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

Abstract

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.

Peroxisome proliferator activated receptor‐gamma stimulation for prevention of 5‐fluorouracil‐induced oral mucositis in mice

“…Oral mucositis is a common acute inflammation of the oral mucosa caused by the cytotoxic effects of cancer chemotherapeutics . Oral mucositis occurs in 40%‐70% of patients undergoing chemotherapy with a higher rate of >90% in children . This condition directly affects patients' quality of life due to severe oral pain and swallowing and speaking difficulties, resulting in impaired nutrition, dehydration, and weight loss .…”

“…The damage caused to cells by oxidative stress may activate transcription factors, such as nuclear factor‐kappa B (NF‐κB), which in turn may lead to a significant increase in inflammatory cytokine, chemokine secretion, and activation of signaling pathways that further amplify the inflammatory cascade. These processes result in the formation of mucosal ulcerations and increased risk of secondary infections . The healing phase occurs only after the end of oncologic treatment …”

“…The purpose of this study was to evaluate if RGZ protected against normal tissue damage induced by chemotherapeutics in a murine model of oral mucositis. In particular, we used the antimetabolite 5‐fluorouracil (5‐FU), an analog of uracil that nonspecifically blocks DNA synthesis, which induces several side effects, including oral mucositis …”

“…1 Oral mucositis occurs in 40%-70% of patients undergoing chemotherapy with a higher rate of >90% in children. 2,3 This condition directly affects patients' quality of life due to severe oral pain and swallowing and speaking difficulties, resulting in impaired nutrition, dehydration, and weight loss. 4,5 Moreover, mucositis can adversely affect the curative effects of chemotherapy due to the increased risk of local and systemic infections, which may lead to discontinuation of Mariangela chemotherapy or dose reductions that can potentially cause a decrease in patient survival.…”

“…4,5 Moreover, mucositis can adversely affect the curative effects of chemotherapy due to the increased risk of local and systemic infections, which may lead to discontinuation of Mariangela chemotherapy or dose reductions that can potentially cause a decrease in patient survival. 3,5,6 Although the exact pathogenesis of mucositis is still unclear, the etiological process of oral mucosal damage has been described in a 5-phase model. 5,7 In particular, the reactive oxygen species generated by cytotoxic agents used in chemotherapy lead to the initiation of mucosal injury through DNA strand breaks.…”