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

Cheng Liu; Yi Li; Xiaojia Qin; Ziyi Yang; Jianmin Luo; Jianping Zhang; Brian Gray; Koon Y Pak; Xiaoping Xu; Jingyi Cheng; Yingjian Zhang

doi:10.1016/j.biopha.2020.109947

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

Biomed Pharmacother. 2020 May:125:109947. doi: 10.1016/j.biopha.2020.109947. Epub 2020 Feb 12.

Authors

Cheng Liu¹, Yi Li¹, Xiaojia Qin¹, Ziyi Yang¹, Jianmin Luo¹, Jianping Zhang¹, Brian Gray², Koon Y Pak², Xiaoping Xu³, Jingyi Cheng⁴, Yingjian Zhang¹

Affiliations

¹ Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 201321, China; Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China; Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai 200433, China.
² Molecular Targeting Technologies, Inc., West Chester, PA, 19380, USA.
³ Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 201321, China; Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China; Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai 200433, China. Electronic address: xxp0012@ustc.edu.
⁴ Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 201321, China; Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China; Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai 200433, China. Electronic address: jcheng13@fudan.edu.cn.

PMID: 32058215
DOI: 10.1016/j.biopha.2020.109947

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.

Keywords: (99m)Tc-duramycin; Cell death; Cetuximab; Nasopharyngeal carcinoma; Radiotherapy.

Publication types

Comparative Study

MeSH terms

Animals
Antineoplastic Agents, Immunological / administration & dosage
Antineoplastic Agents, Immunological / pharmacology
Bacteriocins / administration & dosage*
Cell Line, Tumor
Cetuximab / administration & dosage
Cetuximab / pharmacology*
Combined Modality Therapy
Humans
In Situ Nick-End Labeling
Male
Mice
Mice, Inbred BALB C
Nasopharyngeal Carcinoma / pathology
Nasopharyngeal Carcinoma / therapy*
Nasopharyngeal Neoplasms / pathology
Nasopharyngeal Neoplasms / therapy*
Peptides / administration & dosage*
Technetium / chemistry
Treatment Outcome
Tumor Burden / drug effects
Tumor Burden / radiation effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Immunological
Bacteriocins
Peptides
duramycin
Technetium
Cetuximab