Introduction
Cancer remains one of the most important causes of death worldwide. According to Agency for Research on Cancer (IARC) information in 2012, 14.1 million new cases of cancer and 8.1 million cancer deaths have been occurred worldwide (1). Although the use of multiple approaches, including chemotherapy, radiotherapy, improve survival and quality of life in cancer patients, but the side effects of these methods is considerable. Chemotherapy and radiotherapy can cause non-specific toxicity in tissues that have a high rate of cell division such as the mouth and bone marrow, unfortunately, this leads to more adverse effects in these tissues (2) .
Oral cavity and oral mucositis:
It is estimated that more than 600 species of bacteria in the oral cavity are resident (3). Oral microbial flora consists of both types of Gram-negative and positive bacteria. Induction and intensification of inflammatory processes and the formation of ulcers are caused by gram-negative bacteria.Oral microbial flora prevents colonization of exogenous organisms through several mechanisms such as competition for ligands and receptors which are essential for attachment for colonization (4). Pediatric populations differ from adults in their resident oral flora, and likely in their response to chemotherapeutic regimens. Most of the oral bacterial changes noted in the pediatric studies involved Gram-positive Streptococci and Staphylococci, whereas in the studies of adults, most changes involved Gram-negative organisms such as Enterobacteriaceae and Pseudomonas sp (5).
Oral mucositis is the most frequent side effect after radio/chemotherapy in cancer patients ‘especially in head and neck cancer (HNC), and is characterized by inflammation and ulceration of the mouth (6). Highest incidence of oral mucositis is occurred in HNC patients that are between 85-100%. Up to now, several grading scales have been suggested for diagnosis and evaluation of oral mucositis; that most commonly used scales are the World Health Organization (WHO) scale and the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) (7).
Pathobiology of oral mucositis due to Radio/chemotherapy:
A 5-Step Plan to explain the biological processes during oral mucositis has been proposed by Sonis ST. These phases including initiation, message generation, signaling and amplification, ulceration and healing phase (8).
The rational use for radiotherapy in cancer is that tumor cells with high division index undergoing apoptosis in response to DNA damage induced by radiation, but slowly dividing cells are less affected. After DNA double strands breaks induced by radiation, molecular cascade started with ROS generation due to interaction of ionizing radiation and other atoms or molecules in the cell (initiation phase) (9). As previously mentioned, message generation is second phase of oral mucositis. Previously studies indicated that ROS and DNA damage rapidly stimulated nuclear factor kappa B (NF-κB) activity, as one major inflammatory mediator. The NF-κB family consists of five transcription factors including RELA (p65), c-BEL, RELB, NF-κB1 (p50/p105), and NF-κB2 (p52/p100), that plays key roles in the immune system and in inflammation as well as in regulation of proliferation and survival (10). NF-κB plays a central role in the development of oral mucositis, results in up-regulation of the several transcription genes involved in mucositis.
TNF, interleukins, chemokines, COX-2, 5-LOX, and MMP-9 are all regulated via NF-kB. In unstimulated cells, NF-κB proteins are connected to inhibitory IκB proteins that preserve NF-κB in an inactive state in the cytosol. TNF and Toll-like receptors Activation lead to recruitment of adaptor proteins that activate the IκB kinase, which phosphorylates IκB. Following the phosphorylation IκB targets by the proteasome for ubiquitination and degradation. Released NF-κB translocate to the nucleus and induce expression of its target genes such as TNF-α, IL-1β and IL-6,cyclin D1, Bcl-2, Bcl-xL, MMP, and VEGF (11, 12). As a result of these responses a biologic process has been started that leads to mucosal injury.
As well as ionizing radiation, several chemotherapeutic agents increased activity of NF-κB, such as anthracyclines, paclitaxel, cisplatin, melphalan, and bleomycin. But contrary aforementioned compounds 5-Fluorouracil leads to reduced activity of NF-κB by mediating the upregulation of IκB-a. In third phase produced cytokines amplify the primary signals and leading to activation of various transcription genes such as mitogen-activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) (13). The role of COX-2 in initiation of the inflammatory cascade previously indicates. , and demonstrated that it’s signaling increased the activation of matrix metalloproteinases (MMPs) 1 and 3. Ultimately, ulceration phase occurred as a result of direct and indirect mechanisms that mentioned above. In this phase due to breakdown of the mucosa, colonization of Gram-negative organisms and yeast on the surface of ulcer occurred, that provides a rich source of cell wall products including lipopolysaccharides, lipoteichoic acid, cell wall antigens, and α-glucans (8). These agents increased secretion of pro-inflammatory cytokines. In this phase clinically significant pain is appeared. Healing is a final phase that occurred in oral mucositis due to radio/chemotherapy. However in the most of cases healing process happened spontaneously after cancer therapy is ceased. Normally, this phase lasts for 12 to 16 days (14).
Prevention or treatment opportunities:
Antimicrobial agents:
In cancer patient main cause of oral mucositis development is colonization of bacteria. These bacteria include both Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella and Enterobacter spp) and Gram-positive (coagulase-negative staphylococci and Enterococcus) and fungi. Until now several compounds have been used for prevention and treatment of oral mucositis induced infections (15).
1- Chlorhexidine: Chlorhexidine gluconate is a compound with a hexamethylene bridge and terminal 4-chlorophenyl groups, which widely used in dentistry. This substance (as a mouthwash, at concentrations below 0.12% and 0.2%) not only produces of protective barrier against mucosal damage but have antibacterial and fungicide effects. The anti-bacterial mechanism of Chlorhexidine gluconate includes binding of the positively charged molecules to the negatively charged bacterial cell wall, which leads to disruption of membrane transport. However, several researchers’ believed that effectiveness of Chlorhexidine solution varies from reducing oral mucositis to no effects. Although it has some disadvantages such as the discoloration of teeth, the bitter taste, and the unpleasant sensation. In spite of that MASCC/ISOO suggested that Chlorhexidine not to be used to prophylaxis of oral mucositis in patients with solid tumors of the head and neck who are undergoing radiotherapy (16, 17).
2- Antiviral agents: acyclovir has been the first-line treatment for herpes simplex virus infections and in addition to its used for treatment of varicella zoster (chickenpox). Within infected cell, acyclovir is phosphorylated by viral thymidine kinase that leads to produce of triphosphate derivative of acyclovir. Due to transportation of this compound to the nucleus, DNA polymerase of virus is inhibited. Valacyclovir and Famciclovir in compared to acyclovir have higher bioavailability (approximately 10-fold).
3- Antifungal agents:
3-1. Polyene antifungal: Nystatin and amphotricin B are polyene antifungal agents that after interaction with ergosterols in fungal cell membranes lead to increase of permability that lead to K+ leakage, acidification, and death of the fungus. However is toxic when given systemically, but is not absorbed from the gut, it is safe for oral use and does not have problems of drug interaction (18).
3-2. Azole antifungal:
3-2-1. Clotrimazole, which as well as fungistatic activity has anti-staphylococcal activity. Troche or throat lozenge preparations are used for oropharyngeal candidiasis (oral thrush) or prophylaxis against oral thrush in neutropenic patients. It binds to phospholipids in the cell membrane and inhibits the biosynthesis of ergosterol and other sterols required for cell membrane production. Although systemic absorption of clotrimazole is limit, but similar to other azoles it is a cytochrome P-450 inhibitor primarily CYP3A4 and may cause of elevation serum levels of several.
3-2-2. Fluconazole is a first-generation triazole antifungal medication. It is a safe oral antifungal agent with a favorable spectrum of activity and pharmacokinetic profile. fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols. Previously studies reported that Candida colonization in head-and-neck cancer patients receiving radiation therapy as high as 75%. In addition Fluconazole is a current standard treatment for patients with oral candidiasis(19). Chlorhexidine gluconate rinse that described previous also has antifungal activity but cannot be swallowed (18).
4- Iseganan (IB 367, protegrin IB 367): is a synthetic protegrin (structural analog of protegrin-1), with broad-spectrum microbial activity for the treatment and prevention of oral mucositis. Its targets includes of Gram-negative and positive bacteria as well as Candida albicans. The main mechanism of Iseganan is binding to lipid membrane of pathogen and disruption of membrane integrity. Iseganan as a cationic antimicrobial peptide has rapid microbicidal activity in saliva. Up to now several studies carried out to evaluate its protective effects of this against oral mucositis in cancer patients. Gilles and et al indicated that treatment with oral iseganan mouthrinse (9 mg/dose) six times a day failed to prevent or reduce stomatitis, ulcerative oral mucositis, or its clinical sequelae relative to a placebo (20). Similar results was obtained by Trotti and collegeous (21), based on these results, development of Intrabiotics for this purpose abandoned (22).
5- Povidone-iodine: The broad antimicrobial spectrum of povidone–iodine is well documented. This compound is a combination of molecular iodine and polyvinylpyrrolidone. The bactericidal component is free iodine, and its levels are dependent on the concentration of the povidone–iodine solution (23).
Adamietz and et al indicated that povidone-iodine significantly reduced severity and incidence of radiotherapy induced oral mucositis in head and neck cancer patients (24). Similar results obtained by Rahn and colleagues, their showed that povidone-iodine reduced incidence of OM as compared to rinsing with sterile water (n=20 in each group)(25).
6- Other
6-1. Triclosan: Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol), a xenoestrogen, is a broad-spectrum antibacterial compound and prevalently used in cosmetics, dentifrices, soap, and other consumer products (26).the mechanism of triclosan is destroy of bacterial cell membranes. In addition indicated that triclosan works by blocking lipid synthesis in Escherichia coli by inhibiting the enzyme enoyl-acyl carrier protein reductase from type II bacterial fatty acid synthesis (27).
Unfortunately recently demonsterated that triclosan may play a role in cancer development, due to estrogenicity or ability to inhibit fatty acid synthesis (26).
Satheeshkumar and et al showed that triclosan in compared to sodium bicarbonate is more effective in reduction of oral mucositis in head aneck cancer patients that were undergoing of radiotherapy (28).
6-2. Kefir: is a fermented dairy beverage that produced by bacteria and yeast that in kefir grains. Several components have been detected in the kefir. Due to kefir fermentation main compounds that produced include lactic acid, ethanol and CO2, which are responsible for viscosity, acidity and low alcohol content of this beverage. Various studies demonstrated that kefir and its constituents have broad-spectrum antimicrobial activity (29). In one study that carried out by Topuz and colleagues’ they concluded that there was no significant effect between kefir and control groups for reduction of chemotherapy induced oral mucositis (30).
7- Antibiotic lozenge/paste:
7-1. PTA: The combination of polymyxin 2 mg, tobramycin 1.8 mg, and amphotericin B 10 mg known as PTA. With consideration to this fact that etiology of oral mucositis in cancer patients mostly is gram-negative bacteria, thus PTA is used for prevention and treatment of this side effect.
Polymyxins are produced by the gram-positive bacterium Bacillus polymyxa and are selectively toxic for gram-negative bacteria. In addition to Tobramycin is an aminoglycoside antibiotic used to treat various types of bacterial infections, particularly gram-negative infections. Up to now several studies conducted for evaluation of PTA in prevention and treatment of oral mucositis in cancer patients. Although initial pilot studies on PTA recommended that the potential efficacy of this combination, but subsequent larger well-controlled studies clearly indicated that topical use of PTA did not prevent oral mucositis or reduce its severity (31).
7-2. BCoG: this product is cheaper than PTA and includes of bacitracin 6 mg, clotrimazole 10 mg, and gentamicin 4 mg. The BCoG lozenge is active against gram-positive cocci, gram-negative bacilli, and yeast micro-organisms (32). Table 1 summarizes several of anti microbial agents until now are used for prevention and treatment of mucositis.
Anti-inflammatory agents:
As described in 2 and 3 phases of oral mucositis the consequent activation of transcription factors eventually leads to the upregulation of genes coding for inflammatory cytokines, such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β, NF-κB and IL-6, which results in increased tissue injury in all compartments of the mucosa (33).
Due to the fact that cytotoxic and radiotherapy for head and neck cancers induced prominent changes in epithelium and mucosa, thus use of anti inflammatory agent could be a strategy for amelioration of radiation-induced oral mucositis (34, 35).
1- Benzydamine
Benzydamine hydrochloride is a nonsteroidal anti-inflammatory drug (NSAID) that has shown topical anti-inflammatory, analgesic, anesthetic, and antimicrobial activities (36). Previous studies demonstrated that this agent has anti-TNF alpha, anti-inflammatory effects in addition to acts as membrane stabilizer (37). Until now several studies indicated that benzydamine hydrochloride has prominent role in prevention and treatment of oral mucositis. Recently Sheibani and their colleagues demonstrated that benzydamine hydrochloride significantly decreased oral mucositis and its complication in head and neck cancer patients (38). However sometimes there are inconsistent results about its efficacy. For instance Lalla and colleagues found that benzydamine hydrochloride could not decreased oral mucositis in head and neck cancer patient who are received radiotherapy (39).
2- Misoprostol
Misoprostol is a prostaglandin E1 analog, has anti-inflammatory and mucosa-protecting effects. Protective effect of this agent against oral mucositis derived from its cytoprotective and radioprotective propertice (40). In a randomized, double-blind, placebo-controlled study that carried out by Lalla and colleagues 22 patients randomized to misoprostol rinse and 26 patients randomized to placebo rinse. Their results indicated that no significant difference between the two groups in mucositis or pain severity (41). In another study that conducted by Duenas-Gonzalez and et al, their demonstrated that the incidence and severity of oral mucositis was increased in patients who treated with misoprostol tablets when compared with the placebo control group (42).
3- Other
Diphenhydramine is an inverse agonist of the histamine H1 receptor. Diphenhydramine in combination with variety of mouthwashes with mixed actions have been evaluated. Rothwell and colleagues indicated that combination of diphenhydramine with hydrocortisone, nystatin, and tetracycline significantly decresed oral mucositis in head and neck cancer patients (43). However in other studies that conducted by Carnel and Barker no significant difference between control and diphenhydramine groups was found (44, 45).
As mentioned in the pathophysiology of oral mucositis, The COX pathway is an important pathway involved in mediating the inflammatory response. arachidonic acid converted to Prostaglandin H2 (PGH2), which this process mediated by COX-1 and COX-2. That followed by conversion of PGH2 to PGE2 by PGE synthase and into PGI2 by prostacyclin synthase (46).
Lalla and colleagues conducted a randomized double-blind placebo-controlled trial up to evaluation of protective role of Celecoxib on radiotherapy induced oral mucositis in head and neck cancer patients. Their results indicated that Daily use of Celecoxib, during period of radiotherapy, did not reduce the severity of clinical oral mucositis, pain, dietary compromise or use of opioid analgesics (47). In another study similar result obtained by Haagen and et al. their showed that TNF-α inhibiting antibody (Infliximab) or a COX-2 inhibitor (Celecoxib) could not reduced radiation induced oral mucositis (34). Porteder and et al demonstrated that PGE2 is capable to reduce oral mucositis and pain in cancer patients who received chemoradiotherapy (48). But this results are not confirmed in the randomized, double-blind, placebo-Controlled study that carried out by Labar and colleagues (49).
Corticosteroids are other anti inflammatory agents, which used for prevention and treatment of oral mucositis in cancer patients. Betamethasone rinse could decrease oral mucositis in all of patients who are received radiotherapy but in prospective, randomized, and controlled trial that conducted by Leborgne and colleagues on 32 head and neck cancer patients, prednisone did not reduce the intensity or duration of oral mucositis (50, 51).
In addition to mentioned compound several anti inflammatory agents until now are used for prevention and treatment of mucositis that you can see these details in table 2.
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