Exposure of oral mucosa to bioactive milk factors reduces severity of chemotherapy-induced mucositis in the hamster.
A biologically active extract containing bovine whey proteins, whey growth factor extract-A (WGFE-A) was administered topically to the oral mucosa of hamsters and its ability to prevent and treat chemotherapy-induced oral mucositis investigated. Oral mucositis was induced in Syrian golden hamsters through a combination treatment of the antimetabolite chemotherapy drug 5-fluorouracil (5-FU), and mild abrasion of the cheek pouch. WGFE-A administered to the oral mucosa via hydrogel and liquid treatments, pre and concurrent to 5-FU therapy, resulted in significantly reduced mucosal ulceration. The protective effect was dose dependent with greatest benefit from WGFE-A doses applied at 4.2 mg/ml gel and 14 mg/ml mouthwash (P<0.01). The protective activity of WGFE-A also appeared related to mode of delivery. Administration of WGFE-A from an alternate vehicle Orabase(R) did not alleviate mucositis compared to WGFE-A applied in hydrogel. When administered continuously after the chemotherapy schedule, WGFE-A failed to reduce ulcer area when applied over a 12-day period. In a separate study, cell cycle staining indicated that cheek pouch mucosal epithelial cells pre-exposed to WGFE-A in-vivo showed a reduced rate of proliferation, measured as a 21% reduction in the bromodeoxyuridine (BrdU) cell labelling index (P<0.04). This was consistent with a protective mode of WGFE-A action against anti-metabolites such as 5-FU which target rapidly dividing cells. The results were also consistent with recent in vitro data showing protective properties from WGFE-A administered to epithelial cells given pre/concurrent to chemotherapy exposure. WGFE-A is known to contain mitogens which stimulate cells of mesenchymal origin and inhibit epithelial cell growth in culture. Several WGFE-A constituents are likely to confer protective effects on the cheek mucosa, including anti-proliferative, anti-apoptotic and anti-microbial factors. WGFE-A provides a potentially valuable source of topically delivered proteins for clinical application in preventing severe oral mucositis caused by chemotherapy.
Clarke
Julie
J
Cooperative Research Centre for Tissue Growth and Repair, Child Health Research Institute, North Adelaide, South Australia 5006, Australia.
Butler
Ross
R
Howarth
Gordon
G
Read
Leanna
L
Regester
Geoff
G
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D002610:Cheek; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D005472:Fluorouracil / Q000009:adverse effects*; D008647:Mesocricetus; D008894:Milk Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects; D013280:Stomatitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D000067816:Whey Proteins
D000964:Antimetabolites, Antineoplastic; D008894:Milk Proteins; D000067816:Whey Proteins; D005472:Fluorouracil