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Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection.

ABSTRACT: Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

SUBMITTER: Varghese JJ

PROVIDER: S-EPMC6151913 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection.

Varghese J J JJ Schmale I L IL Mickelsen D D Hansen M E ME Newlands S D SD Benoit D S W DSW Korshunov V A VA Ovitt C E CE

Journal of dental research 20180410 11

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we ...[more]

PMID: 29634396

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Project description:PurposeXerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage.Methods and materialsWe used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72 hours before receiving 15 Gy of focal irradiation. Saliva flow was measured 3, 7, and 28 days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment.ResultsIrradiated mice showed a 50% reduction in saliva flow after 3 days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3 days after IR. BTX pretreatment reduced LIX levels by 40%. At 4 weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation.ConclusionsThese data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.

Project description:Introduction and importanceSalivary calculi represent the most common salivary gland disease. It can vary significantly in size, ranging from less than 1 mm to several centimeters. As the size of the stone increases, the surgical approach becomes more complex and the function of the gland may be compromised, potentially necessitating total gland removal. Successful outcomes depend on appropriate indications, precise surgical techniques, and comprehensive postoperative care.Case presentationA 50-year-old male presented with a chief complaint of pain and swelling in the submandibular region. The patient reported persistent discomfort in the submandibular area for several weeks. Over the last three weeks, his symptoms had intensified, accompanied by an unpleasant taste in his mouth with pain and swelling, especially during meat time. Clinical examination had shown no salivary secretion observed with tenderness across the Wharton duct. Radiological assessment revealed a large salivary stone obstructing the duct of the submandibular gland, the patient underwent surgery under general anesthesia, and an incision was made over the bulge corresponding to the stone. Dissection proceeded through the mucosa until the duct was accessed. The function of the salivary gland was observed, and the return of salivary secretion was confirmed, which was observed immediately after the surgery, and the patient was discharged 5 days after the surgery.DiscussionThe treatment plans for such cases vary between non-invasive conservative management of sialolithiasis, which includes gland massage (combined with the use of sialogogues and irrigation), and advance aggressive management, which may involve extracorporeal shock-wave lithotripsy, sialoendoscopy, or surgical removal.ConclusionTransoral surgical removal of large stones from the submandibular gland and duct can be an effective and minimally invasive treatment option for sialolithiasis. Proper indications, surgical techniques, and postoperative care are essential for achieving optimal outcomes, minimizing complications, and ensuring successful results.

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Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection.

Publications

Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection.

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