Abstract
PurposeOral mucositis (OM) is a common, painful side effect of radiation therapy used for the treatment of head and neck cancer (HNC). Activation of the innate immune system upon irradiation has been identified as a key precipitating event of OM. To better understand OM’s pathogenesis, we studied pattern recognition receptors (PRRs) and their downstream pro-inflammatory cytokines in a mouse model of radiation-induced OM. We also tested therapeutic efficacy of GM-1111 that targets innate immune system to reduce radiation-induced OM.Methods and materialsThe pathogenesis of OM was studied in a single X-ray induced mouse model. The severity of OM was measured by visual and microscopical examinations. The irradiation-induced changes of PRRs and their downstream effector cytokine gene expression levels were determined. The efficacy of GM-1111 to reduce OM was tested in single and fractionated irradiation mouse models. The impact of the drug on tumor response to radiation therapy was also tested in a mouse model of human HNC.ResultsRadiation-induced tissue ulcerations were radiation-dosage and -time dependent. The lesions showed selective increases in PRR and pro-inflammatory cytokine gene expression levels. Once daily administration of GM-1111 (≥30 mg/kg, s.c.) significantly reduced the severity and the incidence of OM. The drug had little effect on PRRs but significantly inhibited downstream pro-inflammatory cytokine genes. GM-1111 did not interfere radiation therapy to induce HNC SCC-25 tumor regression. Instead, we observed significant drug-induced tumor regression.ConclusionsRadiation induces tissue damages. The increased expression levels of PRRs and their downstream pro-inflammatory cytokine genes in the damaged tissues suggest their important contribution to the pathogenesis of OM. Drug GM-1111 that targets these innate immune molecules may be a potential drug candidate as an intervention for OM.
Highlights
Oral mucositis is a common, painful, and potentially treatment disrupting side effect of radiation therapy used for the treatment of head and neck cancer (HNC)
Oral mucositis (OM) is a common, painful side effect of radiation therapy used for the treatment of head and neck cancer (HNC)
To better understand OM’s pathogenesis, we studied pattern recognition receptors (PRRs) and their downstream proinflammatory cytokines in a mouse model of radiation-induced OM
Summary
Oral mucositis is a common, painful, and potentially treatment disrupting side effect of radiation therapy used for the treatment of HNCs. Pre-clinical and clinical data from studies in which interventional strategies aimed at interfering with either initiating elements suggest their value as druggable targets [3,4,5] and indicate that blocking initiation favorably disrupts the downstream progression of the biological events that amplify tissue injuries. In addition to its role in the initiation of OM, molecules released during cell death serve to exacerbate radiation-induced damage by continuously activating innate immune signaling pathways. These molecules are known as damage-associated molecular patterns (DAMPs, CRAMPs, or alarmins) [6,7,8]. The sequence by which activation of the innate immune system is implicated in radiation-induced tissue injury has not been well described
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