail vein injected B16 amelanotic melanoma (B16a) cells when administered 15 min prior to tumor cells. This effect is potentiated by a phosphodiesterase inhibitor. Initial trapping of 125I Udr labelled tumor cells in pulmonary vascular beds is unaltered by PGI2 but retention time is decreased. PGI2 decreases retention time even when administered 60 min post tumor cells. Structurally unrelated thromboxane (TX) synthetase inhibitors and a TXA2 receptor antagonist also reduce metastasis from tail vein injected B16a cells. Furthermore, one inhibitor, 1-(7-carboxyheptyl)imidazole, when injected intraperitoneally reduced spontaneous metastasis from subcutaneous B16a and Lewis lung carcinoma tumors. These results suggest that selective manipulation of PGI2 and TXA2 can reduce the hematogenous spread of tumor cells.
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Bastida, E., Ordinas, A., and Jamieson, G. A., 1981, Idiosyncratic platelet responses to human tumour cells. Nature, (London), 291, 661–662.
Brain, M. C., Azzopardi, J. G., Baker, L. R. I., Pinco, G. F., Roberts, P. D., and Dacic, J. V., 1970, Microangiopathic haemolytic anemia: the possible role of vascular lesion in pathogenesis. British Journal of Haematology, 18, 183–190.
Carreras, L. O., Chamone, D. A. F., Klercky, P., and Vermylen, J., 1980, Decreased vascular prostacyclin (PGI2) in diabetic rats. Stimulation of PGI2 release in normal and diabetic rats by the antithrombotic compound Bay g 6575. Thrombosis Research, 19, 663–671.
Curatolo, L., Colucci, M., Cambini, A. L., Poggi, A., Morasca, L., Donati, M. B., and Serjeraro, N., 1979, Evidence that cells from experimental tumours can activate coagulation factor X. British Journal of Cancer, 40, 228–233.
Donati, M. B., Davidson, J. F., and Carattini, S., 1981, Malignancy and the Hemostatic System (New York: Raven Press), pp. 138.
Donati, M. B., and Poggi, A., 1980, Malignancy and haemostasis. British Journal of Haematology, 44, 173–182.
Dvorak, H. F., Quay, S. C., Orenstein, N. R., Dvorak, A. M., Hahn, P., and Bitzer, A. M., 1981, Tumor shedding and coagulation. Science, 212, 923–924.
Elias, E. G., Sepulveda, F., and Mink, I. B., 1973, Increasing the efficiency of cancer chemotherpy with heparin: Clinical study. Journal of Surgical Oncology, 5, 189–193.
[9]Fling, T. E., Honn, K. V., Busse, W. D., Suter, F., and Marnett, L. J., 1982, Stimulation of PGI2 biosynthesis by nafazatrom (Bay g 6575). Prostaglandins and Cancer, edited by T. J. Powles, R. S. Bockman, K. V. Honn and P. W. Ramwell (New York: Alan Liss, Inc.), pp. 783–788.
Fantone, J., Kunkel, S., and Varani, J., 1982, Inhibition of tumor cell adherence by prostaglandins. Prostaglandins and Cancer, edited by T. J. Powles, R. S. Bockman, K. V. Honn and P. W. Ramwell (New York: Alan Liss, Inc.), pp. 673–678.
Fidler, I. J., 1978, General considerations for the studies of experimental cancer metastases. Methods of Cancer Research, 25, 399–439.
Fitzpatrick, F. A., Bundy, G. L., Gorman, R. R., and Honohan, R., 1978, 9,11-Epoxyiminoprosta-5,13-dienoic acid is a thromboxane A2 antagonist in human platelets. Nature, (London), 275, 765–766.
Fitzpatrick, F. A., Bundy, G. L., Gorman, R. R., Honahan, R., McGuire, J., and Sun, F., 1979, 9,11-Iminoepoxyprosta-5,13-dienoic acid is a selective thromboxane A2 synthetase inhibitor. Biochimica et biophysica acta, 573, 238–244.
Fitzpatrick, F. A., and Gorman, R. R., 1978, A comparison of imidazole and 9,11azoprosta-5,13-dienoic acid. Two selective thromboxane synthetase inhibitors. Biochimica et biophysica acta, 539, 162–172.
Fulco, G., Granstrom, E., and Kindahl, H., 1977, Albumin stabilizes thromboxane A2. FEBS Letters, 82, 321–326.
Gasic, G. J., Boettiger, D., Catalfamo, J. L., Gasic, T. B., and Stewart, G. J., 1978, Aggregation of platelets and cell membrane vesiculation by rat cells transformed in vitro by Rous Sarcoma virus. Cancer Research, 38, 2950–2955.
Gasic, G. J., Gasic, T. B., Galanti, N., Johnson, T., and Murphy, S., 1973, Platelet-tumor cell interactions in mice. The role of platelets in the spread of malignant disease. International Journal of Cancer, 11, 704–718.
Gasic, G. J., Gasic, T. B., and Jimenez, S. A., 1977, Platelet aggregating material in mouse tumor cells. Laboratory Investigation, 36, 413–419.
[19]Gasic, G. J., Gasic, T. B., and Stewart, C. C., 1968, Antimetastatic effects associated with platelet reduction. Proceedings of the National Academy of Sciences of the United States of America, 61, 46–52.
Gastpar, H., 1977, Platelet-cancer cell interaction in metastasis formation: a possible therapeutic approach to metastasis prophylaxis. Journal of Medicine (Westbury, New York), 8, 103–114.
Gordon, S. G., and Cross, B. A., 1981, A factor X-activating cysteine protease from malignant tissue. Journal of Clinical Investigation, 67, 1665–1671.
Gordon, S. G., Franks, J. J., and Lewis, B., 1975, Cancer procoagulant A: A factor X activating procoagulant from malignant tissue. Thrombosis Research, 6, 127–137.
Harker, L. A., and Slighter, S. J., 1972, Platelet and fibrinogen consumption in man. New England Journal of Medicine, 287, 999–1005.
Honk, K. V., 1982, Prostacyclin/thromboxane ratios in tumor growth and metastasis. Prostaglandins and Cancer, edited by T. J. Powles, R. S. Bockman, K. V. Honn and P. W. Ramwell (New York: Alan Liss, Inc.), p. 733.
Honn, K. V., Cigone, B., and Skoff, A., 1981, Prostacyclin: a potent antimetastatic agent. Science, 212, 1270–1272.
Karpatkin, S., Smerling, A., and Pearlstein, E., 1980, Plasma requirement for the aggregation of rabbit platelets by an aggregating material derived from SV40-transformed 3T3 fibroblasts. Journal of Laboratory and Clinical Medicine, 96, 994–1001.
Kramer, R. H., and Nicolson, G. L., 1979, Interactions of tumor cells with vascular endothelial cell monolayers: a model for metastatic invasion. Proceedings of the National Academy of Sciences of the United States of America, 76, 5704–5708.
Lione, A., and Bosmann, H. B., 1978, The inhibitory effect of heparin and warfarin treatments on the intravascular survival of B16 melanoma cells in syngeneic C57 mice. Cell Biology, International Report, 2, 81–86.
Maat, B., and Hilgard, P., 1981, Anticoagulant and experimental metastases — evaluation of antimetastatic effects in different model systems. Journal of Cancer Research Clinical Oncology, 101, 275–283.
Menter, D., Neagos, G., Dunn, J. R., Palazzo, R., Tchen, T. T., Taylor, J. D., and Honn, K. V., 1982, Tumor cell induced platelet aggregation: inhibition by prostacyclin, thromboxane A2 and phosphodiesterase inhibitors. Prostaglandins and Cancer, edited by T. J. Powles, R. S. Bockman, K. V. Honn and P. W. Ramwell (New York: Alan Liss), p. 809.
Moncada, S., and Vane, J. R., 1977, The discovery of prostacyclin—a fresh insight into arachidonic acid metabolism. Biochemical Aspects of Prostaglandin and Thromboxane Research, edited by N. Kharasch and J. Fried (New York: Academic Press), pp. 155–177.
Pearlstein, E., Amrrogio, L., Gasic, G., and Karpatkin, S., 1981, Inhibition of the platelet-aggregating activity of two human adenocarcinomas of the colon and an anaplastic murine tumor with a specific thrombin inhibitor, dansylarginine N-(3-ethyl-1,5-pentanediyl) amide. Cancer Research, 41, 4535–4539.
Pearlstein, E., Cooper, L. B., and Karpatkin, S., 1979, Correlation between spontaneous metastatic potential, platelet-aggregating activity of cell surface extracts, and cell surface sialvlation in 10 metastatic-variant derivatives of a rat renal sarcoma cell line. Journal of Laboratory and Clinical Medicine, 93, 332–244.
Pearlstein, E., Salk, P. L., Yogeeswaran, G., and Karpatkin, S., 1980, Correlation between spontaneous metastatic potential, platelet-aggregating activity of cell surface extracts, and cell surface sialylation in 10 metastatic-variant derivatives of a rat renal sarcoma cell line. Proceedings of the National Academy of Science of the United States of America, 77, 4336–4339.
Roos, E., and Dingemans, K. S., 1979, Mechanisms of metastasis. Biochimica et biophysica acta, 560, 135–166.
Salmon, J. A., Smith, D. R., Flower, R. J., Moncada, S., and Vane, J. R., 1978, Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin by porcine aorta microsomes. Biochimica et biophysica acta, 523, 250–262.
Seuter, F., Busse, W. D., Meng, K., Hosmeister, F., Moller, E., and Horstmann, H., 1979, The antithrombotic activity of Bay g 6576. Arzneim-Forschung/Drug Research, 29, 54–59.
Skolnik, G., Alpsten, M., and Ivarsson, L., 1980, Studies on mechanisms involved in metastatis formation from circulating tumor cells. Journal of Cancer Research and Clinical Oncology, 97, 249–256.
Sloane, B. F., Dunn, J. R., and Honn, K. V., 1981, Lysosomal cathepsin B: correlation with metastatic potential. Science, 212, 1151–1153.
Smith, J. B., 1980, The prostanoids in hemostasis and thrombosis. American Journal of Pathology, 99, 743–804.
Vargaftig, B. B., Chignard, M., and Benveniste, J., 1981, Present concepts on the mechanism of platelet aggregation. Biochemical Pharmacology, 30, 263–271.
Vermylen, J., Chamone, D. A. F., and Verstraete, M., 1979, Stimulation of prostacyclin release from vessel wall by Bay g 6575. Lancet, 1, 518–520.
Warren, B. A., and Vales, O., 1972, The adhesion of thromboplastic tumour emboli to vessel walls in vivo. Journal of Experimental Pathology, 53, 301–313.
Weiss, S. J., Turk, J., and Needleman, P., 1979, A mechanism for the hydroperoxide mediated inactivation of prostacyclin synthetase. Blood, 53, 1191–1196.
Wood, S., 1971, Mechanisms of establishment of tumor metastases, Pathobiology Annual, Volume 1, edited by H. L. Ioachim (London: Butterworths), p. 281.
Yoshimoto, T., Yamamoto, S., and Hayaishi, V., 1978, Selective inhibition of prostaglandin endoperoxide thromboxane isomerase by 1-carboxyalkyl-imidazoles. Prostaglandins, 16, 529–540.
Zacharski, L. R., Henderson, W. G., Rickles, F. R., Forman, W. B., Cornell, Jr., C. J., Forcier, R. J., Harrower, H. W., and Johnson, R. O., 1979, Platelets and malignancy: rationale and experimental design for the VA cooperative study of RA-233 in the treatment of cancer. Cancer, 44, 732–741.
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Honk, K.V. Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system. Clin Exp Metast 1, 103–114 (1983). https://doi.org/10.1007/BF00121490
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DOI: https://doi.org/10.1007/BF00121490