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。本研究的目的是研究促进血管损伤后新生内膜细胞凋亡是否可以通过局部输送ONO-4007来抑制再狭窄过程。方法：对8只（13.2±2.2kg）双侧股动脉行PTCA导管球囊膨胀术，球囊大小为动脉的1.3 ~ 1.5倍，球囊膨胀时间为30秒3次。单侧采用微孔输液管输送ONO-4007（0.05mg或0.5mg，每组n=4）。另一侧给予生理盐水作为对照。球囊损伤后2 ~ 4周，切除股动脉，准备进行组织学检查。结果：两组间血管总面积（VA）和内侧面积/VA无显著差异。4周时，0.5mg组的内膜面积/VA较对照组（6.42±3.42%）显著降低（2.75±1.06%）。治疗组（0.05mg组，65.5±64.4μm； 0.5mg组，50.5±21.7μm）最大内膜厚度显著低于对照组（128±104μm）。2周时，治疗部位内膜隧道阳性细胞率明显升高（71.4±14.1% vs 12.9±5.3%）。结论：局部给药ONO-4007可促进狗股动脉损伤血管细胞凋亡，抑制股动脉内膜增生。

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.