Bioticla Team, EA1772, IFR 146 ICORE, GRECAN, François Baclesse Cancer Centre and Caen University, Caen, France.
J Nucl Med. 2010 Oct;51(10):1559-64. doi: 10.2967/jnumed.109.073288. Epub 2010 Sep 16.
Targeting the mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming cisplatin resistance in ovarian cancer patients. Because mTOR inhibition affects cell proliferation, we aimed to study whether 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET could be useful for monitoring early response to treatment with mTOR inhibitors in an animal model of cisplatin-resistant ovarian tumor.
BALB/c nude mice bearing subcutaneous human SKOV3 ovarian cancer xenografts were treated with either the mTOR inhibitor everolimus (5 mg/kg) or vehicle, and (18)F-FLT PET was performed at baseline, day 2, and day 7 of treatment. (18)F-FLT uptake was evaluated by calculation of mean standardized uptake value (SUVmean) corrected for partial-volume effect. Ex vivo immunohistochemistry studies were performed on separate cohorts of mice treated as above and sacrificed at the same time points as for the PET studies. The ex vivo analysis included bromodeoxyuridine incorporation as a marker of cell proliferation, and phosphorylation of ribosomal protein S6 as a downstream marker of mTOR activation.
During the treatment period, no significant change in tumor (18)F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, (18)F-FLT SUVmean decreased by 33% (P = 0.003) at day 2 and 66% (P < 0.001) at day 7, compared with baseline. Notably, the reduction of (18)F-FLT uptake observed at day 2 in the everolimus group preceded changes in tumor volume, and a significant difference in (18)F-FLT uptake was observed between vehicle and drug-treated tumors at both day 2 (P = 0.0008) and day 7 (P = 0.01). In ex vivo studies, everolimus treatment resulted in a 98% reduction in phosphorylated ribosomal protein S6 immunostaining at day 2 (P = 0.02) and 91% reduction at day 7 (P = 0.003), compared with the vehicle group. Bromodeoxyuridine incorporation was reduced by 65% at day 2 (not significant) and by 41% at day 7 (P = 0.02) in drug versus vehicle groups.
Reduction in (18)F-FLT uptake correlates well with the level of mTOR inhibition by everolimus in the SKOV3 ovarian tumor model. These data suggest that early treatment monitoring by (18)F-FLT PET may be of use in future preclinical or clinical trials evaluating treatment of cisplatin-resistant ovarian tumors by mTOR inhibitors.
靶向哺乳动物雷帕霉素靶蛋白（mTOR）途径是克服卵巢癌患者顺铂耐药的一种潜在手段。由于 mTOR 抑制作用会影响细胞增殖，我们旨在研究在顺铂耐药卵巢肿瘤动物模型中，3'-去氧-3'-(18)F-氟胸苷（(18)F-FLT）PET 是否可用于监测 mTOR 抑制剂治疗的早期反应。
在携带人 SKOV3 卵巢癌皮下异种移植物的 BALB/c 裸鼠中，给予 mTOR 抑制剂依维莫司（5mg/kg）或载体治疗，并在治疗的基线、第 2 天和第 7 天进行（18）F-FLT PET。通过计算校正部分容积效应后的平均标准化摄取值（SUVmean）来评估（18）F-FLT 摄取。对以相同方式接受治疗并在与 PET 研究相同时间点处死的单独队列的小鼠进行离体免疫组织化学研究。离体分析包括溴脱氧尿苷掺入作为细胞增殖的标志物，以及核糖体蛋白 S6 的磷酸化作为 mTOR 激活的下游标志物。
在治疗期间，载体组肿瘤（18）F-FLT 摄取无明显变化，而在依维莫司治疗的小鼠中，与基线相比，第 2 天（P=0.003）和第 7 天（P<0.001）（18）F-FLT SUVmean 分别下降 33%和 66%。值得注意的是，依维莫司组在第 2 天观察到的（18）F-FLT 摄取减少先于肿瘤体积的变化，并且在第 2 天（P=0.0008）和第 7 天（P=0.01），药物治疗和未治疗肿瘤之间的（18）F-FLT 摄取存在显著差异。在离体研究中，与载体组相比，依维莫司治疗在第 2 天（P=0.02）和第 7 天（P=0.003）使磷酸化核糖体蛋白 S6 免疫染色减少 98%和 91%。第 2 天（无统计学意义）和第 7 天（P=0.02），药物组的溴脱氧尿苷掺入分别减少 65%和 41%。
（18）F-FLT 摄取的减少与依维莫司在 SKOV3 卵巢肿瘤模型中对 mTOR 的抑制程度密切相关。这些数据表明，（18）F-FLT PET 早期治疗监测可能对未来评估 mTOR 抑制剂治疗顺铂耐药卵巢肿瘤的临床前或临床试验有用。
