Heyerdahl Helen, Abbas Nasir, Sponheim Kristine, Mollatt Camilla, Bruland Øyvind, Dahle Jostein
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.
Curr Radiopharm. 2013 Jun 6;6(2):106-16. doi: 10.2174/18744710113069990018.
The aim of the current study was to investigate the therapeutic effect of 227Th-radioimmunotherapy on intraperitoneally growing human bioluminescent HER2 positive ovarian cancer cells.
In vitro toxicity of 227Th-trastuzumab in bioluminescent SKOV3-luc-D3 ovarian cancer cells was assessed in a growth assay. The biodistribution of intraperitoneally administrated 227Th-trastuzumab in athymic nude mice without tumor cells was determined. For in vivo therapy, seventy female athymic nude mice were intraperitoneally inoculated with tumor cells 17 days prior to injection of single 227Th-trastuzumab doses of 1000 kBq/kg, 600 kBq/kg or 400 kBq/kg, or three injections with 400 kBq/kg 227Th-trastuzumab separated by 4 weeks. Two control groups were given either 20 µg unlabeled trastuzumab or 0.9% NaCl. In vivo bioluminescence imaging was performed weekly before and after onset of therapy. Tumor growth, survival and toxicity were compared.
There was a statistically significant therapeutic effect of the 227Th-trastuzumab treatment both with respect to survival and tumor growth. The maximum tolerated dosage was 600 kBq/kg 227Th-trastuzumab. In the in vitro study, two hours incubation with 20 kBq/ml of 227Th-trastuzumab, followed by washing, and subsequent culture of the cells resulted in an average absorbed radiation dose of 6 Gy after 11 days and complete growth inhibition.
Targeted alpha therapy with 227Th-trastuzumab of human SKOV3-luc-D3 cells growing intraperitoneally in nude mice was clearly superior to unlabeled trastuzumab therapy. The results warrant further studies of 227Th-radioimmunotherapy used as adjuvant treatment and for metastatic cancer.
本研究的目的是探讨227Th放射免疫疗法对腹腔内生长的人生物发光HER2阳性卵巢癌细胞的治疗效果。
在生长试验中评估227Th-曲妥珠单抗对生物发光SKOV3-luc-D3卵巢癌细胞的体外毒性。测定腹腔注射227Th-曲妥珠单抗在无肿瘤细胞的裸鼠体内的生物分布。对于体内治疗，70只雌性裸鼠在注射单剂量1000 kBq/kg、600 kBq/kg或400 kBq/kg的227Th-曲妥珠单抗，或分三次注射400 kBq/kg的227Th-曲妥珠单抗（间隔4周）前17天腹腔接种肿瘤细胞。两个对照组分别给予20 μg未标记的曲妥珠单抗或0.9%氯化钠。在治疗开始前后每周进行体内生物发光成像。比较肿瘤生长、生存和毒性。
227Th-曲妥珠单抗治疗在生存和肿瘤生长方面均有统计学显著的治疗效果。最大耐受剂量为600 kBq/kg的227Th-曲妥珠单抗。在体外研究中，用20 kBq/ml的227Th-曲妥珠单抗孵育2小时，然后洗涤，随后培养细胞，11天后平均吸收辐射剂量为6 Gy，生长完全抑制。
用227Th-曲妥珠单抗对裸鼠腹腔内生长的人SKOV3-luc-D3细胞进行靶向α治疗明显优于未标记的曲妥珠单抗治疗。这些结果值得对227Th放射免疫疗法作为辅助治疗和用于转移性癌症进行进一步研究。
