Pharmacodynamics and biodistribution of radiolabeled Platinum-195m (Cisspect) in head and neck squamous cell carcinoma

Abstract

Abstract Background Cisplatin- based chemoradiotherapy is a crucial pillar in the treatment of HNSCC. The use of cisplatin comes with a high burden as 35% of patients cannot sustain the planned dose. 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®) promises to be a potential biomarker of response using imaging and biodistribution. The aim of this study is to investigate the biodistribution of [195mPt]Cisplatin between known cisplatin-sensitive (VU-SCC-1131) and –resistant (VU-SCC-OE) HNSCC cell lines in vitro and xenografts in mice in vivo. Results Being more sensitive to cisplatin than VU-SCC-OE, cell cycle experiments showed a severely hampered G1 and S-phase in VU-SCC-1131 after low dose treatment with cisplatin compared to VU-SCC-OE. Remarkably, VU-SCC-OE was able to accumulate more [195mPt]Cisplatin in the DNA, and showed an increased capability to repair Pt-195m cisplatin crosslinks as compared to VU-SCC-1131. Notably, uptake increased even when cisplatin was removed from the medium, likely by intracellular sources. In vivo, [195mPt]Cisplatin was rapidly distributed to large organs and similar between intravenous and intraperitoneal administration. Most of 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 hr, while decreasing after 6 hrs in accordance with the circulating concentration. Remarkably, there was no significant difference in uptake and retention between xenografts of the sensitive and resistant cell line. Conclusion VU-SCC-1131 with an FA deficiency and VU-SCC-OE displayed a significant difference in sensitivity to and recovery from cisplatin, due to a S-phase problems in VU-SCC-1131 at low dose in line with the genetic defect. Using Pt-195m radioactivity analysis, we demonstrated the limited capability of cisplatin crosslink repair in VU-SCC-1131. We were not able to translate these findings to a mouse model for sensitivity prediction based on the biodistribution in the tumor. The organ-specific distribution data of [195mPt]Cisplatin could possibly be used to predict the toxic side-effects of cisplatin and facilitate optimizing therapeutic dosing schemes.