Reduction of oral mucositis by palifermin (rHuKGF): Dose-effect of rHuKGF
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.
Available from: Nils Cordes
- "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     "
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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.
Available from: Mark D. Hurwitz
- "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 , intestinal damage  and pneumonitis . 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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ABSTRACT: Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an in-tegral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, car-diac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threat-ening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy.
Available from: Tom C Karagiannis
- "The mouse tongue model allows the evaluation of prophylactic and therapeutic approaches to treatment of oral mucositis . 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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ABSTRACT: Radiation therapy is a widely used therapeutic approach for cancer. To improve the efficacy of radiotherapy there is an intense interest in combining this modality with two broad classes of compounds, radiosensitizers and radioprotectors. These either enhance tumour-killing efficacy or mitigate damage to surrounding non-malignant tissue, respectively. Radiation exposure often results in the formation of DNA double-strand breaks, which are marked by the induction of H2AX phosphorylation to generate γH2AX. In addition to its essential role in DDR signalling and coordination of double-strand break repair, the ability to visualize and quantitate γH2AX foci using immunofluorescence microscopy techniques enables it to be exploited as an indicator of therapeutic efficacy in a range of cell types and tissues. This review will explore the emerging applicability of γH2AX as a marker for monitoring the effectiveness of radiation-modifying compounds.
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