(Mascarin et al 1999; Makkonen et al 2000). There is currently no evidence supporting use of G-CSF or GM-CSF subcutaneously or in the form of mouthwash for patients with oral mucositis (Karthaus et al 1998; Dazzi et al 2003). In addition, these medications are very expensive. Repifermin Repifermin is the human keratinocyte growth factor 2 (KGF- 2). This substance has been studied in a phase II trial in which patients received conditioning chemotherapy before autologous HSCT. Repifermin significantly decreased the incidence of grade 2 to 4 mucositis (Freytes et al 2004). Palifermin Palifermin is the recombinant keratinocyte growth factor 1 (rHuKGF-1). This molecule was purified from fibroblast culture fluid in 1989 as a protein of 26–28kDa (Rubin et al 1989). Cloning showed that KGF and its receptor are members of the fibroblast growth factor (FGF) family with 30%–45% homology with other proteins of the FGF family (Finch et al 1989). It is also called FGF-7. Keratinocyte growth factor is produced by fibroblasts and microvascular endothelial cells in different organs like lungs, skin, stomach, and bladder (MacDonald and Hill 2002). Keratinocyte growth factor receptor expression has been found in gut epithelium, hepatocytes, skin keratinocytes, alveolar type II cells, mammary epithelium, and urothelium. Keratinocyte growth factor is also a mediator of hair follicle growth and development (Oelmann et al 2004). It can be considered as a mesenchymally-derived paracrine mediator of epithelial growth and development (MacDonald and Hill 2002). Like other members of the FGF family, KGF is a heparin- binding molecule and heparin is required for maximal KGF stimulation through its receptor (Hsu et al 1999). When bound to the receptor, KGF is internalized by endocytosis (MacDonald and Hill 2002). Keratinocyte growth factor expression seems mediated by pro-inflammatory cytokines like TNF-α, IL-1, and IL-6 (Chedid et al 1994). Glucocorticoids appear to decrease KGF production (impairing wound healing) while estrogen and progesterone increase KGF in mammary gland and endometrium (MacDonald and Hill 2002). Beneficial effects of KGF on mucosa seem to be broader than expected. For instance, KGF upregulates the transcription factor Nrf 2 that encodes genes playing a role in detoxifying radical oxygen species (Braun et al 2002; auf dem Keller et al 2004), attenuating TNF-α, and in the expression of adhesion molecules (Just et al 2003). Therapeutics and Clinical Risk Management 2006:2(2) Oral mucositis and its treatments One major concern about KGF is the presence of the receptor on malignant cells from a variety of tissues (Oelmann et al 2004). This finding has raised the possibility that exogenous KGF might stimulate tumor cells. Interestingly, some authors observed increased expression of the KGF/KGF receptor in more-differentiated and less-advanced tumors, and absence of expression in malignant versus benign cells or a switch to FGF receptor isoforms with low binding affinity to KGF (Oelmann et al 2004). In addition, KGF has been described as stimulating matrix metalloproteinases and inducing angiogenesis, mechanisms related to tumor progression and metastatic potential. Fortunately, several reports have shown that even if KGF modestly stimulated tumor cell growth for a minority of solid tumor samples tested, it did not impair tumor sensitivity to chemotherapy (Oelmann et al 2004) or radiotherapy (Hille et al 2003). Pharmacokinetic variables of palifermin have been determined in healthy volunteers and in metastatic colorectal cancer patients (Neumann and Foote 2003). Palifermin has been tested in clinical trials. In a phase I trial, Meropol determined that KGF was well tolerated at doses up to 40 µg/ kg/day administered IV for 3 days before 5-FU plus leucovorin in patients with advanced colon cancers (Meropol et al 2003). This phase I study was randomized and suggested that patients treated with palifermin had a lower rate of grade 2 to 4 mucositis compared with patients who received placebo. It has been shown recently in a large randomized trial that palifermin reduced the incidence of grade 3 to 4 mucositis, decreased the median duration of mucositis, the duration of opioid analgesic use, and the incidence of use of parenteral nutrition in patients with hematologic cancers receiving total-body irradiation and HDC (Spielberger et al 2004). Adverse events encountered were mild to moderate and transient and consisted mainly of rash, pruritus, erythema, edema, hypoesthesia, paresthesia, and mouth and tongue disorders like thickening and taste (Meropol et al 2003). Asymptomatic and reversible increases of amylases and lipases have also been observed (Sharma et al 2005). In December 2004, palifermin was approved by the FDA for prevention of mucositis in patients receiving HDC and HSCT (Saadeh 2005). This molecule is the first innovative “target-based” biologic agent for prevention of oral mucositis. Many trials are currently ongoing to determine the efficacy of this molecule in patients receiving radiotherapy, various chemotherapy regimens, or an allogenic transplant. In animal models, however, it has been shown that KGF can reduce acute oral and intestinal mucositis after chemoradiotherapy or 165