Harrell R L, Rajanayagam S, Doanes A M, Guzman R J, Hirschowitz E A, Crystal R G, Epstein S E, Finkel T
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1650, USA.
Circulation. 1997 Jul 15;96(2):621-7. doi: 10.1161/01.cir.96.2.621.
Restenosis remains a significant problem after balloon angioplasty. Previous studies have demonstrated that recombinant adenoviruses are efficient vectors for gene transfer to the arterial wall and can be used to inhibit the proliferative aspect of restenosis. We sought to extend these observations using AdCMV.CD, an adenovirus that encodes cytosine deaminase (CD) and is capable of metabolizing 5-fluorocytosine (5-FC) to 5-fluorouracil.
Infection of vascular smooth muscle cells (VSMC) with AdCMV.CD increases by two to three orders of magnitude the growth-inhibitory effects of 5-FC. The degree of VSMC inhibition in vitro was a function of 5-FC concentration and the level of CD expression. Cells infected with AdCMV.CD exhibited a profound bystander effect on the growth of neighboring cells, which did not require direct cell-to-cell contact. The predominant effect of AdCMV.CD on growth of VSMC appeared to be cytostatic, not cytotoxic. Assessment of this strategy in a rabbit femoral artery model of balloon-induced injury demonstrated that compared with animals in either of two control groups, animals treated with the active combination of infection with AdCMV.CD and 1-week treatment with parenteral 5-FC had a significant reduction at 30 days in the neointimal-to-medial ratio.
Our results suggest that adenovirus-mediated gene transfer of CD along with 5-FC administration may be a useful strategy to treat the proliferative aspects of restenosis.
球囊血管成形术后再狭窄仍然是一个重要问题。先前的研究表明，重组腺病毒是将基因转移至动脉壁的有效载体，可用于抑制再狭窄的增殖方面。我们试图利用AdCMV.CD扩展这些观察结果，AdCMV.CD是一种编码胞嘧啶脱氨酶（CD）的腺病毒，能够将5-氟胞嘧啶（5-FC）代谢为5-氟尿嘧啶。
用AdCMV.CD感染血管平滑肌细胞（VSMC）可使5-FC的生长抑制作用增加两到三个数量级。体外VSMC的抑制程度是5-FC浓度和CD表达水平的函数。用AdCMV.CD感染的细胞对邻近细胞的生长表现出显著的旁观者效应，这不需要细胞间的直接接触。AdCMV.CD对VSMC生长的主要作用似乎是抑制细胞生长，而非细胞毒性。在兔股动脉球囊损伤模型中对该策略进行评估，结果表明，与两个对照组中的任何一组相比，用AdCMV.CD感染并联合胃肠外给予5-FC进行1周治疗的动物，在30天时内膜与中膜比值显著降低。
我们的结果表明，腺病毒介导的CD基因转移联合5-FC给药可能是治疗再狭窄增殖方面的一种有用策略。
