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.
Cooperative Research Centre for Tissue Growth and Repair, Child Health Research Institute, North Adelaide, South Australia 5006, Australia.
Julie
J
Clarke
Ross
R
Butler
Gordon
G
Howarth
Leanna
L
Read
Geoff
G
Regester
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