Biological study on Prevention of Restenosis by Intra-arterial Irradiation

本研究旨在探讨电离辐射(IR)抑制PTA术后内膜增生的生物学机制。由于已经知道平滑肌细胞的生长抑制是导致这一现象的主要因素，所以我们使用了原代培养的平滑肌细胞作为模型。当细胞受到20GyX射线照射后，至少在48h内仍未观察到明显的细胞凋亡迹象。照射后未见Fas、Fas-L表达增强或caspase-8激活。此外，未检测到PKC-δ的裂解，这表明照射后的平滑肌细胞的凋亡活性很低。因此，细胞凋亡似乎不是由于IR诱导的平滑肌细胞生长抑制所致。我们发现，在X射线照射后的平滑肌细胞中，依赖增殖细胞核抗原的β修复是有功能的，而另一种碱基切除修复途径，PolDNA依赖的修复途径，在这种情况下不起作用。这些结果强烈地表明，依赖于增殖细胞核抗原的DNA修复对于获得平滑肌细胞的抗凋亡特性可能是重要的。我们还利用接受口腔舌癌近距离放射治疗的患者的临床数据，展示了下颌骨放射骨病(ORN)的放射生物学特性，这是由骨骼中的血管损伤引起的。COX比例回归分析显示，以舌下牙周表面迟发性反应组织的生物有效剂量(BED)作为预测指标，预测效果最好，并得到了α/β剂量-效应曲线。这些结果为分析动脉内照射对再狭窄的抑制作用提供了有用的信息。

The purpose of this study was to pursue the biological mechanisms by which ionizing radiation (IR) inhibits intimal hyperplasia after PTA. Since it is already known that growth inhibition of smooth muscle cells is a major factor of the phenomenon, we used primary cultured smooth muscle cells as a model. When cells were X-irradiated at a dose of 20 Gy, no apparent evidence of poptosis was obtained in terms of morphology at least up to 48h. None of enhanced expression of Fas or Fas-L, or activation of caspase-8 was observed following irradiation. Furthermore, cleavage of PKC-δ was not detected, indicating that apoptotic activities in smooth muscle cells following irradiation is quite low. It was thus suggested that apoptosis does not seem to be attributed to the IR-induced growth inhibition of smooth muscle cells. We found that PCNA-dependent DNA repair is functional in smooth muscle cells following X-irradiation and showed that another base excision repair (BER) pathway, pol β-dependent one, is not functional under the condition. These results strongly imply that PCNA-dependent DNA repair may be important to get apoptosis-refractory properties in smooth muscle cells. We also showed radiobiological properties of osteoradionercrosis (ORN) of the mandibular bone, which is caused by vessel damage in the bone, utilizing clinical data from pataients receiving Ir brachytherapy for oral tongue carcinoma. Cox proportional regression analysis revealed that biological effective dose (BED) using an α/β ratio for late responding tissues estimated at the surface of the lower lingual gum was the best prognosticator to predict ORN, and dose-response curves for ORN were obtained. These results provide useful information to analyze inhibitory effects of restenosis by intra-arterial irradiation.