PDF herunterladen
Thromb Haemost 2003; 90(03): 549-554
DOI: 10.1160/TH03-02-0102
Cellular Proteolysis and Oncology
Schattauer GmbH

Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454

Ali Amirkhosravi
1   Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida, USA Albany College of Pharmacy, Albany, New York, USA
,
Shaker A. Mousa
1   Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida, USA Albany College of Pharmacy, Albany, New York, USA
,
Mildred Amaya
1   Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida, USA Albany College of Pharmacy, Albany, New York, USA
,
Susan Blaydes
1   Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida, USA Albany College of Pharmacy, Albany, New York, USA
,
Hina Desai
1   Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida, USA Albany College of Pharmacy, Albany, New York, USA
,
Todd Meyer
1   Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida, USA Albany College of Pharmacy, Albany, New York, USA
,
John L. Francis
1   Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida, USA Albany College of Pharmacy, Albany, New York, USA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 14. Februar 2003

Accepted after resubmission 25. Mai 2003

Publikationsdatum:
05. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

Platelets are known to play a role in blood borne metastasis. Previous experimental studies have suggested that platelet GpIIb/IIIa may be a therapeutic target. However, the need for intravenous administration limits the potential application of current GpIIb/IIIa inhibitors to cancer therapy. The aim of the present study was to assess the efficacy of a novel, non-peptide oral GpIIb/IIIa antagonist (XV454) on tumor cell-induced platelet aggregation in vivo and on experimental metastasis. A Lewis lung carcinoma (LL2) mouse model of experimental metastasis was used in this study. XV454 (100 μg) was administered intravenously (via tail vein) or orally (gavages) to 20 g mice. To determine the effect of XV454 on platelet aggregation, blood samples were collected by cardiac puncture 10 minutes after intravenous and 1-24 hrs after oral XV454, and platelet function was assessed by aggregometry, thrombelastography and the Platelet Function Analyzer (PFA100®). The effect of XV454 on tumor cell-induced thrombocytopenia was determined 10 minutes after intravenous and 3 hrs after oral XV454 administration. Tumor cells (2 x 106) were injected intravenously and 15 minutes after cell injection, platelet count was measured and compared to baseline (pre-injection) counts. To assess the effect on metastasis, XV454 was administered intravenous or orally 10 minutes and 3 hrs before tumor cell injection, respectively. Eighteen days later, surface lung tumor nodules were counted and the total lung tumor burden assessed. In a fourth group, in addition to the initial oral dose (before tumor cell injection), oral XV454 was given daily for the first week and three times in the second week. Administration of XV454 (5 mg/kg) completely inhibited platelet aggregation and this effect persisted for at least 24 hrs after oral delivery. Both intravenous and oral XV454 significantly inhibited tumor cell-induced thrombocytopenia (P<0.01), the number of surface lung tumor nodules (80-85%; P<0.001) and total tumor burden (83% for intravenous group; 50% oral [single treatment] group; 91% oral [multiple treatment] group, P<0.001). Overall, these data provide further evidence for the effect of oral and intravenous GpIIb/IIIa antagonism on tumor cell-platelet interaction and metastasis.

Keywords

Platelet GpIIb/IIIa antagonists - platelet-tumor interaction - metastasis - thrombosis - cancer
 

  • References

  • 1 Gasic GJ, Gasic TB, Galanti N. et al. Platelet-tumor cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer 1973; 11: 704-18.
    CrossrefPubMedSuche in Google Scholar
  • 2 Karpatkin S, Pearlstein E. Role of platelets in tumor cell metastasis. Annals Int Med 1981; 95: 636-41.
    CrossrefPubMedSuche in Google Scholar
  • 3 Tang DG, Honn KV. Adhesion molecules and tumor metastasis: An update. Invasion Metastasis 1995; 95: 109-31.
    PubMedSuche in Google Scholar
  • 4 Fidler IJ. Metastasis: Quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5 deoxyuridine. J. Natl Cancer Inst 1970; 45: 773-82.
    PubMedSuche in Google Scholar
  • 5 Warren BA. The micro-injury hypothesis and metastasis. Haemostatic mechanisms and metastasis. Honn KV, Sloane BF, eds. M. Nijhoff, Boston 1984; 56.
    PubMedSuche in Google Scholar
  • 6 Nieswandt B, Hafner M, Echtenacher B. et al. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59: 1295.
    PubMedSuche in Google Scholar
  • 7 Cowan DH, Graham J. Effect of platelet growth factor(s) on growth of human tumor colonies. Prog Clin Biol Res 1982; 89: 249-68.
    PubMedSuche in Google Scholar
  • 8 Mohle R, Green D, Moore MA. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human meagkaryocytes and platelets. Proc Natl Acad Sci USA 1997; 94: 663-8.
    CrossrefPubMedSuche in Google Scholar
  • 9 Jun Li J, Qi Huang Y, Basch R. et al. Thrombin Induces the Release of Angiopoietin-1 from platelets. Thromb Haemost 2001; 85: 204-6.
    Thieme ConnectPubMedSuche in Google Scholar
  • 10 Lerner WA, Pearlstein E, Ambrogio C. et al. A new mechanism for tumor-induced platelet aggregation. Comparisons with mechanisms shared by other tumors with possible pharmacologic strategy towards prevention of metastases. Int J Cancer 1983; 31: 463-9.
    CrossrefPubMedSuche in Google Scholar
  • 11 Nierodzik M, Plotkin A, Kajumo F. et al. Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo. J Clin Invest 1991; 87: 229-36.
    CrossrefPubMedSuche in Google Scholar
  • 12 Nierodzik ML, Kajumo F, Karpatkin S. Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. Cancer Res 1992; 52: 3267-72.
    PubMedSuche in Google Scholar
  • 13 Boukerche H, Berthier-Vergnes O, Tabone E. et al. Platelet-melanoma cell interaction is mediated by the glycoprotein IIb-IIIa complex. Blood 1989; Aug 1 74 (02) 658-63.
    PubMedSuche in Google Scholar
  • 14 Grossi IM, Hatfield JS, Fitzgerald LA. et al. Role of tumor cell glycoproteins immunologically related to glycoproteins Ib and IIb/IIIa in tumor cell-platelet and tumor cell-matrix interactions. FASEB J 1988; May 2 (08) 2385-95.
    CrossrefPubMedSuche in Google Scholar
  • 15 Felding-Habermann B, Habermann R, Salvidar E. et al. Role of β3 Integrins in Melanoma Cell Adhesion to Activated Platelets under Flow. J Biol Chem 1996; 271: 5892-900.
    CrossrefPubMedSuche in Google Scholar
  • 16 Karpatkin S, Pearlstein E, Ambrogio C. et al. Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. J Clin Invest 1988; 81: 1012-9.
    CrossrefPubMedSuche in Google Scholar
  • 17 Amirkhosravi A, Amaya M, Siddiqui F. et al. Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor cell-activated platelets and experimental metastasis. Platelets 1999; 10: 285-92.
    CrossrefPubMedSuche in Google Scholar
  • 18 Trikha M, Zhou Z, Timar J. et al. Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 2002; May 15 62 (10) 2824-33.
    PubMedSuche in Google Scholar
  • 19 Mousa SA, Forsythe M, Bozarth J. et al. XV454, a Novel Non-peptide Small-Molecule Platelet GpIIb/IIIa Antagonist with Comparable Platelet αIIbβ3-Binding Kinetics to c7E3. J Cardiovasc Pharmacol 1998; 32: 736-44.
    CrossrefPubMedSuche in Google Scholar
  • 20 Mallett SV, Cox DJA. Thrombelastography. Br J Anaesth 1992; 69: 307-3.
    CrossrefPubMedSuche in Google Scholar
  • 21 Mammen EF, Comp PC, Gosselin R. et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 1998; 24: 195-202.
    Thieme ConnectPubMedSuche in Google Scholar
  • 22 Gatspar H. Stickiness of platelets and tumor cells influenced by drugs. Thromb Diath Haemorrh Suppl 1970; 42: 291.
    PubMedSuche in Google Scholar
  • 23 Kolenich JJ, Mansour EG, Flynn A. Haematological effects of aspirin. Lancet 1972; ii: 714.
    PubMedSuche in Google Scholar
  • 24 Gasic GJ, Gasic TB, Stewart CC. Anti-meta-static effect associated with platelet reduction. Pathology 1968; 61: 46-52.
    PubMedSuche in Google Scholar
  • 25 Nierodzik ML, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo. Thromb Haemost 1995; 74 (01) 282-90.
    Thieme ConnectPubMedSuche in Google Scholar
  • 26 Zacharski LR, Moritz TE. Effect of RA-33 (mopidamole) on survival in carcinoma of the lung and colon. Final report of VA cooperative study #188. Thromb Haemost 1987; 58: 508.
    Thieme ConnectPubMedSuche in Google Scholar
  • 27 Amirkhosravi M, Francis JL. Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation. Thromb Haemost 1995; 73 (01) 59-65.
    Thieme ConnectPubMedSuche in Google Scholar
  • 28 Banks RE, Forbes MA, Kinsey SE. et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 1998; 77: 956-64.
    CrossrefPubMedSuche in Google Scholar
  • 29 Jenkins LA, Lau S, Crawford M. et al. Delayed profound thrombocytopenia after c7E3 Fab (Abciximab) therapy. Circulation 1998; 97: 1214-5.
    CrossrefPubMedSuche in Google Scholar
  • 30 Leclerc JR. Platelet glycoprotein IIb/IIIa antagonists. Lessons learned from clinical trials and future directions. Crit Care Med 2002; 30: S322-40.
    PubMedSuche in Google Scholar