Preclinical and Early Clinical Development of Keratinocyte Growth Factor,an Epithelial- Specific Tissue Growth Factor

Abstract

Keratinocyte growth factor (KGF) is a 28-kDa heparin-binding member of the fibroblast growth factor (FGF) family (alternative designation = FGF-7) that specifically binds to the KGF receptor, a splice variant of FGF receptor 2, which is expressed only in epithelial tissues. KGF has been identified as an important paracrine mediator of proliferation and differentiation in a wide variety of epithelial cells, including hepatocytes and gastrointestinal epithelial cells, type II pneumocytes, transitional urothelial cells, and keratinocytes in all stratified squamous epithelia. Systemic administration of recombinant human KGF (rHuKGF) provides significant cytoprotection to epithelial tissues in a number of different animal models of epithelial/mucosal damage, including models of injury to the gastrointestinal tract, lung, urinary bladder, and hair follicles. The results obtained with these preclinical models prompted an investigation of the use of rHuKGF as a cytoprotective agent against radiation- and/or chemotherapy-induced oral and gastrointestinal mucositis. Several dose- and time-variable studies were conducted in normal rhesus macaques to determine the lowest dose and shortest duration of rHuKGF administration required to induce oral mucosal proliferation without other significant systemic effects. Numerous studies were also conducted in murine models of chemotherapy-induced mucositis to fine-tune the dosing schedule. These studies showed that 2-3 days of rHuKGF administration were sufficient to induce significant oral mucosal proliferation and to protect against gastrointestinal mucositis when administered prior to the initiation of chemotherapy. The results from these models were used to design a phase I study in normal human volunteers to evaluate the safety of rHuKGF and its ability to induce oral mucosal proliferation. rHuKGF was well tolerated and induced a significant increase in markers of oral mucosal proliferation 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.

Keywords

Chemotherapy cytoprotection intestine mucositis oral mucosa proliferation

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