Abstract
The antimetastatic activity of the prostacyclin analog Iloprost has been examined in mice bearing Lewis lung carcinoma. An inhibition of lung colony formation is observed when 100 or 200μg/kg Iloprost are administered i.v. 1h before i.v. injection of tumor cells, which is dependent on the size of tumor inoculum. The effects of 200μg/kg Iloprost persist for 24 h, and are of the same magnitude as those obtained with 10 mg/kg prostacyclin, which last only for 30min. When treatment with Iloprost is followed by surgical removal of primary tumor, spontaneous metastasis formation is reduced, and the survival time of the treated animals is significantly increased over controls treated with surgery only. The antimetastatic effects of Iloprost appear dissociated from drug's effects on the hemostatic system of the host as indicated by the clot retraction assay, performed afterin vivo treatment, using ADP or tumor cells as platelet aggregating agents. Iloprost thus appears to reduce spontaneous metastasis formation and intraoperative tumor cell dissemination, with pharmacological properties more favourable to therapeutic use than those of prostacyclin.
Similar content being viewed by others
References
Belch, J. J. F., Greer, I., McLaren, M., Saniabadi, A. R., Miller, S., Sturrock, R. D., andForbes, C. D., 1984, The effects of intravenous ZK36-374, a stable prostacyclin analogue, on normal volunteers.Prostaglandins,28, 67–77.
Casals-Stenzel, J., Buse, M., andLosert, W., 1983, Comparison of the vasodepressor action of ZK 36 374, a stable prostacyclin derivative, PGI2 and PGE1 with their effect on platelet aggregation and bleeding time in rats.Prostaglandins Leukotrienes and Medicine,10, 197–212.
De Gaetano, G., Vermylen, J., andVerstraete, M., 1973, A simple indirect method to evaluate platelet aggregation. The clot retraction inhibition (CRI) test.Thrombosis et Diathesis Haemorragica (Stuttg.),29, 661–670.
Donati, M. B., Davidson, J. F., andGarattini, S., 1981,Malignancy and the Hemostatic System (New York: Raven Press).
Donati, M. B., Poggi, A., Mussoni, L., de Gaetano, G., andGarattini, S., 1977, Hemostasis and experimental cancer dissemination. In:Cancer Invasion and Metastasis: Biological Mechanism and Therapy edited by S. B. Day, W. P. L. Myers, P. Stansley, S. Garattini and M. G. Lewis (New York: Raven Press), pp. 151–160.
Gasic, G. J., 1984, Role of plasma, platelets, and endothelial cells in tumor metastasis.Cancer Metastasis Review,3, 99–116.
Gasic, G. J., Gasic, T. B., Galanti, N., Johnson, T., andMurphy, S., 1973, Platelettumor cell interactions in mice. The role of platelets in the spread of malignant diseases.International Journal of Cancer,11, 704–718.
Gasic, G. J., Gasic, T. B., andSteward, C. C., 1968, Antimetastatic effects associated with platelet reduction.Proceedings of the National Academy of Science USA,61, 46–52.
Geran, R. I., Greenberg, N. H., MacDonald, M. M., Schumacher, A. M., andAbbott, B. J., 1972, Protocols for screening chemical agents and natural products against animal tumors and other biological systems.Cancer Chemotherapy Reports, Part 3,3, 13.
Gorelik, E., 1987, Augmentation of the antimetastatic effect of anticoagulant drugs by immunostimulation in mice.Cancer Research,47, 809–815.
Gryglewski, R. J., andStock, G., 1987.Prostacyclin and its Stable Analogue Iloprost (Berlin: Springer-Verlag).
Hilgard, P., andThornes, R. D., 1976, Anticoagulants in the treatment of cancer.European Journal of Cancer,12, 755–762.
Honn, K. V., 1983, Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system.Clinical and Experimental Metastasis,1, 103–114.
Honn, K. V., Busse, W. D., andSloane, B. F., 1983, Prostacyclin and thromboxanesimplications for their role in tumor cell metastasis.Biochemical Pharmacology,32, 1–11.
Honn, K. V., Cicone, B., andSkoff, A., 1981, Prostacyclin: a potent antimetastatic agent.Science,212, 1270–1272.
Karpatkin, S., Ambrogio, C., andPearlsten, E., 1984, Lack of effect ofin vivo prostacyclin on the development of pulmonary metastases in mice following intravenous injection of CT26 colon carcinoma, Lewis lung carcinoma, or B16 amelanotic melanoma cells.Cancer Research,44, 3880–3884.
Kimura, A. K., Mehta, P., Xiang, J., Lawson, D., Dugger, D., Kao, K. J., andLee-Ambrose, L., 1987, The lack of correlation between experimental metastatic potential and platelet aggregating activity of B16 melanoma clones viewed in relation to tumor cell heterogeneity.Clinical and Experimental Metastasis,5, 125–133.
Krause, W., andKrais, Th., 1986, Pharmacokinetics and pharmacodynamics of the prostacyclin analogue iloprost in man.European Journal of Clinical Pharmacology,30, 61–68.
Maat, B., andHilgard, P., 1981, Anticoagulants and experimental metastases; evaluation of antimetastatic effects in different model systems.Journal of Cancer Research and Clinical Oncology,101, 275–283.
Maderna, P., Colli, S., Sirtori, C., Tremoli, E., andPaoletti, R., 1985, Control of human and animal platelet aggregation by a new prostacyclin analog.Advances in Prostaglandins, Thromboxane, and Leukotriene Research,13, 363–369.
Menter, D. G., Steiner, B. W., Sloane, B. F., Taylor, J. D., andHonn, K. V., 1987, A newin vitro model for the investigation of tumour cell platelets endothelial cell ineractions and concomitant eicosanoid biosynthesis.Cancer Research,47, 2425–2432.
Ovejera, A. A., Johnson, R. K., andGoldin, A., 1975, Growth characteristics and chemotherapeutic response of intravenously implanted Lewis lung carcinoma.Cancer Chemotherapy Reports, Part 2,5, 111–125.
Schror, K., Darius, H., Matzky, R., andOhlendorf, R., 1981, The antiplatelet and cardiovascular actions of a new carbocylin derivative (ZK 363.74)—equipotent to PGI2 in vitro.Naunyn Schriedeberg's Archive Pharmacology,316, 252–255.
Siegel, S., 1956,Nonparametric Statistics for the Behavioral Sciences (New York: McGraw-Hill), pp. 184–193.
Siegel, S., 1956,Nonparametric Statistics for the Behavioral Sciences (New York: McGraw-Hill), pp. 116–127.
Tallarida, R. J., andMurray, R. B., 1987,Manual of Pharmacologic Calculation with Computer Programs (New York: Springer-Verlag), p. 297.
Tsubura, E., Takashi, Y., andSaburo, S., 1983, Inhibition of the arrest of hematogenously disseminated tumor cells.Cancer Metastasis Review,2, 223–237.
Whittle, B. J. R., andMoncada, S., 1985, Platelet actions of stable carbocyclic analogues of prostacyclin.Circulation,72, 1219–1225.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sava, G., Perissin, L., Zorzet, S. et al. Antimetastatic action of the prostacyclin analog Iloprost in the mouse. Clin Exp Metast 7, 671–678 (1989). https://doi.org/10.1007/BF01753677
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01753677