Locally administered heparin-binding epidermal growth factor-like growth factor reduces radiation-induced oral mucositis in mice

Abstract

Oral mucositis refers to lesions of the oral mucosa observed in patients with cancer being treated with radiation with or without chemotherapy, and can significantly affect quality of life. There is a large unmet medical need to prevent oral mucositis that can occur with radiation either alone or in combination with chemotherapy. We investigated the efficacy of locally administered heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent epithelial proliferation and migration stimulator of the oral mucosa as a potential therapy to prevent radiation induced oral mucositis. Using a single dose (20 Gy) of radiation to the oral cavity of female C57BL/6 J mice, we evaluated the efficacy of HB-EGF treatment (5 µl of 10 µg/ml) solution. The results show that HB-EGF delivered post radiation, significantly increased the area of epithelial thickness on the tongue (dorsal tongue (42,106 vs 53,493 µm2, p < 0.01), ventral tongue (30,793 vs 39,095 µm2, *p < 0.05)) compared to vehicle control, enhanced new epithelial cell division, and increased the quality and quantity of desmosomes in the oral mucosa measured in the tongue and buccal mucosa. This data provides the proof of concept that local administration of HB-EGF has the potential to be developed as a topical treatment to mitigate oral mucositis following radiation.

A preclinical model to investigate normal tissue damage following fractionated radiotherapy to the head and neck

“…Current radical RT of H&N cancer is delivered as fractionated treatment, normally in fractions of 2 Gy to a total dose of typically 70 Gy [4]. Still, most previous studies investigating the side effects of RT in the H&N region of murine model systems have used either single dose (SD) irradiation or extremely hypofractionated schedules with few fractions of very high doses [5][6][7][8][9][10]. Some studies have used fractionation for H&N experiments [11][12][13][14], but without any justification for the choice of dose.…”

A preclinical model to investigate normal tissue damage following fractionated radiotherapy to the head and neck

“…In preclinical research, the selection of different rodent strains for such studies also influences the results due to strain-specific variations in response to RT-induced damage such as oral mucositis (20) and morphological and functional changes of the salivary glands (21). Radiationinduced side effects of the H&N have previously been studied in hamsters (22,23), rats (24)(25)(26), and mice (7,8,10,13,27). Due to the lack of assay reagents available for hamsters, and that it is easier to keep a larger number of mice than hamsters or rats, mice were chosen for the present preclinical model.…”

“…Current radical RT of H&N cancer is delivered as fractionated treatment, normally in fractions of 2 Gy to a total dose of typically 70 Gy (4). Still, most previous studies investigating the side effects of RT in the H&N region of murine model systems have used either single dose (SD) irradiation or extremely hypofractionated schedules with few fractions of very high doses (5)(6)(7)(8)(9)(10). Some studies have used fractionation for H&N experiments (11)(12)(13)(14), but without any justification for the choice of dose.…”

“…Also, the radiation field(s) employed in previous studies did not cover the typical region as seen in patients, which should encompass areas such as the oral cavity, the oropharynx, and the laryngopharynx. Examples from the literature encompass large radiation fields including the entire head or upper body of the animal (5,8,10) or small radiation fields only covering e.g., the tongue or snout of the animal (9,(11)(12)(13), which differ from radiation fields used in the clinic. Thus, preclinical studies employing more clinically relevant radiation fields and fractionated radiation delivery are highly needed.…”

Paradoxical Roles of Desmosomal Components in Head and Neck Cancer

“…The alterations of desmosome expression and localization are vital manifestations of oral tumor development, which can be used as a molecular indicator for early diagnosis and treatment. For example, local administration of heparin-binding epidermal growth factor (HB-EGF), an effective stimulator for preventing radiation-induced oral mucositis, increased the quality and quantity of desmosome in the tongue and buccal mucosa of mice [61]. N,N-dimethylformamide (DMF) is an anti-tumor compound that can induce cancer cells to form better-differentiated phenotypes.…”