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

Abstract

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 micro g) 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 10(6)) 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.

The role of platelet activation in tumor metastasis

“…Abciximab) reduced tumor cell induced platelet aggregations and demonstrated antineoplastic effects [86]. Similarly, small molecule oral antagonist of GPIIb/IIIa was shown to efficiently reduce platelet aggregation and metastasis [87].…”

Modified heparins inhibit integrin αIIbβ3 mediated adhesion of melanoma cells to platelets in vitro and in vivo

“…Accumulating evidence indicates that blocking the function of platelet integrin a IIb b 3 with antagonists can effectively inhibit the initial formation of tumor cell-platelet complexes and prevent hematogenous metastasis, and competitive inhibition of integrin a IIb b 3 , or treatment of a IIb or b 3 subunit with antibodies also diminish metastatic potential. [9][10][11] Some drugs with anticoagulant activities, such as aspirin, hirudin and heparin have been demonstrated to prevent tumor metastasis by the mechanisms of inhibiting tumor cell-induced platelet aggregation. 3,12,13 Heparin is most well known for its anticoagulant activity.…”

Coagulation Facilitates Tumor Cell Spreading in the Pulmonary Vasculature during Early Metastatic Colony Formation

“…Since 1968, when Gasic et al (3) showed that experimental pulmonary metastasis is reduced by platelet depletion and restored by supplementation of platelets, there has been much research supporting the concept of enhancement of cancer metastasis by platelets (4). Inhibition of platelet function using integrin subunit ␣ IIb inhibitors or to a lesser effect using aspirin also inhibits metastasis (5,6). Platelet depletion or anticoagulation only has an inhibitory effect during a short time (0 -6 hours) after introduction of the tumor cells into the circulation.…”