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Mucositis is a common, painful, dose-limiting toxicity of chemotherapy and radiation therapy for cancer. The disorder is characterized by breakdown of the mucosa that results in the formation of ulcerative lesions. Mucositis affects up to 75 percent of patients who undergo hematopoietic stem-cell transplantation and 77 percent of patients with head and neck cancer who receive such treatment. Numerous studies in animals and humans have tried to find a means of preventing and treating mucositis. Kepivance™ (palifermin; ΔN23KGF) is approved in the United States to decrease the incidence and duration of severe oral mucositis in patients with hematological malignancies receiving myelotoxic therapy followed by hematopoietic stem cell transplantation (HSCT). The safety and efficacy of palifermin has not been established in patients with non - hematological malignancies. Here we report studies designed to determine if palifermin alters the anti-tumor activities of a relevant chemotherapy (5FU or cisplatin), Cetuximab, or the combination thereof in a model of colorectal (HT29) or head and neck carcinoma (Fadu). Cetuximab is an anti-epidermal growth factor receptor (EGFR) antibody approved for the treatment of colorectal carcinoma in combination with chemotherapy. The use of Cetuximab, and palifermin is currently being evaluated in patients with various solid tumors in separate clinical trials. The HT-29 and Fadu cell lines were chosen for detailed analysis as they express both the KGF and EGF receptors. The functionality of these receptors was then assessed by phosphorylation of Akt upon in vitro stimulation. Finally these cell lines were used to establish tumor xenograft models where the question of altered efficacy of the anti-tumor agents in the presence of palifermin was assessed. The studies demonstrated that in the presence of a functional KGF receptor on the tumor cells, palifermin had no effect on the growth of either tumor type compared to the vehicle treated control (p ≥ 0.8622). Comparisons between the combination of chemotherapy and Cetuximab versus chemotherapy, Cetuximab and palifermin, also found no statistically significant growth difference in either the HT-29 (p=>0.9999) or the Fadu (p = 0.7441) tumor xenograft models. In addition in the HT-29 tumors, the experiment was established such that comparisons could be made between each of the anti-tumor agents as single agents or in combination with palifermin. The comparison of 5FU alone or in combination with palifermin failed to demonstrate statistical significance (p = >0.9999) as did the same comparison using Cetuximab (p = 0.9985). These studies suggest that palifermin may have therapeutic potential in the treatment of mucositis in solid tumor settings in addition to HSCT, without negatively impacting anti-tumor activities of the relevant chemotherapy.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]