Local Drug Delivery of ONO-4007 Inhibits Neointimal Hyperplasia in Dogs.

ONO-4007是一种有效的抗肿瘤药物，可诱导肿瘤细胞凋亡。本研究的目的是探讨局部应用ONO-4007对血管损伤后新生内膜细胞凋亡的促进作用是否能抑制再狭窄过程。方法：对8只犬双侧股动脉进行3次30s球囊扩张，球囊直径1.3~1.5倍，造成双侧股动脉损伤。一侧注入ONO-4007(0.05 mg或0.5 mg，每组n=4)。另一侧注射生理盐水作为对照。球囊损伤后2~4周，切取股动脉，行组织学检查。结果：两组间总血管面积(VA)和内侧面积/VA差异无统计学意义。术后4周，0.5 mg组内膜面积/VA值(2.75±1.06%)明显低于对照组(6.42±3.42%)。治疗组最大新生内膜厚度(0.05 mg组，65.5±64.4μm；0.5 mg组，5 0.5±2 1.7μm)明显小于对照组(12 8±10 4μm)。术后2周，治疗部位新生内膜隧道阳性细胞率(71.4±14.1%)明显高于对照组(12.9±5.3%)。结论：局部注射ONO-4007可促进损伤血管内皮细胞的凋亡，抑制犬股动脉新生内膜增生。

ONO-4007 is a potent antineoplastic drug, which induces apoptosis in neoplastic cell. The aim of this study was whether facilitation of apoptosis in neointima after vascular injury could inhibit restenosis process by local ONO-4007 delivery. Methods : In eight dogs(13.2±2.2kg)bilateral femoral arteries were injured by three times 30 sec balloon inflation of PTCA catheter, which balloon size was 1.3〜1.5 times as large as the artery. In one side, ONO-4007(0.05mg or 0.5mg, n=4 in each group)was delivered by a microporous infusion catheter. In the other side saline was delivered as a control. Two or four weeks after balloon injury, the femoral arteries were resected and prepared for histological examination. Results : Total vassel area(VA)and medial area/VA did not differ between the groups. At four weeks, the intimal area/VA was significantly reduced in 0.5mg sites(2.75±1.06%)compared with the control sites(6.42±3.42%). Maximum neointimal thickness were significantly thinner in the treatment sites(0.05mg group, 65.5±64.4μm ; 0.5mg group, 50.5±21.7μm)than that in the control sites(128±104μm). At two weeks, Tunnel positive cells rate in the neointima were significantly increased in the treatment sites(71.4±14.1% vs 12.9±5.3%). Conclusion : These data indicate facilitation of apoptosis in the injured vassel by local ONO-4007 delivery inhibits neointimal hyperplasia in dog's femoral artery.