Background and Introduction
Oral mucositis (OM), is a condition in which the mouth, tongue, tonsils, soft palate, and walls of the throat become inflamed due to cancer treatments such as radiation. The symptoms of OM can present themselves in many forms. Symptoms of OM include but are not limited to sever mouth sores, redness of the mouth, pain in the mouth, difficulty swallowing, and ulcers in the mouth and gastrointestinal tract. The development of OM usually leads to a disruption in the cancer treatment of the patient; these disruptions may be dosage reductions, emergency visits, or indefinite disruption of treatment. The most severe form of OM is deep ulceration. The ulcerations can be painful and restricting to the patient due to the disruption of the epithelial barrier (1). It can affect the gastrointestinal tract and may cause the patient to lose weight due to the lack of alimentation.
OM has proven to be one of the most common and severe complication of cancer treatment. OM occurs as a result of radiation therapy, chemotherapy, and even stem cell transplantation. OM can start developing in as little as one week into treatment. It begins when the oral tissues begin to thin out. After thinning out, ulceration begins. Oral mucositis gradually increases in severity within seven to fourteen days after receiving therapy (3, 5). After about two weeks after treatment termination, the oral lesions and possible ulcers begin to heal but still prevent the patient from proceeding with their normal lifestyle. This condition can also be confused for other oral infections and conditions. OM can attack patients differently. In Immunocompromised patients, it can cause infectious complications (1). only approved OM treatment is palifermin. This is most efficient in patients with non-solid tumors of bone marrow transplant.
Due to the fact that patients suffering from OM experience debilitation and interruptions to their lifestyles, many patients affected end up being hospitalized. This is because many of the patients can no longer swallow solid food or liquids. Since patients may also experience severe pain, there may be medical attention required to treat the pain.
Oral mucositis affects approximately 500,000 patients per year in the United States. OM is a common side effect for head and neck cancer patients. However it can affect patients undergoing anticancer therapy for any type of cancer. An estimated 41 percent of the patients suffering of the condition, 21 percent of colo-rectal cancer patients, 15 percent of head and neck cancer patients, 15 percent of breast cancer patients, 5 percent of non-Hodgkin lymphoma patients, and 4 percent of stem cell transplant patients are affected by OM(8, 2). About 11 percent of cases have been discontinued. This treatment is costly and allows for the occurrence of inconvenient dosing (4,8). Treatment for OM can range from $15,000 to $45,000 (4, 7) and can affect the patient’s quality of life. About 11 percent of cases therapy are modified or discontinued.
OM is an important and minor side effect for patients receiving radiotherapy. On the other hand, it is the most common and most detrimental in patients receiving chemotherapy. This is due to the higher frequency of solid tumors that patients have (3). OM can be made more sever if the patient smokes and abuses alcohol while receiving treatment (3). These patient contributing factors can cause more prominent lesions that can lead to infections if proper oral hygiene is not maintained.
Importance
The level of impact that oral mucositis has on cancer patients is very high. Therefore, prevention and treatment of this condition is extremely important for medical professionals and patients alike. Prevention and treatment would most likely better the quality of life of the patients during and after receiving anti-cancer therapy. During treatment, many patients experience pain and lesions in the mouth. Currently, the proposed treatments include but are not limited to local anesthesia, pain relieving substances, and natural agents as mouthwash. These natural agents include chamomile, which helps relieve pain and inflammation; glycerin, which can also help relieve pain and minimize bacterial growth; sage, and myrrh, which can relieve inflammation and sores (3)
Hypothesis
Mucositis is a biological process that has only been recently studied as a side effect of cancer therapy. It follows a 5 model of initiation, upregulation, signaling and amplification, and ulceration and healing. Microbiota, mucosal barrier properties, and immune homeostasis changes are important to the biology of mucositis. Mucosal injury is driven by the innate immune response. Pattern recognition receptors (PRRs) are a family of receptors responsible for the detection of ‘‘pathogen associated molecular patterns’’ (PAMPs) or host derived ‘‘damage associated molecular patterns’’ (DAMPs) which induce innate immune signaling. There are four class of PRRs – the Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), C-type lectin receptors (CLRs). Although these are known to be involved in mucositis, their specific involvement is not yet understood. It is hypothesized that the upregulation of the TLRs and NLRs may play a vital role in the regulation of mucositis. It has been studied that the most effective interventions are those that allow the migration and prevention of the activation and initiation phase of mucositis. The prevention of the activation and initiation of mucositis is important because one the damage has begun, it is difficult to control and bring to a stop. With our continuing knowledge of the human immune system, chemistry, polymer science, it will be possible to develop an intervention therapy for oral mucositis. TLRs and NLRs are a major target for research and for the development of mucositis prevention treatments (2,8).
Ceragenins, also known as cationic steroid antimicrobials (CSAs) are small molecular mimetics of antimicrobial peptides that are produced synthetically. CSAs are critical constituents of the human immune system. These contain a steroid alcohol backbone with amino acids and other groups attached to the backbone. They typically have a positive charge and possess properties such as strong broad-spectrum antimicrobial, anti-inflammatory, and anti-cancer3.
The focus of this research is to comprehend the involvement TLRs and NLRs in the innate regulation of mucositis and to use this for the development of an effective of ceragenins as inhibitors of the TLRs and NLRs for the prevention and possible treatment of oral mucositis.
References:
1. Al-Ansari, S., Zecha, J. A., Barasch, A., Lange, J. D., Rozema, F. R., & Ruber-Durlacher, J. E. (2015). Oral Mucositis Induced By Anticancer Therapies. Curr Oral Health Rep,2, 202-211. doi:10.1007
2. Chiappelli Francesco. The Molecular Immunology of Mucositis: Implications for Evidence-Based Research in Alternative and Complementary Palliative Treatments. Evid Based Complement Alternat Med. 2005 2(4), 489–494.
3. Da Cruz Campos, M. I., Campos, C. N., Aarestrup, F. M., & Aarestrup, B. J. (2014). Oral mucositis in cancer treatment: Natural history, prevention and treatment. Molecular and Clinical Oncology,2, 337-340. doi:10.3892
4. Kinnear Pharmaceuticals “Corporate Overview for BIO 2015” Company report.
5. Redding, S. W. (2005). Cancer Therapy-Related Oral Mucositis. Journal of Dental Education,69(8), 919-929. Retrieved October 16, 2018, from http://www.jdentaled.org/content/69/8/919
6. Savage et al. A Modified Glycosaminoglycan, GM-0111, Inhibits Molecular Signaling Involved in Periodontitis. PLoS ONE 2016 11(6), 1-20.
7. Soligenix “Oral Mucositis- Advancing the Next Generation of Therapies” Company report.
8. Synthesis and Characterization of Polymeric Antioxidant Microparticles, Nihar Shah, Bluegrass Advanced Materials, LLC (1R43DE023523-01A1).