Amirkhosravi Ali, Mousa Shaker A, Amaya Mildred, Blaydes Susan, Desai Hina, Meyer Todd, Francis John L
Clinical and Research Laboratories, Florida Hospital Cancer Institute, 2501 N. Orange Ave, Suite 786, Orlando, Florida 32804, USA.
Thromb Haemost. 2003 Sep;90(3):549-54. doi: 10.1160/TH03-02-0102.
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.
已知血小板在血行转移中发挥作用。以往的实验研究表明，血小板糖蛋白IIb/IIIa（GpIIb/IIIa）可能是一个治疗靶点。然而，静脉给药的需求限制了当前GpIIb/IIIa抑制剂在癌症治疗中的潜在应用。本研究的目的是评估一种新型非肽类口服GpIIb/IIIa拮抗剂（XV454）对体内肿瘤细胞诱导的血小板聚集及实验性转移的疗效。本研究采用Lewis肺癌（LL2）实验性转移小鼠模型。将XV454（100微克）静脉注射（通过尾静脉）或口服（灌胃）给予20克重的小鼠。为确定XV454对血小板聚集的影响，在静脉注射XV454后10分钟以及口服XV454后1 - 24小时通过心脏穿刺采集血样，并通过凝集测定法、血栓弹力图和血小板功能分析仪（PFA100）评估血小板功能。在静脉注射XV454后10分钟以及口服XV454后3小时测定XV454对肿瘤细胞诱导的血小板减少的影响。静脉注射肿瘤细胞（2×10⁶个），细胞注射后15分钟，测量血小板计数并与基线（注射前）计数进行比较。为评估对转移的影响，分别在肿瘤细胞注射前10分钟和3小时静脉注射或口服XV454。18天后，计数肺表面肿瘤结节并评估肺肿瘤总负荷。在第四组中，除了初始口服剂量（在肿瘤细胞注射前）外，在第一周每天口服XV454，第二周口服三次。给予XV454（5毫克/千克）可完全抑制血小板聚集，且口服给药后这种作用至少持续24小时。静脉注射和口服XV454均显著抑制肿瘤细胞诱导的血小板减少（P < 0.01）、肺表面肿瘤结节数量（80 - 85%；P < 0.001）以及肿瘤总负荷（静脉注射组为83%；口服[单次治疗]组为50%；口服[多次治疗]组为91%，P < 0.001）。总体而言，这些数据为口服和静脉注射GpIIb/IIIa拮抗剂对肿瘤细胞 - 血小板相互作用及转移的影响提供了进一步证据。
