de Roest Reinout H, Stigter van Walsum Marijke, van der Schilden Karlijn, Brakenhoff Ruud H
Otolaryngology/Head and Neck Surgery, Head and Neck Cancer Biology and Immunology laboratory, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands.
EJNMMI Res. 2024 Mar 1;14(1):22. doi: 10.1186/s13550-024-01082-w.
Cisplatin- based chemoradiotherapy is a crucial pillar in the treatment of HNSCC. The use of cisplatin comes with high toxicity rates as 35% of patients cannot sustain the planned dose while response is unpredictable. Unfortunately, there are no clinically applicable biomarkers to predict response. Based on the association of response with the number of DNA adducts and the involved molecular pathway to resolve cisplatin-induced DNA crosslinks in HNSCC, [195mPt]cisplatin (CISSPECT®) might have potential to monitor drug uptake and retention before treatment, and predict cisplatin response. The aim of this study is to investigate this concept by analyzing uptake, retention and biodistribution of [195mPt]cisplatin between known cisplatin-sensitive (VU-SCC-1131) and -resistant (VU-SCC-OE) HNSCC cell lines in vitro and xenografted in mice in vivo.
By a variety of experiments in vitro, including cell cycle analyses, and in vivo, the sensitivity of cell line VU-SCC-1131 and resistance of cell line VU-SCC-OE for cisplatin was demonstrated. VU-SCC-OE was able to accumulate more [195mPt]cisplatin in the DNA, and showed an increased capability to repair [195mPt]cisplatin crosslinks compared to VU-SCC-1131. Notably, DNA binding of cisplatin increased even when cisplatin was removed from the medium, likely from intracellular sources. In vivo, [195mPt]cisplatin showed a rapid biodistribution to the large organs such as the liver, with no differences between intravenous and intraperitoneal administration. Most circulating [195mPt]cisplatin was cleared by renal filtration, and accumulation in kidney and liver remained high. Uptake in xenografts was rapid (blood:tumor ratio; 1:1) and highest after 1 h, while decreasing after 6 h in line with the concentration in the blood. Remarkably, there was no significant difference in uptake or retention between xenografts of the cisplatin-sensitive and -resistant cell line.
VU-SCC-1131 with a known FA deficiency and VU-SCC-OE displayed a significant difference in sensitivity to and recovery from cisplatin treatment, due to S-phase problems in VU-SCC-1131 at low doses, in line with the genetic defect. Using Pt-195m radioactivity analysis, we demonstrated the limited capability of cisplatin crosslink repair in VU-SCC-1131. Unexpectedly, we were not able to translate these findings to a mouse model for sensitivity prediction based on the biodistribution in the tumor, most likely as other factors such as influx counterbalanced repair. These data do not support response prediction by [195mPt]cisplatin, and applications to predict the toxic side-effects of cisplatin and to tailor dosing schemes seem more feasible.
基于顺铂的放化疗是头颈部鳞状细胞癌（HNSCC）治疗的关键支柱。顺铂的使用伴随着高毒性率，因为35%的患者无法承受计划剂量，而反应是不可预测的。不幸的是，目前尚无临床适用的生物标志物来预测反应。基于HNSCC中反应与DNA加合物数量以及参与解决顺铂诱导的DNA交联的分子途径之间的关联，[195mPt]顺铂（CISSPECT®）可能有潜力在治疗前监测药物摄取和滞留，并预测顺铂反应。本研究的目的是通过分析[195mPt]顺铂在已知对顺铂敏感（VU-SCC-1131）和耐药（VU-SCC-OE）的HNSCC细胞系中的摄取情况、滞留情况和生物分布，在体外和体内移植到小鼠体内的模型中研究这一概念。
通过包括细胞周期分析在内的多种体外实验以及体内实验，证明了细胞系VU-SCC-1131对顺铂的敏感性和细胞系VU-SCC-OE对顺铂的耐药性。与VU-SCC-1131相比，VU-SCC-OE能够在DNA中积累更多的[195mPt]顺铂，并且显示出修复[195mPt]顺铂交联的能力增强。值得注意的是，即使从培养基中去除顺铂，顺铂与DNA的结合仍会增加，这可能源于细胞内来源。在体内，[195mPt]顺铂迅速分布到肝脏等大器官，静脉注射和腹腔注射之间没有差异。大多数循环中的[195mPt]顺铂通过肾脏滤过清除，肾脏和肝脏中的积累仍然很高。移植瘤中的摄取迅速（血液：肿瘤比值为1:1），在1小时后达到最高，而在6小时后随着血液中浓度的降低而下降。值得注意的是，顺铂敏感和耐药细胞系的移植瘤在摄取或滞留方面没有显著差异。
已知存在FA缺陷的VU-SCC-1131和VU-SCC-OE在对顺铂治疗的敏感性和恢复方面表现出显著差异，这是由于低剂量时VU-SCC-1131中存在S期问题，与遗传缺陷一致。使用Pt-195m放射性分析，我们证明了VU-SCC-1131中顺铂交联修复能力有限。出乎意料的是，我们无法将这些发现转化为基于肿瘤生物分布的小鼠敏感性预测模型，最有可能是因为其他因素如流入量抵消了修复作用。这些数据不支持通过[195mPt]顺铂进行反应预测，而应用于预测顺铂的毒副作用和调整给药方案似乎更可行。
