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W Dörr

Publications and source records attributed to W Dörr.

At least 19 recordsLinked to original sources
PubMed2003

Effect of keratinocyte growth factor on the proliferation, clonogenic capacity and colony size of human epithelial tumour cells in vitro.

PURPOSE: The effect of recombinant human keratinocyte growth factor (rHuKGF) on the proliferation, clonogenic capacity and colony size of low-passage human epithelial tumour cells was tested in vitro. MATERIALS AND METHODS: Five tumour cell cultures derived from head and neck squamous cell carcinomas, three cultures derived from pleural effusions of carcinomas of different origin and normal human nasal epithelial cells were analysed in passages 2-4. Expression of FGF7 and its receptor (FGFR2) were determined by the RNase protection assay. Cells were incubated with rHuKGF (10-200 ng ml(-1)) 3 days before or immediately after plating for clonal growth in serum-depleted media. To determine cellular radiosensitivity, single doses of 1-8 Gy X-rays were applied. Colony formation as well as colony size, reflecting the number of cell divisions, was determined after 10-15 days of growth in rHuKGF-treated and control cells. RESULTS: Normal nasal epithelial cells showed a two- to threefold increase in the number of cell divisions due to rHuKGF-treatment. In tumour cell cultures, significant stimulation of proliferation occurred in only one of eight samples. Tumour cells expressed FGF7 mRNA and protein, and low levels of FGFR2 mRNA. The addition of rHuKGF to the medium of the tumour cell cultures influenced neither radiation-induced impairment of proliferation nor clonogenic cell survival. CONCLUSION: rHuKGF has been shown to ameliorate the radiation tolerance of normal epithelia. The minimum in vitro tumour cell response to rHuKGF compared with normal epithelial cells suggests a potential for selective protection of normal epithelia during radiotherapy. The low FGFR2 expression as well as the FGF7 expression in the tumour cells may contribute to their resistance to rHuKGF treatment.

Cell Division↗
PubMed2002

Radiation-induced oral mucositis in mice: strain differences.

The present study was initiated to investigate strain differences in oral mucosal radiosensitivity in mice with regard to induction of clinically manifest ulceration. Mouse ventral tongue epithelium was used as an established animal model for radiobiological studies of radiation-induced mucositis. Mice from two different strains, C3H/Neu (n = 40) from the Dresden colony, and B6D2F1 (n = 50) from the Harlan/Winkelmann UK colony were subjected to irradiation of tongue mucosa. Graded single doses were applied to a 3 x 3 mm2 test field in the centre of the lower tongue with 25 kV X-rays in order to generate full dose-effect curves for acute mucosal ulceration, as a clinically relevant reaction. For both groups, dose-effect curves were computed by logit analysis; comparison of the curves was by maximum-likelihood chi2 test. In addition, the time course of ulceration, i.e. latent time and individual ulcer duration, was analysed. In both mouse strains, a well-defined dose effect was observed. The ED50 values, i.e. the doses at which ulceration is expected in 50% of the animals irradiated, and their standard deviation sigma, calculated by logit analysis, can be used to describe radiosensitivity. The ED50 was 11.0 +/- 3.4 Gy (95% confidence interval (7.2; 15.4), P for dose dependence: 0.014) and 13.4 +/- 3.6 Gy (95% confidence interval (10.6; 16.1), P for dose dependence: 0.0002) in C3H and BDF1 mice, respectively. Hence, oral mucosa in BDF1 mice was found to be marginally more radioresistant (P = 0.1). The latent time to ulceration, i.e. the time between irradiation and first diagnosis of ulcer, was 11.6 +/- 0.2 days (mean +/- SEM, n = 18) in C3H mice and 5.6 +/- 0.1 days (n = 27) in BDF1 mice (P = 0.0001). Both were independent of dose (PC3H = 0.94, PBDF1 = 0.33) and hence were calculated for all responding animals of the respective strain. Ulcer duration was 2.8 +/- 0.2 days and 2.4 +/- 0.1 days in C3H and B6 mice, respectively, and was also independent of dose (PC3H = 0.25, PBDF1 = 0.99), but was dependent on the mouse strain (P = 0.036). In conclusion, no statistically significant difference in oral mucosal radiosensitivity was observed between the mouse strains. This, however, may be attributed to the small number of animals used per dose group. The time course data, with a shorter latency and ulcer duration in BDF1 mice, are in good accordance with the higher proliferation rates reported for oral mucosa in this mouse strain.

Animals↗
PubMed2002

The effect of keratinocyte growth factor on healing of manifest radiation ulcers in mouse tongue epithelium.

The purpose of this study was to examine the effect of recombinant human keratinocyte growth factor (rHuKGF) on clinically manifest acute oral mucositis. The animal model utilized in this investigation was ventral tongue epithelium of C3H/Neu mice. In a first experiment, graded single doses were applied in order to define dose effect and time course of acute mucosal ulceration, as a clinically relevant endpoint. Irradiation was given to a 3 x 3 mm2 test field in the centre of the ventral tongue with 25 kV X-rays. A single dose of 18 Gy, i.e. a dose after which ulceration is expected in more than 99% of the animals, was applied in subsequent experiments. In the study group of 20 animals, rHuKGF was applied at a daily dose of 5 mg/kg subcutaneously from the time of first diagnosis of ulcer for a maximum of 5 days. In the control group, phosphate-buffered saline was used as a placebo. The time course of ulceration, i.e. individual ulcer duration, was analysed in both the control group without rHuKGF and the study group. Irradiation with graded single doses yielded an ED50 of 11.5 +/- 0.7 Gy (logit analysis). In responding animals, the latent time to first diagnosis of ulceration and the individual ulcer duration were independent of dose. Mean latency (+/- standard deviation) was 10.5 +/- 0.5 days, mean ulcer duration 3.9 +/- 0.6 days for doses 11, 13 and 16 Gy. After a dose of 18 Gy, 39 animals developed ulceration after a mean latency of 9.3 +/- 0.3 days (control and KGF-treated). The average ulcer duration was 4.2 +/- 0.9 days in the placebo group and 4.8 +/- 0.8 days in the KGF group (P = 0.02). We conclude that when rHuKGF treatment is delayed until radiation-induced ulcers are manifest, the therapeutic activity previously reported with other treatment schedules was not observed and there was a slight prolongation of duration of ulceration. These data suggest that during tumour radiotherapy, effective rHuKGF therapy schedules should include administration before the onset of ulcerative mucositis.

Animals↗
PubMed2002

Effect of dose and dose-distribution in damage to the kidney following abdominal radiotherapy.

PURPOSE: To define the effects of abdominal radiotherapy on the kidney with regard to dose-distribution parameters. MATERIALS AND METHODS: Ninety-one patients with abdominal radiotherapy were included in the study, and the minimum follow-up was 1 year. Conventional fractionation, 5 x 1.8-2.0 Gy week(-1) to total doses of 30.6-62.5 Gy, was employed. Assessment of organ function was performed before, immediately after, and at 6 months and 1 year after radiotherapy. In cases with a significant radiation response at 1 year, subsequent follow-ups were done at 6-month intervals. Documented parameters included clinical examination, static and sequential scintigraphy of the kidneys, abdominal computed tomography, and sonography. RESULTS: Twenty-one patients (23%) developed a reduction in kidney function detected by static scintigraphy. Only in 15 of these patients was impairment of renal function observed by sequential scintigraphy. The contribution of the irradiated kidney to overall renal function decreased progressively to 34-40% by the third year after treatment. Hypertension was seen in two patients. No changes were found in laboratory parameters. ED(50) for scintigraphic changes decreased from 27 Gy for 10% of the volume to 7.6 Gy for 100%. ED(5) were in the range of 3-6 Gy, and this was independent of volume. CONCLUSIONS: Sophisticated imaging techniques allow the identification of radiation effects in partial volumes of the kidneys. A dose-response relationship in relation to the volume of kidney irradiated can thus be established for scintigraphic changes. As in a number of other organs, such changes do not relate directly to loss of renal function due to the reserve capacity of unirradiated kidney tissue.

Blood Pressure↗
PubMed2001

[Chronic radiation effects on dental hard tissue (radiation caries). Classification and therapeutic strategies].

OBJECTIVES: Since the first description of rapid destruction of dental hard tissues following head and neck radiotherapy 80 years ago, "radiation caries" is an established clinical finding. The internationally accepted clinical evaluation score RTOG/EORTC however is lacking a classification of this frequent radiogenic alteration. MATERIAL AND METHODS: Medical records, data and images of radiation effects on the teeth of more than 1,500 patients, who underwent periradiotherapeutic care, were analyzed. Macroscopic alterations regarding the grade of late lesions of tooth crowns were used for a classification into 4 grades according to the RTOG/EORTC guidelines. RESULTS: No early radiation effects were found by macroscopic inspection. In the first 90 days following radiotherapy 1/3 of the patients complained of reversible hypersensitivity, which may be related to a temporary hyperemia of the pulp. It was possible to classify radiation caries as a late radiation effect on a graded scale as known from RTOG/EORTC for other organ systems. This is a prerequisite for the integration of radiation caries into the international nomenclature of the RTOG/EORTC classification. CONCLUSIONS: The documentation of early radiation effects on dental hard tissues seems to be neglectable. On the other hand the documentation of Late radiation effects has a high clinical impact. The identification of an initial lesion at the high-risk areas of the neck and incisal part of the tooth can lead to a successful therapy as a major prerequisite for orofacial rehabilitation. An internationally standardized documentation is a basis for the evaluation of the side effects of radiooncotic therapy as well as the effectiveness of protective and supportive procedures.

Adult↗
PubMed2001

Consequential late effects in normal tissues.

Unconventional, more aggressive irradiation protocols are usually associated with aggravation of acute reactions. In recent clinical studies, this has resulted in modulation of late effects in the same organ. This phenomenon has been termed consequential late effect (CLE). Correlations between acute and late effects have been reported in a number of tissues. Moreover, some radiobiological parameters may be used to differentiate between consequential and generic late effects: Dose fractionation and overall treatment time have a similar effect on acute and consequential responses, but opposing effects on generic late effects. Modulation of acute effects will affect the consequential component of late sequelae. Similarly, it will be influenced by the irradiated volume if a volume effect exists for the acute response. Moreover, markers for the acute response should be predictive for consequential effects. The present review gives preclinical and clinical evidence for CLE. These are predominantly found in organ systems where the acute response (of the epithelial lining) is associated with an impairment of the barrier against mechanical or chemical stress, which may cause additional trauma to the underlying tissues. Therefore, CLE are mainly found in the urinary and intestinal system, in mucosa and, to some extent, in skin. In these tissues with a consequential component of the late sequelae, amelioration of the acute response to irradiation may be a useful approach to minimize late side effects of effective radiation therapy.

Digestive System↗
PubMed2001

Modification of oral mucositis by keratinocyte growth factor: single radiation exposure.

PURPOSE: The aim was to quantify the effect of recombinant human keratinocyte growth factor (rhKGF) on acute oral mucositis induced by a single radiation dose, simulating accidental radiation exposure. MATERIAL AND METHODS: Tongue epithelium of the C3H/Neu mouse was irradiated with graded single doses of 25 kV X-rays to a 3 x 3 mm2 area in the centre of the lower tongue surface. Acute mucosal ulceration, as a clinically relevant reaction, was used as the quantal endpoint for dose response analyses by probit analysis. As a secondary endpoint the time-course, i.e. time to first diagnosis of ulcer (latent time) and individual ulcer duration, was analysed. KGF was applied before, after or in combination before and after radiation exposure. RESULTS: Administration of KGF in all protocols resulted in a significant reduction of the incidence of oral mucosal ulceration, as illustrated by an increase in iso-effective dose from 10.9 to 24.9 Gy; the corresponding dose-modification factors ranged between 1.7 and 2.3. The effect was most pronounced when KGF was applied after irradiation. In all protocols where KGF was given after irradiation, a significant shortening of the latent time to ulceration from 11 to 6-8 days was observed. CONCLUSIONS: The mechanisms underlying the amelioration of the oral mucosal response to single-dose irradiation remain unclear. However, KGF represents a promising approach for the effective management of acute radiation reactions in oral, gastrointestinal and cutaneous epithelia after radiation exposure.

Animals↗
PubMed2001

A mathematical model for cell density and proliferation in squamous epithelium after single-dose irradiation.

PURPOSE: To establish a mathematical model describing changes in cell density in squamous epithelia induced by single-dose irradiation. Detailed data from previous studies in mouse tongue epithelium have been used for this study. MATERIALS AND METHODS: The major mechanisms of the epithelial regeneration response, i.e. loss of division asymmetry and accelerated proliferation of stem cells, in combination with residual, abortive proliferation of sterilized cells, have been included in a tissue compartment model. These phenomena have been incorporated via three parameters; T(delay), the duration of the cell cycle block; T(min), the minimum stem cell cycle time due to acceleration; and T(stop), the duration of abortive proliferation. The compartments introduced in the model are normal stem cells, S1; sterilized stem cells, S2; and post-mitotic, functional cells, F. The flux rats between the tissue compartments were defined by autoregulation of the stem cell population, and by overall cell numbers. The model was applied to fit experimental data on changes in oral mucosal cell density after single-dose exposure with 13 and 20 Gy. The best-fit sets of parameters were identified by L2 norm error analysis based on the total cell count. RESULTS: For 13 Gy, the best fit was achieved with T(min) = 1.0 days, T(delay) = 1.2 days and T(stop) = 7.5 days. For 20 Gy, the parameters were, T(min) =0.7 days, T(delay)= 1.0 days and T(stop) =9.5 days. In both data sets, T(min) was the most influential parameter. The resulting fluctuations in stem cell numbers were in good accordance with changes in radiation tolerance after 13 Gy. CONCLUSIONS: The model can be used to define dose-dependent parameters describing the morphological response of squamous epithelia to single-dose irradiation. Based on these parameters, post-irradiation fluctuations in radiosensitivity can be predicted. For developing more complex and reliable mathematical models, which could incorporate transit divisions or fractionated radiotherapy, further experimental data at various dose levels are required.

Animals↗
PubMed2001

Effect of keratinocyte growth factor on radiation survival and colony size of human epidermal keratinocytes in vitro.

Keratinocyte growth factor (FGF7, also known as KGF) ameliorates the radiation response of mouse oral mucosa and other epithelial tissues. However, the precise mechanisms remain unclear. The aim of the present study was to investigate the effect of FGF7 on the survival and colony size of normal human epidermal keratinocytes in vitro. Primary neonatal keratinocytes (HEKn) were irradiated with doses of 0 and 2 Gy of 200 kV X rays and incubated in the presence or absence of 100 ng/ml FGF7. The plating efficiency (PE) and surviving fraction (SF2) were determined using a clonogenic assay. In cell cultures without FGF7, the mean PE was 4.6 +/- 0.2%. Irradiation with 2 Gy resulted in an SF2 of 51 +/- 2%. In cell cultures with FGF7, the mean PE was identical, and a similar SF2 of 54 +/- 1% was observed (P = 0.4). However, the individual colony size was significantly increased in all cultures incubated with FGF7 compared to those incubated without FGF7. The number of extremely large colonies (> or =2 mm) was clearly higher (P < 0.0001) in cultures with FGF7. This was accompanied by a significant reduction in the diameter of individual cells from 29 microm in controls to 23 microm with FGF7. In conclusion, FGF7 does not affect the survival of keratinocytes after irradiation, but it does stimulate proliferation of surviving cells.

Cell Survival↗
PubMed2000

Blood hemoglobin level may affect radiosensitivity-preliminary results on acutely reacting normal tissues.

PURPOSE: To evaluate the influence of blood hemoglobin concentration on the radiosensitivity of acutely reacting normal tissues. METHODS AND MATERIALS: Weekly scores (EORTC/RTOG criteria) for acute reactions of skin and mucosa are available for 60 patients with cancer of the head and neck undergoing a standard conventional radiotherapy. The prognostic significance of blood hemoglobin levels on the development of acute reactions is studied by multivariate analysis (Cox Proportional Hazards Model). Further, the incidence and the time to development of these reactions is looked at in cohorts of patients with different mean blood hemoglobin concentrations during radiotherapy. Patients are therefore classified into a "severely anemic group" (hemoglobin < 11.0 g/100 mL), and into a cohort with a blood hemoglobin value equal or above 11.0 g/100 mL. RESULTS: Normal tissue scoring and monitoring of blood hemoglobin levels allows for a detailed analysis of possible correlations. A decrease in the mean blood hemoglobin value of 1 g/100 mL predicts a reduced risk to develop a skin reaction of Grade 2 or 3 (RR = 0.9; p = 0.08; RR = 0.8; p = 0.26, respectively) or a mucosa reaction of Grade 3 (RR = 0.8; p = 0.16), independent from the radiation dose, the treatment time and from previous surgery within the radiation volume (multivariate analysis). Likewise, patients with severe anemia develop grade 3 mucositis or dermatitis less often (0%; 13%) as compared to those with blood hemoglobin concentrations equal or above 11.0 g/100 mL (21%; 19%). Skin and mucosa reactions further tend to occur later in the course of radiation. The observations are not statistically significant and possible reasons will be discussed. CONCLUSIONS: A decreased blood hemoglobin concentration may-perhaps by an impaired tissue oxygenation-reduce the radiosensitivity of normal tissue such as skin and mucosa. However, the data is preliminary and needs further confirmation.

Adult↗
PubMed2000

Report on the third annual meeting of the Society for Biological Radiation Research, GBS '99.

During the past few decades radiation research has developed into specialized sub-disciplines, ranging from basic physics and chemistry to tumor biology and experimental radiotherapy. Scientific issues as well as the techniques and methodologies applied are subject to diverging discussion. The annual scientific meetings of the German "Gesellschaft für Biologische Strahlenforschung (GBS)" were established with the primary aim of allowing up-to-date transfer of current knowledge in any of the topics in radiation research and of promoting interaction between different research groups. This report provides a summary of the presentations at the third annual meeting which took place in 1999 in Dresden, Germany. The meeting particularly focussed on frontline research in radiation chemistry, modeling of radiation effects, dosimetry of non-ionizing radiation and unconventional radiation qualities, e.g., heavy ions or soft x-rays, stochastic radiation effects, DNA repair, and various aspects of radiobiological research of cells, normal tissues and tumors.

Animals↗
PubMed2000

Repopulation in mouse oral mucosa: changes in the effect of dose fractionation.

PURPOSE: To define the fractionation effect, including the magnitude and kinetics of dose compensation, on days 3 and 8 after a single priming dose of 8 Gy. MATERIALS AND METHODS: Graded radiation doses were given to the snouts of C3H/Neu mice in 1 to 5 fractions within a time period of < or = 36 h, or in four fractions with intervals from 5 min to 4 h. Each protocol was terminated by a top-up dose of 2.5 Gy to a 3 x 3 mm2 test area in order to precipitate the subclinical damage induced by the snout treatment and to generate the full dose response. RESULTS: No significant increase in isoeffective dose by increasing fraction numbers or by increasing interfraction intervals could be detected at each time point after the priming treatment. This indicates that the effect of dose fractionation was entirely lost. CONCLUSIONS: The loss of fractionation effect may be interpreted as a substantial impairment of the processes underlying recovery from sublethal damage as a consequence of a repopulation-inducing priming dose given 3 days or 8 days in advance.

Animals↗
PubMed2000

[Biological principles for multimodal therapy approaches].

Cancer development and progression has been associated with numerous genetic events in tumor cells. Germline mutations of caretaker and gatekeeper genes are responsible for hereditary cancer syndromes. Exogenous factors in conjunction with functional germline variants of a variety of genes may contribute to tumor initiation in sporadic malignant disease. Furthermore, pathways to neoplasia require somatic events in the developing tumor. Acquired or inherited genetic instability permits stepwise tumor progression. The most fearsome aspect of tumor progression is dissemination of tumor cells to draining lymph nodes of the primary or to distant organs, which limits effectiveness of surgical therapy. Cellular heterogeneity of malignant neoplasms has important implications for chemotherapy and radiotherapy. An increasing understanding of the molecular biology of tumors is the prerequisite for improved prediction, prevention and therapy of malignant disease.

Cell Transformation, Neoplastic↗
PubMed1999

Response of pig lung to irradiation with accelerated 12C-ions.

The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.

Animals↗
PubMed1999

Late functional response of mouse urinary bladder to fractionated X-irradiation.

PURPOSE: Late functional changes in mouse urinary bladder were studied after fractionated irradiation in order to define parameters of repair of sublethal radiation damage. MATERIALS AND METHODS: In the repair capacity study, 1 to 10 fractions were applied within 5 days. To assess the kinetics of repair, 4 fractions were applied with intervals of 0, 0.5, 1, 2, 4, or 8h. The endpoint used to establish dose-effect relationships was a reduction in the cystometrically measured bladder capacity by > or = 50% of the individual pre-treatment value. Data analysis was performed with a linear-quadratic mixture model, which includes latent-time analysis in an effect-dependent manner. RESULTS: The alpha/beta values were found to be 4.4 Gy (95% confidence interval [2.0-8.4]) for the repair capacity data alone and 3.7 Gy (1.7-6.7) in combination with the repair kinetics data. The half-time of repair, assuming mono-exponential repair kinetics, was 0.39 h (95% CI [0.23-1.3]). The mean latent time decreased from around 40 weeks to 12 weeks, inversely dependent on the biologically effective dose. In animals experiencing an acute response during the first month after treatment, the incidence of severe late responses was significantly increased (p=0.0025). CONCLUSIONS: The present results confirm that the sparing effect in the mouse urinary bladder by dose fractionation is in the lower range of chronically responding tissues. The half-time of repair is in the lower range reported for mouse tissues.

Animals↗
PubMed1999

Short-term immobilization of mice by methohexitone.

The feasibility of short-term immobilization for <5 min of female mice by methohexitone sodium was studied. In C3H/Neu mice, methohexitone at a dose <40 mg/kg did not result in chemical restraint, doses >50 mg/kg caused considerable lethality. A dose of 44 mg/kg, applied intraperitoneally at a concentration of 6.46 mg/ml, is suitable for immobilization without complications. This concentration was chosen in order to achieve an injection volume of about 0.15 ml for a mouse with an average body weight of 22 g, corresponding to about 1 mg/mouse. Complete immobilization, defined as absence of the righting reflex, was observed within 3.3 +/- 0.8 min (mean +/- SD, n = 10) after the injection and lasted for 1.5 +/- 0.7 min. Recovery of the animals was complete after a total period of 10 to 15 min post-injection. No gross pathomorphological changes were induced when intraperitoneal injections of methohexitone were repeated 10 times within 10 days. In the present study, complete immobilization of the mice was safely achieved after 87 out of 90 injections. In conclusion, immobilization by intraperitoneal injection of methohexitone is a feasible and reliable method in the experimental studies of female mice.

Anesthesia Recovery Period↗