Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis

Abstract

Oral and intestinal mucositis are among the most significant dose-limiting toxic effects of intensive cancer treatment and are associated with adverse clinical and economic outcomes. Palifermin (Kepivancetrade mark), an N-truncated recombinant human keratinocyte growth factor-1, is the first agent to be approved for prevention of oral mucositis. Keratinocyte growth factor, a potent epithelial mitogen, appears to play a major role in the healing process. Palifermin has multiple biological activities that appear to protect the mucosal epithelium and promote its early regeneration after irradiation- and chemotherapy-induced injury. These include inhibition of epithelial cell apoptosis and DNA damage, up-regulation of detoxifying enzymes and down-regulation of pro-inflammatory cytokines, as well as enhanced migration, proliferation and differentiation of epithelial cells. Palifermin reduces the incidence, severity and duration of oral mucositis in patients with haematological malignancies undergoing myelotoxic conditioning therapy and haematopoietic stem-cell transplantation. Clinical sequelae, including febrile neutropenia and resource use (opioid analgesia and parenteral feeding), are concomitantly reduced. Other potential applications being explored include use in the solid tumour setting, reduction of intestinal mucositis and reduction of GVHD in allogenic transplantation. Thus, the development of palifermin and other potential new agents for preventing chemotherapy- and radiotherapy-induced mucositis represents an important breakthrough in oncological supportive care.

Keratinocyte Growth Factor Administration Attenuates Murine Pulmonary Mycobacterium tuberculosis Infection through Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF)-dependent Macrophage Activation and Phagolysosome Fusion

“…Effects of KGF that are potentially distinct from those of GM-CSF, such as those on alveolar epithelial antimicrobial protein expression (36), collectin expression (37), barrier integrity, permeability, wound healing, and fluid transport (38), may be playing a role in KGF-enhanced survival and bacterial clearance following challenge with M. tuberculosis.…”

The Prospective Oral Mucositis Audit: relationship of severe oral mucositis with clinical and medical resource use outcomes in patients receiving high-dose melphalan or BEAM-conditioning chemotherapy and autologous SCT

“…14 The association of fever with oral mucositis has been attributed to local and systemic infections, as disruption of the mucosal barrier may provide an entry point for pathogens. 2,13 However, infection frequently cannot be documented in febrile patients. An alternative hypothesis is that fever may be a manifestation of the inflammatory process that is induced by conditioning chemotherapy 2,[15][16][17] and driven by acute phase cytokines such as tumour necrosis factor a (TNF-a) and interleukin 6 (IL-6).…”

“…2 Clinical manifestations of OM include signs and symptoms of an inflammatory process, ranging from mild erythema, oedema and soreness to extreme pain and ulceration. Severe OM interferes with daily activities such as speaking, eating and swallowing and has a negative impact on quality of life.…”

Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial

“…6. has anti-apoptotic effects via the Akt pathway (Ray P, Devaux Y et al 2003) Recombinant human KGF (palifermin) is a 140 amino acid protein with a molecular weight of 16.3 kilodaltons (kDa) and differs from endogenous KGF in that the first 23 Nterminal amino acid residues have been to deleted to improve protein stability. Palifermin is produced by recombinant DNA technology in Escherichia coli (Blijlevens and Sonis 2007). Palifermin is already used to decrease the incidence, duration and severity of oral mucositis in patients with malignancies associated with chemo and/or radiotherapy (Blijlevens and Sonis 2007).…”

“…Palifermin is produced by recombinant DNA technology in Escherichia coli (Blijlevens and Sonis 2007). Palifermin is already used to decrease the incidence, duration and severity of oral mucositis in patients with malignancies associated with chemo and/or radiotherapy (Blijlevens and Sonis 2007). The recommended dosage for palifermin is 60 micrograms/kg/day administered as an intravenous bolus and is licensed for a duration of 6 days (British National Fomularly 2010).…”