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Amifostine and melatonin attenuate radiation-induced oxidative stress, inflammation, and fibrotic remodeling in the vocal folds and subglottic glands of rats

Published on Wednesday, 22 October 2025

Abstract

Head and neck radiotherapy is an effective treatment for cancer but often causes collateral injury to adjacent laryngeal tissues, leading to complications such as impaired voice production and mucosal dysfunction.

This study examined whether pretreatment with amifostine or melatonin could mitigate radiation-induced morphological and molecular alterations in the vocal fold (VF) lamina propria and subglottic glands (SGs).

Twenty-four male Sprague Dawley rats were randomly assigned to control, radiation only (RT), RT plus amifostine (RT+AMI), or RT plus melatonin (RT+MEL) groups. A single 15 Gy dose was delivered to the head and neck, and tissues were collected on day 10.

Radiation induced early fibrotic remodeling in the VFs, characterized by increased collagen I/III deposition and TGF-β1 expression, and caused pronounced SG structural damage, including ductal dilation, acinar atrophy, and elastin fiber disorganization. Both agents attenuated collagen accumulation, preserved elastin architecture, and reduced fibrotic marker expression, with melatonin showing a greater effect in the VFs. Despite these structural improvements, mRNA levels of AQP5, AMY1, and hyaluronic acid synthase remained unchanged, suggesting that functional decline had not yet fully manifested at this early stage.

These findings indicate that amifostine and melatonin provide partial radioprotection against acute fibrotic and structural damage in laryngeal tissues, supporting their potential as adjunctive agents for preserving vocal and mucosal functions during radiotherapy.

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About this publication.

The Di Bella's Method: Use of Melatonin, pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea, Somatostatin/Octreotide analogues and/or derivatives with Cabergoline and/or Bromocriptine (together with others chemical compounds) in Head&Neck Cancer:

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day and more orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);