Effects of I-125 seeds combined with anlotinib on tumor growth and bone metabolism in A549 tumor-bearing mice

Abstract

Purpose

This study aimed to investigate the therapeutic potential of tumor suppression and mechanism for different implantation modes of iodine-125 (I-125) seeds irradiation in a mice xenograft model, and its skeletal complications.

Materials and methods

A total of 24 mice carrying A549 lung tumor-derived xenografts were randomly assigned to four groups, including non-radioactive (sham) seeds implantation, I-125 seeds fractional implantation, I-125 seeds single implantation and I-125 seeds single implantation combined with anlotinib. Ki67 immunohistochemistry, TUNEL immunofluorescence and CD31 morphometric analysis were used to determine the proliferation index, rate of apoptotic cells and microvessel density, respectively. Additionally, the side effects on the skeletal system in mice treated with I-125 seeds implantation were evaluated by histomorphometric staining with tartrate-resistant acid phosphate (TRAP) and alkaline phosphatase (ALP) expression in femur, tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen type I N-terminal propeptide (PINP) levels in serum were evaluated by enzyme-linked immunosorbent assay (ELISA).

Results

The I-125 seeds single and fractionated implantation had similar therapeutic effects and complications when the total number of I-125 seeds was the same. A single implantation of I-125 seeds with or without anlotinib could analogously inhibit the tumor growth in xenografts mice, while the single implantation combined with anlotinib had more effective in tumor inhibition. The results of Ki67, TUNEL and CD31 staining confirmed an evident reduction in tumor cell proliferation and angiogenesis, as well as an increase in apoptosis. A relatively integrated bone metabolism was indicated after I-125 seeds single implantation with or without anlotinib, and the results were similar in I-125 seeds fractional implantation, including a reduction in the number of TRAP-positive cells and an increase in ALP expression level. Additionally, the serum TRACP-5b activity was decreased and the serum PINP concentration was increased following I-125 seeds implantation.

Conclusions

Single and fractionated implantation pattern of I-125 radioactive seeds had similar therapeutic efficacy against tumor growth, while brachytherapy with I-125 seeds implantation may be an effective and safe treatment strategy for its potential protection against cancer treatment-induced bone loss.

Keywords:

• I-125 radioactive seed
• lung cancer
• bone metabolism
• anlotinib

Ethics approval and consent to participate

All the animal experimental procedures were approved by the Committee for Ethical Use of Experimental Animal at Fudan University.

Authors contributions

F. H., Q. B., J. B., J. W., and W. G. performed the experiments. F. H., Q. Y., C. W., K. Z., and J. Z. supervised data collection and analysis. F. H., W. S., and G. Z. designed the study and wrote the paper. All authors have read and approved the final version of the manuscript.

Disclosure statement

The authors declare no conflict of interest exits in this manuscript.

Data availability statement

The datasets generated and analyzed in the present study are available from the corresponding author on reasonable request.

Additional information

Funding

This study was funded by Shanghai Municipal Health Commission under Contract Number GWV-10.1-XK10. This study was supported by the Shanghai Natural Science Fund [Grant No. 14ZR1401600] and the Shanghai Municipal Commission of Health [Grant Nos. 2013ZYJB0801 and 20154Y0202].

Notes on contributors

Feilong He

Feilong He, MSc, graduated from Institute of Radiation Medicine, Fudan University. Now he is a public health physician in Shanghai municipal center for disease control & prevention, Shanghai, PR China.

Qi Bao

Qi Bao, PhD, a professor and associate chief physician of Department of Thoracic Surgery, Long Hua Hospital Affiliated to Shanghai TCM University. His research focuses on effects of traditional Chinese medicine.

Jiangtao Bai

Jiangtao Bai, MSc, MA, a graduated student of Institute of Radiation Medicine, Fudan University, Shanghai, PR China. Her research focuses on effects of bone damage induced by radiation.

Jianping Wang

Jianping Wang, a senior technologist in the Institute of Radiation Medicine, Fudan University, Shanghai, PR China. He has an extent experience in cell culture and animal experiment.

Jianglong Zhai

Jianglong Zhai, MSc, an Assistant Researcher in the Institute of Radiation Medicine, Fudan University, Shanghai, PR China. He has an extent experience in radiotherapy planning.

Qiquan Yu

Qiquan Yu, MSc, MA, an attending physician of Department of Thoracic Surgery, Long Hua Hospital Affiliated to Shanghai TCM University.

Wentao Guo

Wentao Guo, MSc, an attending physician in the Department of Thoracic Surgery, Long Hua Hospital Affiliated to Shanghai TCM University.

Chunxiao Wu

Chunxiao Wu, MSc, an attending physician in the Department of Thoracic Surgery, Long Hua Hospital Affiliated to Shanghai TCM University.

Kun Zhang

Kun Zhang, MSc, an attending physician in the Department of Thoracic Surgery, Long Hua Hospital Affiliated to Shanghai TCM University.

Weizhen Shou

Weizhen Shou, MD, PhD, a Professor and chief physician of Department of Thoracic Surgery, Long Hua Hospital Affiliated to Shanghai TCM University. Dr. Shou’s research focuses on traditional Chinese medicine clinical research.

Guoying Zhu

Guoying Zhu, MD, PhD, a Professor of Radiation Medicine, and a Senior Researcher in the Institute of Radiation Medicine, Fudan University, Shanghai, PR China. Dr. Zhu’s research focuses on effects of bone tissue damage induced by radiation and environmental heavy metal.