The role of melatonin on acute thyroid damage induced by high dose rate X-ray in head and neck radiotherapy
Introduction
Radiotherapy (RT) is a reliable and successful treatment method applied in the treatment of malignant diseases in the head and neck. The aim is to provide the highest dose to the tumor tissue, while minimizing damage to surrounding healthy tissue, however symptoms associated to radiotherapy may occur simultaneously or separately that affect daily life activity of patients (Satheeshkumar et al., 2010). Although new treatment devices and techniques such as Intensity Modulated Radiotherapy (IMRT), Volumetric Arc Therapy (VMAT), Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiotherapy (SBRT) have been developed in addition to conventional 3-Dimension Conformal Radiotherapy (3D-CRT), unnecessary radiation exposure is unavoidable in non-target healthy tissues such as thyroid and salivary glands during RT for head and neck cancer patients (Graff et al., 2007).
Thyroid gland is an organ usually exposed to undesired radiation in the head & neck region. The ionizing radiation (IR) used in RT treatment technique can cause severe tissue damage in the thyroid gland, which is not part of the tumor tissue, especially in head & neck RT. The undesirable effects can occur at the molecular level causing changes in thyroid morphology and thyroid function (Alterio et al., 2007). In experimental rat studies, damaging effects of RT such as necrosis, celllular and vascular degeneration, thrombosis, acute and chronic inflammation and partial epithelial regeneration have been demonstrated on thyroid tissue (Bhandare et al., 2007). While minor changes in the thyroid tissue occur up to 5 Gy, larger damage have been demonstrated with different studies when thyroid tissue is exposed to much higher doses (Jereczek-Fossa et al., 2004a). Radiation-induced thyroiditis is associated with the primary damage to the thyroid gland, resulting in thyroiditis, hyperthyroiditis or hypothyroiditis. Thyroid cancer, graves disease, benign adenoma, hyperthyroiditis and hypothyroiditis radiation-induced thyroid complications have been reported in the literature (Massimino et al., 2007). Radiation-related biological effects consist of damage to the thyroid blood vessels and cell function, but the exact mechanism of damage due to radiation is not fully known (Hodgson et al., 1988).
High energy ionizing X-rays used in RT produce reactive oxygen species (ROS), toxic substances and other free radicals that interact with critical macromolecules such as lipids, proteins and DNA, causing serious cellular dysfunctions and cell death (Valko et al., 2007). Antioxidants scavenge toxic substances and free radicals produced due to conventional Flattening Filter (FF) low dose rate radiotherapy (LDR-RT) as well as Flattening Filter Free (FFF) high dose rate radiotherapy (HDR-RT). Interest in the clinical use of FFF beams have been increasing recently with advances in technology. Removal of the flattening filter causes significant increase in dose rate, less head scattering and reduced dose leakage, allowing for faster treatment and better protection of organ at risk compared to FF beams (Nakano et al., 2018).
Melatonin (Mel) is a powerful free radical scavenger and antioxidant and a remarkable chemical known as the main secretion production hormone of the pineal gland (Davanipour et al., 2009). In both in vitro and in vivo studies, it has been discovered that melatonin protects tissues against damage that can occur by significantly reducing oxidative stress and apoptosis (Shirazi et al., 2013).
These pronounced protective effects of melatonin against oxidative stress by crossing through biological membranes, reaching the highest concentration in the cell nucleus, protects DNA in the nucleus from free radicals caused by IR (Najafi et al., 2017). There are many studies showing that melatonin protects IR related tissue damages in many organs of our body such as thyroid gland, urinary bladder and lung (Sener et al., 2004; Aricigil et al., 2017). However, in experimental rat models using high energy IR, a comparative study has not yet been carried out showing the radioprotective effects of melatonin on radiation-induced thyroid gland dysfunction damage between HDR-RT and LDR-RT beam.
Therefore, in this study, we aimed to investigate the acute period radioprotective effects of melatonin against radiation-induced tissue damage in the thyroid gland by applying LDR-RT and HDR-RT ionizing X-rays to experimental rat models without any cancerous tissue. In addition, we show the radiobiological effects of FF LDR-RT and FFF HDR-RT rays on thyroid gland via scintigraphy using radioactive uptake ratios of Na99mTcO4.
Section snippets
Experimental design
Forty-eight female Sprague Dawley rats, each weighing an average of 250 ± 20 g, were used to assess thyroid tissue dysfunction caused by IR. Animal experiments and procedures were carried out in accordance with the relevant guidelines for the care and use of laboratory animals. The study protocol was approved by the Yeditepe University Animal Experiments Ethics Committee. Rats were kept in 22 ± 2 °C temperature and 55–60% humidity conditions, under controlled lighting cycle (12/12 h dark/light)
Results
Static thyroid gland scintigraphy technique with 99mTc radionuclide is often used in rats to assess dysfunction of tissue caused by low and high dose IR. In the current study, radioisotope uptake was measured in thyroid glands of rats.
Target tissue thyroid gland (T) and background (B) ratio (T/B) were examined in groups exposed to FF and FFF mode irradation and melatonin administration. In rats, before exposure to low and high dose rate radiation, T/B ratio is observed to be about 4 in thyroid
Discussion
In this study, in the pre- and post-radiotherapy period, functional damage states due to thyroid complications were demonstrated at two different dose rates using LDR-RT and HDR-RT. We demonstrated the acute period effects of changes in the thyroid gland damage after the RT process using the thyroid gland scintigraphy imaging technique.
RT is an effective treatment method for head and neck cancerous tumors. When the head and neck area is exposed to radiation, adjacent healthy tissue such as
Conclusion
In this study, we showed that 10 mg/kg melatonin administered to rats 15 min before RT procedure protected against acute rat thyroid gland dysfunction caused by single dose LDR-RT and HDR-RT. It was also observed that melatonin significantly increased the Na99mTcO4 uptake in thyroid glands. Further study could explore the radioprotective effects of melatonin not only in acute phase of thyroid tissue damage but also in the late stage due to the FF and FFF modes.
Ethics
Ethical committee approval has been obtained prior to study.
Authors contributions
Concept – SA, IOT.; Design – SA, IOT.; Supervision – SA, IOT, UC, ES.; Funding – SA, UC, ES.; Materials – SA, UC, ES, KNB.; Data Collection and/or Processing – SA, IOT, UC.; Analysis and/or Interpretation – SA, IOT, KNB, UC.; Literature Review – SA, UC.; Writer – SA, IOT; Critical Review – SA, IOT, UC, ES, KNB.
Statistical Analysis
All data were analysed in SPSS 25. Experimental data were expressed as the mean and standard deviation (SD).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
This study was supported by the Scientific Research Projects (BAP) Grants Unit, University of Health Sciences, Istanbul, TURKEY [Grant Number: 2019/055].
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