Department of Internal Medicine II-Cardiology, University of Ulm, Ulm, Germany.
Med Sci Monit. 2011 Jan;17(1):PI1-6. doi: 10.12659/msm.881310.
Treatment of the human cytomegalovirus (HCMV) infection with ganciclovir has beneficial indirect effects on the complex interactions of HCMV with restenosis, atherosclerosis, and transplant vascular sclerosis. The current study reports on direct effects of ganciclovir on expression of ICAM-1 and cell proliferation, key events of coronary atherosclerosis/restenosis. A potential clinical relevance of the data will be evaluated with the help of SI/MPL-ratio's.
MATERIAL/METHODS: Definition of the SI/MPL-ratio: relation between significant inhibitory effects in vitro/ex vivo and the maximal plasma level after systemic administration in vivo (ganciclovir: 9 µg/ml). Part I of the study investigated in cytoflow studies the effect of ganciclovir (0.05-5000 µg/mL) on TNF-a induced expression of intercellular adhesion molecule 1 (ICAM-1) in endothelial cells derived from umbilical veins (HUVEC), human coronary endothelial cells (HCAEC), and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of ganciclovir (0.05-5000 µg/mL) on cell proliferation (HUVEC, HCAEC, and HCMSMC). In part III cytotoxic effects of ganciclovir (0.05-5000 µg/mL) were studied (HUVEC, HCAEC, and HCMSMC).
Ganciclovir caused slight but significant inhibitory effects on expression of ICAM-1 in HUVEC, HCAEC, and HCMSMC. In all three cell types studied strong dose depending significant antiproliferative effects of ganciclovir were detected. Partially, the antiproliferative effects of ganciclovir were caused by cytotoxic effects.
SI/MPL-ratio's >1 in HCAEC and HCMSMC indicate that the inhibitory effects of gancliclovir on ICAM-1-expression and cell proliferation may only be expected in vivo following local high dose administration e.g. in drug eluting stents (DES).
更昔洛韦治疗人类巨细胞病毒（HCMV）感染对 HCMV 与再狭窄、动脉粥样硬化和移植血管硬化的复杂相互作用具有有益的间接影响。本研究报告了更昔洛韦对细胞间黏附分子 1（ICAM-1）表达和细胞增殖的直接影响，这是冠状动脉粥样硬化/再狭窄的关键事件。将通过 SI/MPL-比值评估数据的潜在临床相关性。
材料/方法：SI/MPL-比值的定义：体外/体内显著抑制作用与全身给药后体内最大血浆水平之间的关系（更昔洛韦：9μg/ml）。研究的第一部分通过细胞流式研究了更昔洛韦（0.05-5000μg/ml）对 TNF-a 诱导的脐静脉内皮细胞（HUVEC）、人冠状动脉内皮细胞（HCAEC）和人冠状动脉平滑肌细胞（HCMSMC）中细胞间黏附分子 1（ICAM-1）表达的影响。研究的第二部分分析了更昔洛韦（0.05-5000μg/ml）对细胞增殖的影响（HUVEC、HCAEC 和 HCMSMC）。在第三部分研究了更昔洛韦（0.05-5000μg/ml）的细胞毒性作用（HUVEC、HCAEC 和 HCMSMC）。
更昔洛韦对 HUVEC、HCAEC 和 HCMSMC 中 ICAM-1 的表达仅产生轻微但有统计学意义的抑制作用。在所有三种研究的细胞类型中，均检测到强烈的剂量依赖性更昔洛韦的抗增殖作用。部分更昔洛韦的抗增殖作用是由细胞毒性作用引起的。
HCAEC 和 HCMSMC 中的 SI/MPL-比值>1 表明，只有在局部高剂量给药（例如在药物洗脱支架（DES）中）后，更昔洛韦对 ICAM-1 表达和细胞增殖的抑制作用才可能在体内出现。
