骨肉瘤的缺氧微环境与放疗增敏进展

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Abstract Radiotherapy is an important adjuvant treatment for malignant tumors, but osteosarcoma is not very sensitive to radiotherapy, furthermore, there is a certain radiotherapy resistance. Radiation doses, equivalent to or larger than radiation-sensitive tumors needed (such as retinoblastoma, nasopharyngeal carcinoma, ovarian cancer in ovarian cancer, testicular seminoma, renal embryonal tumor, malignant lymphoma, etc.), are not enough to achieve local control rates. Many studies have shown that the 5-year local control rate of low-dose fractionated radiothe-rapy for osteosarcoma (2 Gy/time, total 60 Gy) is 40%—68%, but there is no correlation between 5-year local control rate and survival rate. However, the concept of osteosarcoma with inherent radiotherapy resistance has been questioned by many studies. Some osteosarcoma have better radiotherapy effects than melanoma, while melanoma is recognized as a radiotherapy-resistant tumor. In addition, if a large fractionated radiotherapy is taken (the total amount is unchanged, increasing the dose of each radiotherapy),although osteosarcoma is not sensitive to ordinary X-rays, its response rate to proton and heavy ion treatment is significantly improved. Therefore, choosing the appropriate patient and adopting appropriate radiotherapy methods can improve the radiotherapy effect.
The direct cause of radiotherapy resistance is the ability of tumor cells to repair DNA damage, which is related to tumor heterogeneity. Many studies have shown that hypoxic microenvironment is the most important environmental factor for radiotherapy resistance. First, the hypoxic mic-roenvironment provides an important condition for the development of radiotherapy resistance in tumor cells. Hypoxic microenvironment stimulates cells to produce hypoxia-inducible factors (HIF). Hypoxic preconditioning can increase the radiotherapy resistance of osteosarcoma cells. Hypo-xia-inducible factor (HIF-1, HIF-2) and autophagy-related factor (LC3-II) are highly expressed in osteosarcoma tissues. If HIF gene is knocked out, autophagy level and apoptosis are significantly increased, but inhibiting autophagy, the apoptosis did not decrease, indicating that the cells were resistant to chemoradiotherapy mainly through HIF-2 in the hypoxic microenvironment. The repair of DNA damage can be assessed by monitoring DNA damage repair proteins γ-H2AX and 53BP1 for a long time.
Therefore, changing the tumor hypoxia microenvironment is an effective means of radiosensitization. The hyperbaric oxygen chamber can provide a hyperbaric oxygen environment and directly increase the oxygen content of the tumor tissue, but the patient compliance is poor and the sensitization effect is not accurate. The combination of nicotinamide (for acute hypoxia) and chronic hypoxia improvers (such as a mixture of O₂ and CO₂ gases) can significantly improve the acute and chronic anoxic environment of tumor tissue, thereby enhancing the effect of radiotherapy. In addition, it has been suggested that hyperthermia is an effective method to overcome radiotherapy resistance and increase the sensitivity of radiotherapy. Studies have shown that radiotherapy can also be significantly improved by heating the tumor tissue to 43 ℃.
In the future, radiotherapy for osteosarcoma will be based on radiotherapy sensitization research, combined with advanced techniques such as stereotactic radiotherapy, proton radiotherapy and heavy ion radiotherapy and organic combination of surgical treatment and chemotherapy, to achieve better treatment effect at a low dose and high precision.

Key words： osteosarcoma hypoxic microenvironment radiotherapy resistance radiosensitization

Published: 25 November 2019

CLC number:

TB3

Fund:This work was financially supported by the Natural Science Foundation of Beijing, China(7192226).

About author:: Chuanchao Du, received Bachelor of clinical medicine from Shandong University Qilu Medical Center, and got Medical practice Certificated in 2012. He furtherly got Master of surgery diploma from Peking University in 2014. Then he worked in the first of hospital of Tsinghua University from 2014 to 2018 as attending physician in Orthopaedic Surgery Department. Now as a PHD candidate, he focus on the diagnosis and treatments of tumors orginating from bones. Since then, he has published over ten articles about orthopaedic surgery and bone diseases.
Xiaoguang Liu, Professor of Peking University, vice President of Peking University Health Science Center, Deputy director of Orthopedics, director of the Pain Center. Pro.Liu graduated from Peking University in 1991, since then work in Peking University Third Hospital. He has published more than 220 journal papers, applied and authorized 117 national invention patents. Responsible for completing more than 11 provincial and above level scientific research projects. National 51 labor medal winner, Earthquake relief advanced figures.

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Cite this article:

DU Chuanchao,JIA Fei,LIANG Chen, et al. Hypoxic Microenvironment of Osteosarcoma and Radiotherapy Sensitization[J]. Materials Reports, 2019, 33(Z2): 97-103.

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http://www.mater-rep.com/EN/ OR http://www.mater-rep.com/EN/Y2019/V33/IZ2/97

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