Reduction of oral mucositis by palifermin (rHuKGF): Dose-effect of rHuKGF

Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Dresden, Germany.
International Journal of Radiation Biology (Impact Factor: 1.69). 09/2005; 81(8):557-65. DOI: 10.1080/09553000500196136
Source: PubMed


The aim of the present study was to determine the dose effect of palifermin (recombinant human keratinocyte growth factor, rHuKGF) for reduction of the response of oral mucosa to fractionated radiotherapy in a mouse model.
Ulceration (confluent mucositis) of mouse tongue epithelium was analysed as the clinically relevant endpoint. Palifermin at doses from 1 - 30 mg/kg was administered before the onset (day -3), at the end of the first (day +4) or the second week of irradiation (day +11) with 5 x 3 Gy/week. Each protocol was terminated by graded radiation test (top-up) doses. In a further experiment, optimally effective doses were given on days -3 and +4, or -3, +4 and +11.
Single dose irradiation of mouse mucosa yielded an ED50 (dose inducing ulcer in 50% of the mice) of 10.7 +/- 1.0 Gy. With fractionated irradiation for 1 week an ED50 for test irradiation (day +7) of 5.1 +/- 1.9 Gy was observed. After 2 weeks (day +14), the ED50 was 7.3 +/- 1.9 Gy. Palifermin significantly increased the ED50 values in all protocols tested. Maximally effective doses for single injections were 15.0 mg/kg (day -3, +11) or 22.5 mg/kg (day +4), which yielded ED50 values of 12.1 +/- 1.3 Gy, 13.7 +/- 1.5 Gy and 14.4 +/- 1.3 Gy, respectively. Higher palifermin doses did not further increase the ED50. Repeated injections on days -3 and +4 did not increase the ED50 beyond the value obtained with injections on day +4 alone. An additional injection on day +11 increased the ED50 further to 15.1 +/- 0.1 Gy.
A significant palifermin dose-effect was seen at doses below 15 mg/kg. However, a significant increase in oral mucosal radiation tolerance by palifermin over untreated control tissue was observed already with low doses of 1 mg/kg. This indicates that in clinical studies with palifermin, the dose of the growth factor may be of minor relevance over a wide dose range.

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    • "Hence, the additional fractionated dose applied in week 2 did not induce any further reduction in mucosal tolerance. This indicates compensation of the complete weekly dose in week 2 by repopulation, which is in excellent accordance with previous studies in the same model [28] [29] [30] [31] "
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    ABSTRACT: Oral mucositis is a severe side effect of radio(chemo)therapy for head and neck tumors, for which β1 integrins have been proposed as potential therapeutic targets. The present study was initiated to determine the effect of selective inhibition of β1 integrin on the oral epithelial radiation response. Daily fractionated irradiation was given with 5 × 3 Gy/week over 1 or 2 weeks with/without the β1 integrin-inhibiting monoclonal antibody AIIB2 or an IgG control. Each protocol was terminated by graded test doses to generate full dose-effect curves for mucosal ulceration. The same technique was used for single dose irradiation. Combined single dose irradiation plus AIIB2 resulted in a significant decrease of the ED50 compared to irradiation alone or control IgG. No effect of AIIB2 was found with fractionated irradiation over 1 week. With 2 weeks of fractionation, AIIB2 induced a significant increase in the ED50 for the terminating test irradiation when administered in week 2. The time course of the response was largely unaffected by β1 integrin inhibition. A reduction of mucosal reactions by β1 integrin inhibition later in a course of fractionation was observed, i.e. when epithelial repopulation processes were active. Further mechanistic studies are required.
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    • "Haematopoietic growth factors have been used for many years to stimulate the recovery of the bone marrow and to prevent chemotherapy or total body irradiation (TBI)-induced neutropenia after myeloablative conditioning for stem cell transplantation. This approach is now being extended to non-haematopoietic growth factors, such as keratinocyte growth factor (KGF), and preclinical studies have shown substantial protection against ionizing radiation-induced oral mucositis [109], intestinal damage [110] and pneumonitis [111]. Transient inhibition of p53 can be an effective strategy for protection against acute ionizing radiation injury in specific epithelial and lymphoid tissues, through the direct inhibition of apoptosis in the relevant stem cell compartments. "
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    • "The mouse tongue model allows the evaluation of prophylactic and therapeutic approaches to treatment of oral mucositis [59]. In this model, radiation-induced changes of the mouse tongue epithelium are scored on a daily basis from the onset of first symptoms such as erosions and ulcerations until complete repopulation of the epithelium [148,149]. "
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