Effect of a mouth rinse formulation with human trefoil factor 1-secreting Lactococcus lactis in experimental oral mucositis in hamsters

e14570 Background: Oral mucositis (OM) is a painful and dose-limiting toxicity of cancer chemotherapy and irradiation, characterized by breakdown of the oral mucosa. Trefoil factors (TFFs) are involved in protecting and healing mucosal tissue, and might thus represent a pharmacological tool for treatment of OM. Local delivery of recombinant TFFs at the oral mucosa by living, genetically modified Lactococcus (L.) lactis bacteria (ActoBiotics) seems a promising, safe and cost-effective clinical approach for the prevention and attenuation of oral mucositis. Methods: An environmentally contained Lactococcus lactis strain (AG013), engineered to express human (h)TFF1, was formulated for topical administration in the form of a mouth rinse. Efficacy of AG013 was assessed in a clinically relevant hamster model of acute, radiation-induced OM. The dosing regimen was 1.3 x 109 CFU/dose, once (qd) or three rinses (tid) daily, from day 0 (=day of radiation) to day 18. OM was scored from day 6 to day 28 using the WHO grading scale, and compared to the score of placebo-treated hamsters. The viability and survival of live L. lactis and the pharmacokinetics of the hTFF1 secreted were studied in healthy and OM hamsters. Results: Topical application of AG013 to the oral mucosa significantly reduced the severity and course of radiation-induced OM. In the AG013-treated groups, the number of animals days with ulcerative mucositis (grade 3 or higher) was significantly reduced to 27.5% and 30.8% (qd and tid respectively; P < 0.001), compared to 45.8 % in the placebo-treated group. Based on the observed survival and weight changes, AG013 appeared to be well-tolerated. Pharmacokinetic studies demonstrated that both living L. lactis and the hTFF1 secreted could be recovered from the administration site, for maximum 24 hours post-dosing, without systemic exposure. Conclusions: Oral administration of AG013 is safe and effective in reducing the severity and the course of OM in the hamster model, and therefore supports proof-of-concept for a mouth rinse formulation of AG013 to treat OM patients. [Table: see text]

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Radiation‐induced oral mucositis hamster model using a linear accelerator enhances clinical relevance of preclinical studies for treatment strategy investigation

Animal Models and Experimental Medicine ◽

10.1002/ame2.12148 ◽

2021 ◽

Author(s):

Carolyn T. Jordan ◽

Emily M. Bradford ◽

Dennis C. Cheek ◽

Mahesh Kudrimoti ◽

Craig S. Miller ◽

...

Keyword(s):

Oral Mucositis ◽

Treatment Strategy ◽

Clinical Relevance ◽

Linear Accelerator ◽

Preclinical Studies ◽

Hamster Model ◽

Radiation Induced

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AG013, a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis

Oral Oncology ◽

10.1016/j.oraloncology.2010.04.008 ◽

2010 ◽

Vol 46 (7) ◽

pp. 564-570 ◽

Cited By ~ 72

Author(s):

Silvia Caluwaerts ◽

Klaas Vandenbroucke ◽

Lothar Steidler ◽

Sabine Neirynck ◽

Peter Vanhoenacker ◽

...

Keyword(s):

Lactococcus Lactis ◽

Oral Mucositis ◽

Mouth Rinse ◽

Trefoil Factor ◽

Therapeutic Tool ◽

Trefoil Factor 1

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Therapeutic Effect of Ecdysterone Combine Paeonol Oral Cavity Direct Administered on Radiation-Induced Oral Mucositis in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms20153800 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3800

Author(s):

Li Yang ◽

Jian Pan

Keyword(s):

Oral Cavity ◽

Therapeutic Effect ◽

Oral Mucositis ◽

Influential Factor ◽

Therapeutic Effects ◽

X Rays ◽

Weight Changes ◽

Cortex Moutan ◽

Radiation Induced ◽

Underlying Mechanisms

Radiation-induced oral mucositis represents an influential factor in cancer patients’ accepted radiation therapy, especially in head and neck cancer. This research investigates the treatment effect of Ecdysterone (a steroid derived from the dry root of Achyranthes bidentate) and Paeonol (a compound derived from Cortex Moutan) on radiation-induced oral mucositis and possible underlying mechanisms. Concisely, 20 Gy of X-rays (single-dose) irradiated the cranial localization in rats for the modeling of oral mucositis. The therapeutic effects of Ecdysterone-Paeonol oral cavity directly administered on radiation-induced oral mucositis were investigated by weight changes, direct observations, visual scoring methods, ulcer area/total area, and basic recovery days. Assessments of tumor necrosis factor α and interleukin-6 were performed to evaluate the inflammatory cytokines secretion in the damaged areas of tongues harvested post-treatment, and changes in signaling pathways were investigated by Western blotting. System Drug Target (SysDT) methods revealed the targets of Ecdysterone-Paeonol in order to support compound-target network construction. Four representative targets with different functions were chosen. The binding interactions between the compound and receptor were evaluated by molecular docking to investigate the binding affinity of the ligand to their protein targets. Ecdysterone-Paeonol, administered orally, effectively improved radiation-induced oral mucositis in rats, and the therapeutic effect was better than Ecdysterone administered orally on its own. In this study, calculational chemistry revealed that Ecdysterone-Paeonol affected 19 function targets associated with radiation-induced oral mucositis, including apoptosis, proliferation, inflammation, and wound healing. These findings position Ecdysterone-Paeonol as a potential treatment candidate for oral mucositis acting on multiple targets in the clinic.

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The effect of a calcium phosphate mouth rinse on (chemo) radiation induced oral mucositis in head and neck cancer patients: a prospective study

International Journal of Dental Hygiene ◽

10.1111/j.1601-5037.2012.00574.x ◽

2012 ◽

Vol 10 (3) ◽

pp. 175-180 ◽

Cited By ~ 9

Author(s):

MA Stokman ◽

FR Burlage ◽

FKL Spijkervet

Keyword(s):

Head And Neck Cancer ◽

Calcium Phosphate ◽

Prospective Study ◽

Head And Neck ◽

Cancer Patients ◽

Neck Cancer ◽

Oral Mucositis ◽

Mouth Rinse ◽

Radiation Induced ◽

A Prospective Study

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

Scientific Reports ◽

10.1038/s41598-020-73875-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jing Chen ◽

Laurent A. Bekale ◽

Kelly M. Khomtchouk ◽

Anping Xia ◽

Zhixin Cao ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Oral Mucosa ◽

Oral Mucositis ◽

Heparin Binding ◽

Patients With Cancer ◽

Dorsal Tongue ◽

Radiation Induced ◽

Epidermal Growth ◽

And Migration

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.

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