Abbas Nasir, Bruland Øyvind Sverre, Brevik Ellen Mengshoel, Dahle Jostein
Department of Radiation Biology, Norwegian Radium Hospital, Oslo, Norway.
Nucl Med Commun. 2012 Aug;33(8):838-47. doi: 10.1097/MNM.0b013e328354df7c.
The aim of the present study was to compare the biodistribution, normal tissue toxicity, and therapeutic effect of two low-dose rate radioimmunoconjugates (RICs) in mice with HER2-expressing ovarian cancer xenografts: the α-particle-emitting (227)Th-trastuzumab and the β-particle-emitting (177)Lu-trastuzumab.
Trastuzumab (Herceptin), conjugated to DOTA and radiolabeled with (227)Th or (177)Lu, was injected intravenously into mice bearing SKOV-3 xenografts. The biodistribution was determined at different time points after injection. The organs were collected and measured for radioactivity content using a gamma spectrometer. Inhibition of tumor growth was measured after a single injection of (227)Th-trastuzumab, (227)Th-rituximab, (177)Lu-trastuzumab, trastuzumab alone, and NaCl. The toxicity of (227)Th-trastuzumab and (177)Lu-trastuzumab was evaluated by measurement of body weight, determination of blood cell counts, analysis of clinical chemistry parameters, and histological examination of tissue specimens.
The absorbed radiation dose to the tumor was 4 Gy after administration of 400 kBq/kg (227)Th-trastuzumab and 72 MBq/kg (177)Lu-trastuzumab. A significantly better antitumor effect of (227)Th-trastuzumab (8 and 30 days' growth delay for 400 and 600 kBq/kg, respectively) was observed as compared with untreated control, trastuzumab alone, 600 kBq/kg (227)Th-rituximab (nonspecific targeting), and 72 MBq/kg (177)Lu-trastuzumab. Mean survival of mice after treatment with (227)Th-trastuzumab (107 ± 9 and 129 ± 12 days for 400 and 600 kBq/kg (227)Th-trastuzumab, respectively) was significantly improved compared with control (88 ± 11 days) and other RICs (85 ± 8 and 66 ± 6 days for 72 MBq/kg (177)Lu-trastuzumab and 600 kBq/kg (227)Th-rituximab, respectively) (P<0.05, Kaplan-Meier). Treatment-related toxicity was not observed in any group except for a transient decrease in white blood cells between 3 and 9 weeks after treatment with 400 and 600 kBq/kg (227)Th-trastuzumab.
The α-particle-emitting RIC (227)Th-trastuzumab effectively delayed tumor growth and prolonged survival of mice compared with β-emitting (177)Lu-trastuzumab administered at the same absorbed radiation dose to tumor. This new therapeutic approach warrants further studies aiming at clinical testing in patients with micrometastatic ovarian cancer.
本研究旨在比较两种低剂量率放射免疫偶联物（RICs）在表达HER2的卵巢癌异种移植小鼠中的生物分布、正常组织毒性和治疗效果：发射α粒子的（227）Th-曲妥珠单抗和发射β粒子的（177）Lu-曲妥珠单抗。
将与DOTA偶联并分别用（227）Th或（177）Lu进行放射性标记的曲妥珠单抗（赫赛汀）静脉注射到携带SKOV-3异种移植瘤的小鼠体内。在注射后的不同时间点测定生物分布。收集器官并用γ能谱仪测量放射性含量。在单次注射（227）Th-曲妥珠单抗、（227）Th-利妥昔单抗、（177）Lu-曲妥珠单抗、单独的曲妥珠单抗和氯化钠后测量肿瘤生长抑制情况。通过测量体重、测定血细胞计数、分析临床化学参数以及对组织标本进行组织学检查来评估（227）Th-曲妥珠单抗和（177）Lu-曲妥珠单抗的毒性。
给予400 kBq/kg（227）Th-曲妥珠单抗和72 MBq/kg（177）Lu-曲妥珠单抗后，肿瘤的吸收辐射剂量为4 Gy。与未治疗的对照组、单独的曲妥珠单抗、600 kBq/kg（227）Th-利妥昔单抗（非特异性靶向）和72 MBq/kg（177）Lu-曲妥珠单抗相比，观察到（227）Th-曲妥珠单抗具有显著更好的抗肿瘤效果（400和600 kBq/kg分别使肿瘤生长延迟8天和30天）。与对照组（88±11天）和其他RICs（72 MBq/kg（177）Lu-曲妥珠单抗和600 kBq/kg（227）Th-利妥昔单抗分别为85±8天和66±6天）相比，用（227）Th-曲妥珠单抗治疗的小鼠的平均生存期（400和600 kBq/kg（227）Th-曲妥珠单抗分别为107±9天和129±12天）显著延长（P<0.05，Kaplan-Meier法）。除了在用400和600 kBq/kg（227）Th-曲妥珠单抗治疗后3至9周白细胞出现短暂下降外，在任何组中均未观察到与治疗相关的毒性。
与以相同肿瘤吸收辐射剂量给予的发射β粒子的（177）Lu-曲妥珠单抗相比，发射α粒子的RIC（227）Th-曲妥珠单抗有效地延迟了肿瘤生长并延长了小鼠的生存期。这种新的治疗方法值得进一步开展研究，旨在对微转移性卵巢癌患者进行临床试验。
