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Early prediction of tumor response after radiotherapy in combination with cetuximab in nasopharyngeal carcinoma using 99m Tc-duramycin imaging - 14/03/20

Doi : 10.1016/j.biopha.2020.109947 
Cheng Liu a, b, c, d, e, f, Yi Li a, b, c, d, e, f, Xiaojia Qin a, b, c, d, e, f, Ziyi Yang a, b, c, d, e, f, Jianmin Luo a, b, c, d, e, f, Jianping Zhang a, b, c, d, e, f, Brian Gray g, Koon Y. Pak g, Xiaoping Xu a, b, c, d, e, f, , Jingyi Cheng a, b, c, d, e, f, , Yingjian Zhang a, b, c, d, e, f
a Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 201321, China 
b Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China 
c Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 
d Center for Biomedical Imaging, Fudan University, Shanghai 200032, China 
e Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China 
f Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai 200433, China 
g Molecular Targeting Technologies, Inc., West Chester, PA, 19380, USA 

Corresponding authors at: 4365 Kangxin Road, Shanghai 201321, China.4365 Kangxin RoadShanghai201321China

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Highlights

High levels of EGFR are observed in mostly NPC patients, which is related to poor clinical outcomes.
A combination of radiotherapy and cetuximab exhibited more profound effects on NPC tumors by inducing more apoptosis.
The uptake of 99mTc-duramycin accurately reflects the level of cell death as validated by ex vivo histology.
99mTc-duramycin offers an early, noninvasive and dynamic method to monitor the therapy, knowing the early response in vivo.

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Abstract

Purpose

99mTc-duramycin imaging enables specific visualization of cell death qualitatively and quantitatively. This study aimed to investigate the potential of 99mTc-duramycin imaging in the early prediction of the curative effect of radiotherapy in combination with or without cetuximab in a nasopharyngeal carcinoma (NPC) model.

Methods

Male BALB/c mice bearing NPC xenografts were randomized into four groups (six mice each group). Group 1 received radiotherapy (RT, 15 Gy/mouse) in combination with cetuximab (CTX, 2 mg/mouse), group 2 received RT (15 Gy/mouse), group 3 was treated using CTX (2 mg/mouse), and group 4, the control group, was treated using a vehicle. 99mTc-duramycin imaging was performed before treatment and 24 h after treatment to evaluate tumor response. Tumor uptake of 99mTc-duramycin was validated ex vivo using γ-counting. Treatment response was further validated by cleaved caspase-3 (CC3) and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL). Another four groups were treated parallelly under the same conditions to observe treatment response by tumor volume changes.

Results

After 24 h treatment, 99mTc-duramycin uptake in the NPC tumor models were significantly higher in group 1 than in group 2 (P < 0.05), group 3 (P < 0.05), or group 4 (P < 0.05); the uptake also increased notably in comparison with baseline values (P < 0.05). Compared with group 4, group 2 and group 3 both showed significant 99mTc-duramycin uptake in the tumors (P < 0.05). Although the 99mTc-duramycin uptake of group 2 was moderately higher than group 3, there were no significant differences between these two groups (P >0.05). There was a strong positive correlation between tumor 99mTc-duramycin uptake and CC3 (r = 0.893, p < 0.0001) and TUNEL (r = 0.918, P < 0.0001). Tumor volume decreased remarkably in the RT in combination with CTX group on day 5, in the RT alone group on day 7, and was inhibited on day 8 in the CTX alone group, whereas the tumors grew continuously in the control group.

Conclusions

We demonstrated that RT in combination with CTX treatment significantly improved disease control in a NPC xenograft model compared with monotherapy with either. 99mTc-duramycin imaging might be able to reliably identify response to RT in combination with CTX as early as 24 h after therapy initiation in NPC xenograft models. This might help to isolate non-responding patients in a timely manner and avoid unnecessary side effects in the clinic in the future.

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Keywords : 99mTc-duramycin, Nasopharyngeal carcinoma, Cell death, Radiotherapy, Cetuximab


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