Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor

Keratinocyte growth factor (KGF) is a 28-kDa heparin-binding member of the fibroblast growth factor (FGF) family (alternative designation = FGF-7) tha t specifically binds to the KGF receptor, a splice variant of FGF receptor 2, which is expressed only in epithelial tissues. KGF has been identified a s an important paracrine mediator of proliferation and differentiation in a wide variety of epithelial cells, including hepatocytes and gastrointestin al epithelial cells, type SI pneumocytes, transitional urothelial cells, an d keratinocytes in all stratified squamous epithelia. Systemic administrati on of recombinant human KGF (rHuKGF) provides significant cytoprotection to epithelial tissues in a number of different animal models of epithelial/mu cosal damage, including models of injury to the gastrointestinal tract, lun g, urinary bladder, and hair follicles. The results obtained with these pre clinical models prompted an investigation of the use of rHuKGF as a cytopro tective agent against radiation- and/or chemotherapy-induced oral and gastr ointestinal mucositis. Several dose- and time-variable studies were conduct ed in normal rhesus macaques to determine the lowest dose and shortest dura tion of rHuKGF administration required to induce oral mucosal proliferation without other significant systemic effects. Numerous studies were also con ducted in murine models of chemotherapy-induced mucositis to fine-tune the dosing schedule. These studies showed that 2-3 days of rHuKGF administratio n were sufficient to induce significant oral mucosal proliferation and to p rotect against gastrointestinal mucositis when administered prior to the in itiation of chemotherapy. The results from these models were used to design a phase I study in normal human volunteers to evaluate the safety of rHuKG F and its ability to induce oral mucosal proliferation, rHuKGF was well tol erated and induced a significant increase in markers of oral mucosal prolif eration following 3 days of administration at the highest doses. Phase I/II studies to evaluate the safety and efficacy of rHuKGF in the prevention of chemotherapy-induced mucositis are currently in progress.