Department of Radiation Biology, Institute for Cancer Research, Oslo University, Hospital - The Norwegian Radium Hospital, Oslo, Norway.
PLoS One. 2012;7(8):e42345. doi: 10.1371/journal.pone.0042345. Epub 2012 Aug 3.
The aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT) in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate (227)Th-DOTA-p-benzyl-trastuzumab.
METHODOLOGY/PRINCIPAL FINDINGS: Nude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts were treated with 1000 kBq/kg (227)Th-trastuzumab as single injection or four injections of 250 kBq/kg with intervals of 4-5 days, 2 weeks, or 4 weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p<0.01) and survival with tumor diameter less than 16 mm was prolonged (p<0.05) in all TAT groups compared to the control groups. No statistically significant differences were seen among the treated groups. In SKBR-3 xenografts tumor growth to 10-fold size was delayed in the single injection and 4-5 days interval groups (p<0.001) and all except the 4 weeks interval TAT group showed improved survival to the control groups (p<0.05). Toxicity was assessed by blood cell counts, clinical chemistry measurements and body weight. Transient reduction in white blood cells was seen for the single injection and 4-5 days interval groups (p<0.05). No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of body weight was significantly prolonged in 4 weeks interval group compared to single injection group (p<0.05) for SKOV-3 animals and in 2 weeks interval group compared with the 4-5 days interval groups (p<0.05) for SKBR-3 animals.
CONCLUSIONS/SIGNIFICANCE: The same concentration of radioactivity split into several fractions may improve toxicity of (227)Th-radioimmunotherapy while the therapeutic effect is maintained. Thus, it might be possible to increase the cumulative absorbed radiation dose to tumor with acceptable toxicity by fractionation of the dosage.
本研究旨在探讨低剂量率放射性免疫偶联物（227）Th-DOTA-p-苄基曲妥珠单抗单次和分次靶向 α 治疗（TAT）对 HER2 表达的乳腺癌和卵巢癌异种移植小鼠的治疗效果和正常组织毒性。
方法/主要发现：携带 HER2 过表达皮下 SKOV-3 或 SKBR-3 异种移植的裸鼠接受 1000 kBq/kg（227）Th-曲妥珠单抗单次注射或 250 kBq/kg 的 4 次注射，间隔 4-5 天、2 周或 4 周。对照动物接受生理盐水或未标记的曲妥珠单抗治疗。在 SKOV-3 异种移植中，与对照组相比，所有 TAT 组的肿瘤生长至 10 倍大小的时间延迟（p<0.01），肿瘤直径小于 16 mm 的存活时间延长（p<0.05）。在 SKBR-3 异种移植中，单次注射和 4-5 天间隔组的肿瘤生长至 10 倍大小的时间延迟（p<0.001），除 4 周间隔 TAT 组外，所有组的存活时间均优于对照组（p<0.05）。通过血细胞计数、临床化学测量和体重评估毒性。单次注射和 4-5 天间隔组的白细胞计数短暂减少（p<0.05）。红细胞、血小板或临床化学参数无明显变化。与单次注射组相比，4 周间隔组的无生命威胁性体重减轻的存活时间明显延长（p<0.05），SKOV-3 动物；与 4-5 天间隔组相比，2 周间隔组的存活时间延长（p<0.05），SKBR-3 动物。
结论/意义：将相同浓度的放射性物质分成几个分数可能会改善（227）Th-放射免疫治疗的毒性，同时保持治疗效果。因此，通过剂量分割，有可能在可接受的毒性范围内增加肿瘤的累积吸收辐射剂量。
