Myerson Robert J, Singh Anurag K, Bigott Heather M, Cha Bibiana, Engelbach John A, Kim Joonyoung, Lamoreaux Wayne T, Moros Eduardo, Novak Petr, Sharp Terry L, Straube William, Welch Michael J, Xu Mai
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Int J Hyperthermia. 2006 Mar;22(2):93-115. doi: 10.1080/02656730600594191.
Mild hyperthermia can improve tumour oxygenation and enhance radiosensitivity. Imaging the hypoxic fraction of a tumour can guide hyperthermia treatment planning and facilitate treatment optimization. 64Cu-ATSM (Copper-diacetyl-bis(N4-methylthiosemicarbazone)) is a positron emitting compound that has been demonstrated to have rapid uptake and selective retention in hypoxic cells and has been used for imaging human and animal tumours. The purpose of the present report is to establish methodology that will allow one to use Cu-ATSM PET scanning to detect the impact of hyperthermia on tumour physiology in as little time as possible.
EMT6 tumours (mouse mammary carcinoma) were implanted into the subcutaneous tissue of both thighs of 10 BALB/c mice (one heated, one control tumour per animal). The target thermal dose was 41.5 degrees C x 45 min. Without interrupting heating, 64Cu-ATSM (mean activity 1.8 mCi) was then injected and serial PET scans were obtained. In a sub-group of four animals, a low administered activity (approximately 0.3 mCi) 64Cu-ATSM scan was also conducted before heating to permit a direct comparison of the effects of hyperthermia on the same tumours. In another sub-group of five animals, a low activity (approximately 0.3 mCi) 64Cu-PTSM (pyruvaldehyde-bis(N*-methylthiosemicarbazone)) scan was conducted before heating, to confirm a posited correlation between perfusion and early 64Cu-ATSM uptake.
This study corrected for perfusion differences by dividing tumour uptake by the average early (first minute) uptake ('self-normalized uptake'). The 10 heated tumours showed a significantly (p = 0.007) lower self-normalized uptake than control tumours by 2 min. For the four mice with low activity Cu-ATSM scans performed before hyperthermia, the tumours to be heated demonstrated self-normalized uptake consistent with the unheated control tumours and which departed significantly (p < or = 0.02) from their post-hyperthermia scans by 5 min. Comparisons between scans and needle electrode surveys were performed in an additional four animals with eight tumours. For technical reasons electrode surveys were done after the end of hyperthermia-and, therefore, these animals also had comparison scans taken after hyperthermia. Reduced self-normalized uptake on scans was associated with increased pO2 on electrode surveys. These data also suggested a substantial degradation of the effect on tumour hypoxia by approximately 15-45 min after the end of mild hyperthermia.
Short imaging times of approximately 5 min with modest (approximately 4-10) numbers of mice can discriminate the effects of mild hyperthermia on tumour physiology. The long-term objective is to use this tool to identify as short and mild a hyperthermia session as possible.
轻度热疗可改善肿瘤氧合并增强放射敏感性。对肿瘤缺氧部分进行成像可指导热疗治疗计划并促进治疗优化。64Cu-ATSM（双乙酰双（N4-甲基硫代半卡巴腙）铜）是一种正电子发射化合物，已被证明在缺氧细胞中具有快速摄取和选择性滞留的特性，并已用于对人类和动物肿瘤进行成像。本报告的目的是建立一种方法，使人们能够使用Cu-ATSM正电子发射断层扫描（PET）在尽可能短的时间内检测热疗对肿瘤生理学的影响。
将EMT6肿瘤（小鼠乳腺癌）植入10只BALB/c小鼠双侧大腿的皮下组织中（每只动物一个加热肿瘤，一个对照肿瘤）。目标热剂量为41.5摄氏度×45分钟。在不中断加热的情况下，然后注射64Cu-ATSM（平均活度1.8毫居里）并进行系列PET扫描。在四只动物的亚组中，在加热前还进行了低给药活度（约0.3毫居里）的64Cu-ATSM扫描，以便直接比较热疗对同一肿瘤的影响。在另一个五只动物的亚组中，在加热前进行了低活度（约0.3毫居里）的64Cu-PTSM（丙酮醛双（N4-甲基硫代半卡巴腙））扫描，以确认灌注与早期64Cu-ATSM摄取之间的假定相关性。
本研究通过将肿瘤摄取量除以平均早期（第一分钟）摄取量（“自归一化摄取量”）来校正灌注差异。10个加热肿瘤在2分钟时的自归一化摄取量显著低于对照肿瘤（p = 0.007）。对于在热疗前进行低活度Cu-ATSM扫描的四只小鼠，待加热的肿瘤显示出与未加热对照肿瘤一致的自归一化摄取量，并且在5分钟时与热疗后的扫描结果有显著差异（p≤0.02）。在另外四只患有八个肿瘤的动物中进行了扫描与针电极测量之间的比较。由于技术原因，电极测量在热疗结束后进行，因此这些动物在热疗后也进行了比较扫描。扫描中自归一化摄取量的降低与电极测量中pO2的增加相关。这些数据还表明，在轻度热疗结束后约15 - 45分钟，对肿瘤缺氧的影响有显著下降。
使用适度数量（约4 - 10只）的小鼠，成像时间约5分钟，即可区分轻度热疗对肿瘤生理学的影响。长期目标是使用该工具确定尽可能短且温和的热疗疗程。
