Mucositis In Hamsters Research Articles

Therapeutic Effects of Hydrogel Formulations Incorporating Troxipide Nanoparticles on Oral Mucositis in Hamsters.

Medical therapies, such as the use of anti-inflammatory agents, are commonly used for the treatment of oral mucositis (OM). However, these treatments have limited efficacy in treating severe cases of OM. In this study, we aimed to develop a carbopol gel incorporating troxipide (TRO) nanoparticles and methylcellulose (TRO-NP gel) and demonstrate its efficacy in accelerating wound healing in a hamster model of OM (OM model) induced by acetic acid injection. TRO nanoparticles were prepared using bead milling. The crystalline form was determined by powder X-ray diffraction, and the particle size was measured using a NanoSight LM10 instrument. The drug release was determined using a Franz diffusion cell, and the hamsters injected with acetic acid were selected to evaluate the therapeutic effect of OM. After preparing TRO nanoparticles, we observed a mixture of crystals and amorphous TRO, and the particle size of TRO in the TRO-NP gel ranged from 50 to 280 nm. The TRO-NP gel exhibited a more uniform TRO distribution and viscosity compared to the Carbopol gel containing TRO microparticles (TRO-MP gel). However, the solubility of TRO was comparable in both TRO-MP and TRO-NP gels. The TRO-NP gel released a higher amount of TRO than that from the TRO-MP gel, with detectable release of TRO nanoparticles. TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were higher than those treated with TRO-MP gel. The increased TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were attenuated by treatment with 40 μM dynasore, an inhibitor of clathrin-dependent endocytosis (CME). Moreover, the therapeutic effect of the TRO-NP gel was superior to that of the TRO-MP gel in the hamster model of OM. We have designed a TRO-NP gel, and this gel showed excellent TRO delivery into the cheek pouch tissue through the CME pathway. Moreover, the TRO-NP gel treatment enhanced wound healing after acetic acid injection.

Red, infrared, and simultaneous laser-wavelengths irradiation effects on 5-Fluorouracil-induced oral mucositis in hamsters.

The association of more than one wavelength for photobiomodulation therapy (PBMT) to treat oral mucositis (OM) is unusual in the literature. Thus, this study aims to compare the simultaneous irradiation effects with their isolated application to treat OM. In order of that, 48 male Syrian hamsters were divided into 4 groups: Chemotherapy (Ch), which received only a OM induction protocol (5-Fluorouracil chemotherapy and superficial oral mucosa scratches); Red laser (RL), which received the OM induction and a PBMT protocol at 660 nm; Infrared laser (IRL), which received the OM induction, and a PBMT protocol at 808 nm; and the RL+IRL group, which received the simultaneous application, of 660 nm and 808 nm wavelengths. Clinical (OM grade classification), histological (light microscopy analysis with H&E and collagen staining), immunohistochemical (TNF-α expression), and biochemical (TNF-α and hydroxyproline concentration) analyzes were performed after 7 and 10 days. Mainly on the 10th day, the RL and IRL groups showed lower OM grades and faster microscopic repair process, with greater expression of collagen fibers and lower TNF-α levels, besides the higher hydroxyproline concentrations, mainly in comparison with the Ch group. In conclusion, in this study, the simultaneous protocol did not present superior results than the isolated irradiations. This article is protected by copyright. All rights reserved.

The chromatographic constitution of andiroba oil and his healing effects, compared to the LLLT outcomes, in oral mucositis induced in golden Syrian hamsters: a new treatment option.

The oral mucositis is a mucosal alteration that usually arises from oncological treatments, such as chemotherapy, and it is characterized as an inflammatory process. The aim of this study is to demonstrate the chromatographic constitution of Andiroba oil, comparing and evaluating Andiroba oil and laser scarring efficiency in treatments of oral mucositis in hamsters. These animals were submitted to 5-Fluorouracil. A total of 122 animals were used, randomized and divided into the following groups: (a) positive control; (b) laser associated to andiroba oil; (c) laser; (d) andiroba oil; (e) negative control; (f) cyclophosphamide (genotoxicity control). The induction of oral mucositis occurred by the administration of intraperitoneal Fluorouracila (60 mg/kg) and trauma to the mucosa. The laser protocol was performed once a day and the andiroba oil applied 3 times a day (1,5 ml/day). The mucosae were photographed and removed for clinical and histopathological analysis on day 4, 8, 12 and 15. The analysis was based in OM severity, in specific scoring for the clinical and histopathological aspect. Toxicity was evaluated on day 15 using comet assay and it was performed by variant DNA damage parameters. The data were analysed using analysis of variance (ANOVA) Tukey post-test and Kruskal-Wallis Dunn post-test. The "andiroba oil" and "laser" groups presented better results when compared to the control groups and the treatment associations. The andiroba oil presented the best scarring results, even considering its efficiency proximity to the laser treatment. Andiroba and laser, separately, did not present genotoxicity, however their association evidences damage to DNA.

Curcuma longa extract protects against 5-fluorouracil-induced oral mucositis in hamsters

Curcumin, contained at Turmeric (Curcumalonga), can exert many beneficial pleiotropic activities in the gastrointestinal tract. This study evaluated the antioxidant and anti-inflammatory activity of C. longa on 5-fluorouracil (5-FU)-induced oral mucositis (OM) in hamsters. Phytochemical analysis of crude C. longa extract (CLE) was performed to detect the presence of curcumin by TLC and HPLC. Golden Syrian hamsters were orally pre-treated with CLE (5, 50, or 100mg/kg). Cheek pouch samples were subjected to macroscopic and histopathological evaluation. ELISA was performed to quantify the inflammatory cytokines IL-1β and TNF-α. Superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) levels were assessed by ultraviolet-visible spectroscopy analysis. Behavior analysis was conducted by the open field test. Curcumin content in the CLE was 0.55%m/m ± 0.0161 (2.84%). The group treated with 5mg/kg CLE showed healing evidence with macroscopic absence of ulceration (p<0.05) and microscopic aspect of re-epithelialization, discrete inflammatory infiltrate and absence of edema. Treatment with 5mg/kg CLE significantly increased GSH levels, and reduced MDA levels and SOD activity (p˂0.05), and decreased IL-1β (p˂0.05) and TNF-α (p˂0.01) levels. A significant reduction in walking distance, ambulation, speed, and rearing was observed for motor activity. Curcumin reduced oxidative stress, inflammation, and motor activity in hamsters with 5-FU-induced OM.

Wound healing process with different photobiomodulation therapy protocols to treat 5-FU-induced oral mucositis in hamsters

ObjectivesThe aim of this study was to analyze the effects of three different Photobiomodulation Therapy (PBMT) protocols in the treatment of 5-fluorouracil-induced oral mucositis in hamsters. Design: 60 hamsters were divided into five groups: group “C”, which did not receive oral mucosa scratching, 5-fluorouracil (5-FU) or PBMT; group “Ch”, which received anesthesia, superficial oral mucosa scratching and 5-FU (oral mucositis induction); and three groups that received oral mucositis induction and a PBMT protocol: groups ChLI, ChLII and ChLIII that received 0.24 J (one point), 1 J (one point) and 1.2 J (five points of 0.24 J) of energy, respectively. The laser equipment used had λ = 660 nm and 0.04 cm2 of spot area (0.226 cm diameter). The animals were euthanized on days 7 and 10 of the experiment, and their oral mucosas were removed for histological (light microscopy and collagen staining), immunohistochemical (NF-kB and TNF-α), and biochemical (TNF-α, NF-kB and hydroxyproline) analysis. Results: Group ChLI (less energy), showed the most accelerated repair rates and a lower concentration of inflammatory biomarkers than group Ch. Comparing the three PBMT protocols for treatment of 5-FU-induced oral mucositis in hamsters, the one with low energy (0.24 J) showed better results, regarding reduction of inflammatory biomarkers and tissue repair, than the ones with higher energy (1 and 1.2 J).

Anti-inflammatory effect of L-cysteine (a semi-essential amino acid) on 5-FU-induced oral mucositis in hamsters.

Oral mucositis is an inflammation of the oral mucosa mainly resulting from the cytotoxic effect of 5-fluorouracil (5-FU). The literature shows anti-inflammatory action of L-cysteine (L-cys) involving hydrogen sulfide (H2S). In view of these properties, we investigate the effect of L-cys in oral mucositis induced by 5-FU in hamsters. The animals were divided into the following groups: saline 0.9%, mechanical trauma, 5-FU 60-40mg/kg, L-cys 10/40mg and NaHS 27µg/kg. 5-FU was administered on days 1st to 2nd; 4th day excoriations were made on the mucosa; 5th-6th received L-cys and NaHS. For data analysis, histological analyses, mast cell count, inflammatory and antioxidants markers, and immunohistochemistry (cyclooxygenase-2(COX-2)/inducible nitric oxide synthase (iNOs)/H2S) were performed. Results showed that L-cys decreased levels of inflammatory markers, mast cells, levels of COX-2, iNOS and increased levels of antioxidants markers and H2S when compared to the group 5-FU (p < 0.005). It is suggested that L-cys increases the H2S production with anti-inflammatory action in the 5-FU lesion.

Phototherapy With LED as an Effective Treatment for Chemotherapy-Induced Oral Mucositis in Hamsters.

Introduction: Oral mucositis (OM) has been considered one of the most feared collateral effects of oncological treatments. Some therapies have been used, such as light-emitting diode (LED), with promising results, but with no sufficient evidence in the literature. Objective: Our study aimed to evaluate, by clinical and histological analysis, the effect of LED on the treatment of chemotherapy-induced OM (CIOM) in an animal model. Methods: Twenty male hamsters were equally distributed to two groups: control (C), which received anesthesia and CIOM induction; and LED (L), which received anesthesia, CIOM induction, and LED treatment (635 nm, 120 mW, 0.48 J). The clinical analysis was performed through two specific scales for OM analysis on days 5, 7 and 10 of the experiment. In addition, the injured area of all hamsters check pouch mucosa was removed and processed for histological analysis on the last experimental day. Results: After statistical analysis, group L showed less severity of OM when compared with the C group (P <0.05); beyond that, both healed completely on day 10. Conclusion: Our results suggested that the phototherapy with LED had a positive effect on accelerating repair, reducing the severity of CIOM.

Effect of Gold Nanoparticle on 5-Fluorouracil-Induced Experimental Oral Mucositis in Hamsters.

Background: Oral mucositis (OM) is a severe inflammation of the oral mucosal cells associated with chemotherapy and/or radiotherapy-induced toxicity, resulting in epithelial ulcers and higher risk of death from sepsis. The aim of the present study was to evaluate the nanoparticle (AuNp) effect on OM induced in hamsters. Materials and methods: 5-fluorouracil (5FU) was used on the first and second day of the experimental model in Golden sirian hamsters, and on the fourth day, mechanical trauma was applied to induce OM. The animals were divided into groups, i.e., polyvinylpyrrolidone (PVP), mechanical trauma (MT), 5FU, and groups treated with gold nanoparticles (AuNps) (62.5, 125, and 250 μg/kg). On the 10th day, animals were euthanized for macroscopic, histopathological, immunohistochemical, western blot, quantitative polymerase chain reaction (qRT-PCR), and AuNp quantification. Results: AuNp (250 μg/kg) reduced TNF-α, IL-1β, COX-2, NF-κB, TGF-β, and SMAD 2/3; increased glutathione levels; decreased the expression of Kelch ECH-associated protein 1 (KEAP1); and induced heme oxygenase 1 (HMOX-1) and NAD (P) H quinone oxidoreductase 1 (NQO1) genes. Conclusions: AuNp (250 μg/kg) prevented 5-FU-induced OM in hamsters and improved the parameters of inflammation and oxidative stress.

Anti-inflammatory and antioxidant activity of hydroethanolic extract of Spondias mombin leaf in an oral mucositis experimental model

BackgroundSpondias mombin has been used in folk medicine to treat inflammation in the oral cavity. This study aimed to evaluate the antioxidant and anti-inflammatory activity of S. mombin extract in an oral mucositis experimental model. MethodsMale hamsters were orally pre-treated with hydroethanolic extract of S. mombin leaves (HESM) (50, 100, or 200 mg/kg) for ten days. Cheek pouch samples were subjected to macroscopic, histopathological and immunohistochemical analysis (Cox-2, iNOS, NF-kB p50 NLS and MMP-2). IL-1β and TNF-α levels were analyzed by ELISA immunoassay, and Superoxide dismutase estimative (SOD), glutathione (GSH) and malondialdehyde (MDA) levels were submitted to spectroscopy analysis. ResultsThe group treated with HESM at a dose of 200 mg/kg showed the best healing effect, showing no evidence of ulceration in the macroscopic analysis (p < 0.05). Histopathological analysis showed re-epithelialization, discrete mononuclear inflammatory infiltrate and absence of hemorrhage and edema score of 1 (1-1) (p < 0.05), as well as a large amount of collagen fibers and a lower immunoexpression of Cox-2, iNOS, NF-kB p50 NLS and MMP-2. Decrease in SOD (p < 0.05), MDA (p<0.001), IL-1β (p < 0.05), and TNF-α levels (p < 0.001), with an increase in GSH (p < 0.01) levels. ConclusionHESM (200 mg/kg) reduced oxidative stress and inflammation in the 5-fluorouracil-induced oral mucositis in hamsters.

Protective effect of dexamethasone on 5-FU-induced oral mucositis in hamsters.

Oral mucositis (OM) is an important side effect of cancer treatment, characterized by ulcerative lesions in the mucosa of patients undergoing radiotherapy or chemotherapy, which has marked effects on patient quality of life and cancer therapy continuity. Considering that few protocols have demonstrated efficacy in preventing this side effect, the aim of this study was to examine the effect of dexamethasone (DEX) on OM induced by 5-fluorouracil (5-FU) in hamsters by studying signaling pathways. OM was induced in hamsters by 5-FU followed by mechanical trauma (MT) on day 4. On day 10, the animals were euthanized. The experimental groups included saline, MT, 5-FU, and DEX (0.25, 0.5, or 1 mg/kg). Macroscopic, histopathological, and immunohistochemical analyses as well as immunofluorescence experiments were performed on the oral mucosa of the animals. The oral mucosal samples were analyzed by enzyme-linked immunosorbent assays, and quantitative real-time polymerase chain reaction (qPCR). DEX (0.5 or 1 mg/kg) reduced inflammation and ulceration of the oral mucosa of hamsters. In addition, DEX (1 mg/kg) reduced the cytokine levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and macrophage migration inhibitory factor (MIF). DEX (1 mg/kg) also reduced the immunoexpression of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-2, transforming growth factor (TGF)-β, MIF, Smad 2/3, Smad 2/3 phosphorylated and NFκB p65 in the jugal mucosa. Finally, DEX (1 mg/kg) increased interleukin-1 receptor-associated kinase 3 (IRAK-M), glucocorticoid-induced leucine zipper (GILZ), and mitogen-activated protein kinase (MKP1) gene expression and reduced NFκB p65 and serine threonine kinase (AKt) gene expression, relative to the 5-FU group. Thus, DEX improved OM induced by 5-FU in hamsters.

Dosimetric study of photobiomodulation therapy in 5-FU-induced oral mucositis in hamsters.

Oral mucositis (OM) is a debilitating consequence of cancer treatment that could be treated with photobiomodulation therapy (PBMT); however, there is no consensus about its dosimetric parameters for OM healing. The aim of this study was to compare different PBMT protocols on OM treatment, through clinical and histological analysis. Thirty hamsters were used, in an induced model of OM by 5-fluorouracil (5-FU) and superficial scratching, in seven days of follow-up. The animals were divided into five groups: control (C), which received only anesthesia and chemotherapeutic vehicle; chemotherapy (Ch), which received anesthesia, 5-FU, and scratches; laser 1 (L1), the same as Ch group, PBMT 6 ?? J / c m 2 and 0.24 J (one point); laser 2 (L2), the same as Ch group, PBMT 25 ?? J / c m 2 and 1 J (one point); and laser 3 (L3), the same as Ch group, PBMT 4 points of 0.24 J and 6 ?? J / c m 2 each. The laser used has ? = 660 ?? nm , 0.04 ?? c m 2 of spot area, and 40 mW. The best PBMT protocol to maintain lowest OM levels compared to Ch group was L1, followed by L2 and L3. Our results suggest that the application mode of PBMT and the energy delivered per area could interfere with the OM healing.

The Therapeutic Effect of PLAG against Oral Mucositis in Hamster and Mouse Model.

Chemotherapy-induced mucositis can limit the effectiveness of cancer therapy and increase the risk of infections. However, no specific therapy for protection against mucositis is currently available. In this study, we investigated the therapeutic effect of PLAG (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol, acetylated diglyceride) in 5-fluorouracil (5-FU)-induced oral mucositis animal models. Hamsters were administered 5-FU (80 mg/kg) intraperitoneally on days 0, 6, and 9. The animals’ cheek pouches were then scratched equally with the tip of an 18-gage needle on days 1, 2, and 7. PLAG was administered daily at 250 mg/kg/day. PLAG administration significantly reduced 5-FU/scratching-induced mucositis. Dramatic reversal of weight loss in PLAG-treated hamsters with mucositis was observed. Histochemical staining data also revealed newly differentiated epidermis and blood vessels in the cheek pouches of PLAG-treated hamsters, indicative of recovery. Whole blood analyses indicated that PLAG prevents 5-FU-induced excessive neutrophil transmigration to the infection site and eventually stabilizes the number of circulating neutrophils. In a mouse mucositis model, mice with 5-FU-induced disease treated with PLAG exhibited resistance to body-weight loss compared with mice that received 5-FU or 5-FU/scratching alone. PLAG also dramatically reversed mucositis-associated weight loss and inhibited mucositis-induced inflammatory responses in the tongue and serum. These data suggest that PLAG enhances recovery from 5-FU-induced oral mucositis and may therefore be a useful therapeutic agent for treating side effects of chemotherapy, such as mucositis and cachexia.

A novel model of megavoltage radiation-induced oral mucositis in hamsters: Role of inflammatory cytokines and nitric oxide

Purpose: To design a novel model to study Cobalt-60 (Co-60)-induced radiation mucositis and to describe the pathways involved in its development.Materials and methods: Hamsters’ cheeks were treated with Co-60 radiation (10, 20, 30 or 35 Gy). Three days later, oral mucosa scarification was performed with a needle. The animals were euthanized at day 13 (D + 13) after irradiation. Gross and microscopic alterations were evaluated by a new score system that we developed. Also, neutrophil infiltration, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-10, inducible nitric oxide synthase (iNOS), nitric oxide (NO) and nitrite were assessed in oral mucosa. We also tried to establish the roles of TNF-α and IL-1β and iNOS in our model using pharmacological approaches with pentoxiphylline (PTX) and aminoguanidine (AMG), respectively.Results: We found that a single administration of 35 Gy of Co-60, followed by mechanical scratches 3 days later, induced oral mucositis in hamsters. Animals with mucositis lost weight and had a survival median of 13 days, the time at which peak inflammation occurs. We noticed increased levels of NO, iNOS, TNF-α and IL-1β and a reduced concentration of IL-10. PTX partially prevented the mucositis phenotype by reducing the levels of inflammatory mediators and iNOS expression. Additionally, AMG, a selective inhibitor of iNOS, reduced Co-60-induced oral mucositis through reducing NO production.Conclusion: We described a novel model of megavoltage radiation-induced oral mucositis in hamsters. TNF-α, IL-1β and NO seem to play a role in the pathophysiology of this model.

Comparative assessment of the therapeutic effects of the topical and systemic forms of Hypericum perforatum extract on induced oral mucositis in golden hamsters

Oral mucositis is a common and irritating complication of chemotherapy and radiotherapy for malignancies. Current treatments have failed to achieve complete remission of this complication. The St. John's wort plant (Hypericum perforatum) has long been known for its anti-inflammatory and antibacterial effects. The current study was designed to investigate the therapeutic efficacy of the topical and systemic administration of H. perforatum extract on oral mucositis. Oral mucositis was induced in 72 male golden hamsters by administration of 5-fluorouracil (60mg/kg), on days 0, 5, and 10 of the study. The cheek pouch was scratched with a sterile needle on days 1 and 2. On days 12–17, H. perforatum extract topical gel 10%, oral H. perforatum extract (300mg/kg), and gel base groups were treated and then compared with a control group. Weights and blood samples were evaluated, biopsies from buccal lesions were examined histopathologically, and tissue malondialdehyde (MDA) was measured. Both of the H. perforatum extract treatment groups saw a significant relief in oral mucositis compared to the control and base gel groups; the systemic form was superior to the topical form. H. perforatum extract, administered orally or topically, expedited the healing of chemotherapy-induced oral mucositis in hamsters.

Alteration of the Redox State with Reactive Oxygen Species for 5-Fluorouracil-Induced Oral Mucositis in Hamsters

Oral mucositis is often induced in patients receiving cancer chemotherapy treatment. It has been reported that oral mucositis can reduce quality of life, as well as increasing the incidence of mortality. The participation of reactive oxygen species (ROS) in the pathogenesis of oral mucositis is well known, but no report has actually demonstrated the presence of ROS. Thus, the purpose of this study was thus to demonstrate the involvement of ROS and the alteration of the redox state in oral mucositis using an in vivo L-band electron spin resonance (ESR) technique. An oral mucositis animal model induced by treatment of 5-fluorouracil with 10% acetic acid in hamster cheek pouch was used. Lipid peroxidation was measured as the level of malondialdehyde determined by the thiobarbituric acid reaction. The rate constants of the signal decay of nitroxyl compounds using in vivo L-band ESR were calculated from the signal decay curves. Firstly, we established the oral mucositis animal model induced by treatment of 5-fluorouracil with acetic acid in hamster cheek pouch. An increased level of lipid peroxidation in oral mucositis was found by measuring malondialdehyde using isolated hamster cheek pouch ulcer. In addition, as a result of in vivo L-band ESR measurements using our model animals, the decay rate constants of carbamoyl-PROXYL, which is a reagent for detecting the redox balance in tissue, were decreased. These results suggest that a redox imbalance might occur by excessive generation of ROS at an early stage of oral mucositis and the consumption of large quantities of antioxidants including glutathione in the locality of oral mucositis. These findings support the presence of ROS involved in the pathogenesis of oral mucositis with anti-cancer therapy, and is useful for the development of novel therapies drugs for oral mucositis.

Platelet-rich fibrin has a healing effect on chemotherapy-induced mucositis in hamsters

The aim of this study was to evaluate the healing effect of topically applied platelet-rich fibrin (PRF) on experimental oral mucositis induced by chemotherapy in hamsters. Oral mucositis was induced in 93 Syrian golden hamsters by an intraperitoneal injection of 5-fluorouracil, which was followed by light scratching of the cheek pouch. The hamsters were randomly divided into a PRF group, a fibrin group, and an untreated control group. The recovery stage of oral mucositis was evaluated through daily weighing, measurements of the ulcer area, histopathologic analysis, and a myeloperoxidase activity assay. The PRF group exhibited significant improvements in the size and histologic features of the ulcer and in the myeloperoxidase activity compared with the control group (P < .05). The current findings suggest the consideration for future clinical trials in humans.

Protective effect of bilberry extract as a pretreatment on induced oral mucositis in hamsters

This study evaluated the effect of standardized bilberry extract containing anthocyanosides on chemotherapy-induced oral mucositis in hamsters. Twenty-four hamsters were randomly chosen and assigned to groups. Groups A and B were pretreated with deionized water, whereas group C was pretreated with bilberry extract daily for 7 days. Groups B and C underwent chemotherapy by intraperitoneal injections of 5-fluorouracil (days 4, 9, and 14); group A received normal saline. Potentiation of oral mucositis was achieved by scratching both cheek pouches of all animals with needles (days 5, 6, and 14). The pouches were histopathologically examined on day 17 after visual examination and blood sampling by cardiac puncture. The bilberry extract group showed significantly lower oral mucositis clinical and histopathologic scores (P < .05) and less percentile of mean daily weight reductions compared with animals receiving vehicle. Frequent administration of bilberry extract had a protective effect on oral mucosal damage induced by 5-fluorouracil in an animal model.

Effect of laser phototherapy in the prevention and treatment of chemo-induced mucositis in hamsters

The aim of this study was to investigate the effect of laser phototherapy (LPT) in the prevention and/or treatment of oral mucositis induced by 5-fluorouracil (5-FU; Eurofarma, São Paulo, Brazil) in hamsters. Ninety-six hamsters were divided into four groups (n=24): Control (no treatment); Preventive [LPT from day (D) D-5 to D+5]; Therapeutic (LPT from D+5 to D+15); and Combined (preventive plus therapeutic LPT from D-5 to D+15). The animals received an intraperitoneal injection of 5-FU on Days 0 and 2. The pouch mucosa was scratched on Days 3 and 4. The irradiation parameters were: indium-gallium-aluminum-phosphide (InGaAlP) diode laser (MM Optics, São Carlos, Brazil) (660 nm), beam area of 0.036 cm2, 40 mW, 1.11 W/cm2, 6.6 J/cm2, power density applied daily of 39.6 J/cm2, in punctual mode (six points and six seconds per point) and contact mode, one application per day. The animals were sacrificed on Days 0, 5, 10 and 15 (n=6) and weighed, and the pouch mucosa was removed for histopathological analysis. Clinical and corresponding histological scores were compared using ANOVA and Tukey's test (p≤0.05). Similar weight losses ranging from 5% to 10% occurred in all groups. The therapeutic group had significantly lower clinical and histological scores than the other groups at Day 10. This study showed that positive effects on oral mucositis management were obtained only when LPT was applied in the therapeutic protocol (from D+5 to D+15 after chemotherapy).

Effect of Rice Cell-Derived Human Granulocyte-Macrophage Colony-Stimulating Factor on 5-Fluorouracil-Induced Mucositis in Hamsters

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important regulator of the maturation and function of cells in the granulocyte and macrophage lineages, and also plays a significant role in wound healing. In a previous study, we expressed human GM-CSF in rice cells (rice cell-derived human GM-CSF; rhGM-CSF). The purpose of the present study was to evaluate its effect on wound healing in oral mucositis. Oral mucositis was induced in Syrian hamster cheek pouches by 5-fluorouracil treatment and mechanical scratching. Ulcerated areas were treated from days 3 to 14 with an application of 200 µL saline, or of the same volume of a solution containing 0.04, 0.2, or 1 µg/mL rhGM-CSF. Treatment of hamsters with rhGM-CSF reduced the ulcerated areas of the oral mucosa, compared with the control. Early in the healing process, the mucositis tissue layer of the rhGM-CSF-treated group showed significantly decreased myeloperoxidase activity and increased numbers of proliferating cell nuclear antigen (PCNA)-positive cells. Treatment with rhGM-CSF also affected expression of inflammatory cytokines in the ulcerative mucosal tissue. These results demonstrate the efficacy of plant-produced rhGM-CSF in wound healing and have significant implications for the development of rhGM-CSF as a therapeutic agent for ulcerative oral mucositis.

Glycine supplementation reduces the severity of chemotherapy-induced oral mucositis in hamsters

Objective: Oral mucositis (OM) is a devastating toxicity associated with cytotoxic cancer therapy. The OM pathogenesis and the complex interactions occur in response to tissue insult. Application of this evolving model has aided in the development of mechanistically based therapies for the prevention and treatment of mucositis. The present study was to assess the effects of glycine supplementation on chemotherapy-induced oral mucositis. Methods: In a hamster cheek pouch model of chemotherapy-induced oral mucositis, one group of 20 animals received systemic glycine supplementation for 7 days, while another similar control group did not. Clinical mucositis severity and neutrophil infiltrate (on histology) were assessed by blinded examiners. Free radical production was measured as malondialdehyde (MDA) levels. Results: As compared to control animals, glycine-treated animals demonstrated a highly significant reduction in clinical severity of oral mucositis, neutrophil infiltrate, and MDA levels (p < 0.001 for all). Conclusions: Glycine supplementation reduces the severity of chemotherapy-induced oral mucositis in an animal model. This effect is at least partly mediated through inhibition of the inflammatory response and reduced production of damaging free radicals.