An engineered biopolymer prevents mucositis induced by 5-fluorouracil in hamsters.
Oral mucositis is a common, treatment-limiting, and costly side effect of cancer treatments whose biological underpinnings remain poorly understood. In this study, mucositis induced in hamsters by 5-fluorouracil (5-FU) was observed after cheek-pouch scarifications, with and without administration of RGTA (RG1503), a polymer engineered to mimic the protective effects of heparan sulfate. RG1503 had no effects on 5-FU-induced decreases in body weight, blood cell counts, or cheek-pouch and jejunum epithelium proliferation rates, suggesting absence of interference with the cytotoxic effects of 5-FU. Extensive mucositis occurred in all of the untreated animals, and consisted of severe damage to cheek pouch tissues (epithelium, underlying connective tissue, and muscle bundles). Only half of the RG1503-treated animals had mucositis, over a mean area 70% smaller than in the untreated animals. Basement membranes were almost completely destroyed in the untreated group but was preserved in the RG1503 group. RG1503 blunted or abolished the following 5-FU-induced effects: increases in matrix metalloproteinase (MMP)-2, MMP-9, and plasmin, and decreases in tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These data indicate that mucositis lesions are related to massive release of proteolytic enzymes and are improved by RG1503 treatment, this effect being ascribable in part to restoration of the MMP-TIMP balance. RG1503 given with cancer treatment might protect patients from mucositis.
Morvan
Frédéric O
FO
Laboratoire de Biologie et Physiopathologie Crânio-Faciales, Faculté de Chirurgie Dentaire, Université Paris-5, Montrouge, France.
Baroukh
Brigitte
B
Ledoux
Dominique
D
Caruelle
Jean-Pierre
JP
Barritault
Denis
D
Godeau
Gaston
G
Saffar
Jean-Louis
JL
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D001485:Basement Membrane / Q000187:drug effects / Q000473:pathology; D001704:Biopolymers / Q000627:therapeutic use; D015153:Blotting, Western; D006224:Cricetinae; D005472:Fluorouracil / Q000633:toxicity; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D008647:Mesocricetus; D009061:Mouth Mucosa / Q000473:pathology*; D009844:Oligosaccharides / Q000627:therapeutic use*; D013280:Stomatitis / Q000139:chemically induced / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D001704:Biopolymers; D009844:Oligosaccharides; C431384:RG 1503; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005472:Fluorouracil