Roelcke Ulrich, Hausmann Oliver, Merlo Adrian, Missimer John, Maguire Ralph P, Freitag Peter, Radü Ernst W, Weinreich Regin, Gratzl Otmar, Leenders Klaus L
PET Program, Paul Scherrer Institute, Villigen, Switzerland.
J Nucl Med. 2002 Nov;43(11):1444-51.
Locoregional administration may yield higher tumor drug concentrations compared with intravenous injection and may reduce the risk of systemic adverse effect. Furthermore, in the case of brain tumors, it may circumvent limited drug delivery imposed by the blood-brain barrier. We used PET to study the retention and spatial distribution of iododeoxyuridine (IUdR), which has been used as a DNA-targeting radiosensitizing drug and which can be charged with therapeutic nuclides.
Locoregional (resection cavity, tumor) instillation of 5-19 MBq (124)I-IUdR was achieved in 7 postoperative patients with malignant gliomas through a reservoir implanted in the skull. Patients were scanned with PET during the first hour and at 2, 24, and 48 h after (124)I-IUdR instillation. (124)I-IUdR metabolism was measured in the reservoir fluid in the presence or absence of a degradation inhibitor (5'-butyryl-IUdR [butyryl-IUdR]). Region-of-interest analysis was applied to calculate intratumoral retention (K(local)) of (124)I-IUdR from the PET images after a 24-h washout phase using an autoradiographic method.
At 24 h, radioactivity concentration in the reservoir was approximately 1% of the concentration 5 min after tracer instillation. The major metabolite of (124)I-IUdR in the reservoir was (124)I-iodouracil. (124)I-IUdR degradation could be partially inhibited by butyryl-IUdR. In the plasma, radioactivity peaked between 2 and 6 h. The area of tissue radioactivity increased with time up to 3-fold compared with the initial distribution. Tumor (124)I-IUdR retention (K(local)) ranged from 0.006 to 0.017 micro L/g/min, which is substantially lower compared with the IUdR-DNA incorporation reported recently after intravenous injection of (124)I-IUdR (K(i), 3.9 +/- 2.3 micro L/g/min, where K(i) is the DNA incorporation rate of (124)I-IUdR after intravenous tracer injection).
Although a single injection of (124)I-IUdR resulted in radioactivity distribution over the tumor, retention at 24 h was substantially lower compared with intravenous injection of (124)I-IUdR. Slow diffusion after locoregional administration, in contrast to fast delivery via tumor capillaries after intravenous injection, may account for our findings, resulting in a low amount of drug incorporation into DNA before degradation and washout from tissue.
与静脉注射相比，局部给药可能产生更高的肿瘤药物浓度，并可能降低全身不良反应的风险。此外，对于脑肿瘤，它可能规避血脑屏障所造成的药物递送受限问题。我们使用正电子发射断层扫描（PET）来研究碘脱氧尿苷（IUdR）的滞留情况和空间分布，IUdR已被用作一种靶向DNA的放射增敏药物，并且可以负载治疗性核素。
通过植入颅骨的储液器，对7例恶性胶质瘤术后患者进行局部（切除腔、肿瘤）滴注5 - 19兆贝可（MBq）的（124）I - IUdR。在（124）I - IUdR滴注后的第1小时以及2、24和48小时对患者进行PET扫描。在有或没有降解抑制剂（5'-丁酰 - IUdR [丁酰 - IUdR]）存在的情况下，测量储液器液体中的（124）I - IUdR代谢情况。在24小时洗脱期后，使用放射自显影方法从PET图像进行感兴趣区分析，以计算（124）I - IUdR在肿瘤内的滞留率（K（局部））。
在24小时时，储液器中的放射性浓度约为示踪剂滴注后5分钟时浓度的1%。储液器中（124）I - IUdR的主要代谢产物是（124）I - 碘尿嘧啶。丁酰 - IUdR可部分抑制（124）I - IUdR的降解。在血浆中，放射性在2至6小时达到峰值。与初始分布相比，组织放射性面积随时间增加高达3倍。肿瘤（124）I - IUdR滞留率（K（局部））范围为0.006至0.017微升/克/分钟，与最近静脉注射（124）I - IUdR后报道的IUdR - DNA掺入率（K（i），3.9±2.3微升/克/分钟，其中K（i）是静脉注射示踪剂后（124）I - IUdR的DNA掺入率）相比，显著更低。
尽管单次注射（124）I - IUdR导致放射性分布在肿瘤上，但与静脉注射（124）I - IUdR相比，24小时时的滞留率显著更低。与静脉注射后通过肿瘤毛细血管的快速递送相比，局部给药后的缓慢扩散可能解释了我们的发现，导致在降解和从组织中洗脱之前，药物掺入DNA的量较低。
