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.