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Saki M.,University of Tubingen | Toulany M.,University of Tubingen | Sihver W.,Helmholtz Center Dresden | Zenker M.,Helmholtz Center Dresden | And 6 more authors.
Strahlentherapie und Onkologie | Year: 2012

Purpose. Anti-EGFR antibody cetuximab (C225) is used in combination with radiotherapy of head and neck squamous cell carcinoma (HNSCC) patients. We investigated whether conjugation of cetuximab with trans-cyclohexyl-diethylene- triamine-pentaacetic acid (CHX-A''-DTPA) and radiolabeling with 90Yttrium affect the molecular and cellular function of cetuximab and improve its combined effect with external-beam irradiation (EBI).Methods. The following cell lines were used: HNSCC UT5, SAS, FaDu, as well as A43, Chinese hamster ovary cells (CHO), and human skin fibroblast HSF7. Binding affinity and kinetics, specificity, retention, and the combination of 90Y- cetuximab with EBI were evaluated.Results. Control cetuximab and CHX-A''-DTPA-cetuximab blocked the proliferation activity of UT5 cells. In combination with EBI, CHX-A''-DTPA-cetuximab increased the radiosensitivity of UT5 to a similar degree as control cetuximab did. In contrast, in SAS and HSF7 cells neither proliferation nor radiosensitivity was affected by either of the antibodies. Binding [ 90Y]Y-CHX-A''-DTPA-cetuximab ( 90Y-cetuximab) to EGFR in HNSCC cells occurred time dependently with a maximum binding at 24 h. Retention of 90Y-cetuximab was similar in both HNSCC cell lines; 24 h after treatment, approximately 90% of bound activity remained in the cell layer. Competition assays, using cell membranes in the absence of an internalized fraction of cetuximab, showed that the cetuximab affinity is not lost as a result of conjugation with CHX-A''-DTPA. Cetuximab and CHX-A''-DTPA-cetuximab blocked EGF-induced Y1068 phosphorylation of EGFR. The lack of an effect of cetuximab on EGF-induced Akt and ERK1/2 phosphorylation and the inhibition of irradiation (IR)-induced Akt and ERK1/2 phosphorylation by cetuximab were not affected by DTPA conjugation. 90Y-cetuximab in combination with EBI resulted in a pronounced inhibition of colony formation of HNSCC cells.Conclusions. Conjugation of CHX-A''-DTPA to cetuximab does not alter the cellular and biological function of cetuximab. 90Y-labeling of cetuximab in combination with EBI may improve radiotherapy outcome. © Springer-Verlag 2012. Source


Karsch L.,OncoRay National Center for Radiation Research in Oncology
Physics in Medicine and Biology | Year: 2016

Gas-filled ionization chambers are widely used radiation detectors in radiotherapy. A quantitative description and correction of the recombination effects exists for two cases, for continuous radiation exposure and for pulsed radiation fields with short single pulses. This work gives a derivation of a formula for pulsed beams with arbitrary pulse rate for which the prerequisites of the two existing descriptions are not fulfilled. Furthermore, an extension of the validity of the two known cases is investigated. The temporal evolution of idealized charge density distributions within a plane parallel chamber volume is described for pulsed beams of vanishing pulse duration and arbitrary pulse repetition rate. First, the radiation induced release, movement and collection of the charge carriers without recombination are considered. Then, charge recombination is calculated basing on these simplified charge distributions and the time dependent spatial overlap of positive and negative charge carrier distributions. Finally, a formula for the calculation of the saturation correction factor is derived by calculation and simplification of the first two terms of a Taylor expansion for small recombination. The new formula of saturation correction contains the two existing cases, descriptions for exposure by single pulses and continuous irradiation, as limiting cases. Furthermore, it is possible to determine the pulse rate range for which each of the three descriptions is applicable by comparing the dependencies of the new formula with the two existing cases. As long as the time between two pulses is lower than one third of the collection time of the chamber, the formalism for a continuous exposure can be used. The known description for single pulse irradiation is only valid if the repetition rate is less than 1.2 times the inverse collection time. For all other repetition rates in between the new formula should be used. The experimental determination by Jaffe diagrams can be applied for all repetition rates which are not single pulse irradiation but will result in a small deviation from the correct saturation correction value. © 2016 Institute of Physics and Engineering in Medicine. Source


Iwanowska J.,National Center for Nuclear Research | Swiderski L.,National Center for Nuclear Research | Krakowski T.,National Center for Nuclear Research | Moszynski M.,National Center for Nuclear Research | And 2 more authors.
Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment | Year: 2015

The purpose of this work is to present a measurement method for determining the neutron responses of various liquid organic scintillators using a time-of-flight technique in conjunction with a D-T neutron generator. The method is based on fast-neutron scattering on protons in a liquid-scintillator medium and on the acquisition of the neutron response of the medium as a function of the proton-recoil energy. This method can be applied to all scintillators that utilize fast-neutron elastic scattering. © 2015 Elsevier B.V. Source


Karsch L.,OncoRay National Center for Radiation Research in Oncology | Richter C.,Helmholtz Center Dresden | Pawelke J.,OncoRay National Center for Radiation Research in Oncology
Zeitschrift fur Medizinische Physik | Year: 2011

In gas-filled ionization chambers as radiation detectors, the collection of the charge carriers is affected by the recombination effect. In dosimetry this effect must be accounted for by the saturation correction factor k S. The physical description of the correction factor by Boag, Hochhäuser and Balk for pulsed radiation is well established. However, this description is only accurate when the pulse length is short compared to the collection time of the ionization chamber. In this work experimental investigations of the saturation correction factor have been made for pulses of 4μs up to pulse doses of about 230 mGy, and the theory of Boag, Hochhäuser and Balk was again confirmed. For longer pulses, however, the correction factor decreases and at a pulse duration of about 200μs reaches 75% of the value valid for short pulses. This reduced influence of the ion recombination is interpreted by the reaction kinetics of ion recombination as a second-order reaction. This effect is negligible for PTW Roos chambers at clinical linear accelerators with 4μs pulse duration for pulse doses up to 120 mGy. © 2010. Source


Storch K.,OncoRay National Center for Radiation Research in Oncology | Storch K.,Helmholtz Center Dresden | Cordes N.,OncoRay National Center for Radiation Research in Oncology | Cordes N.,TU Dresden | And 2 more authors.
International Journal of Oncology | Year: 2016

Cyclin-dependent kinase 9 (CDK9), mainly involved in regulation of transcription, has recently been shown to impact on cell cycling and DNA repair. Despite the fact that CDK9 has been proposed as potential cancer target, it remains largely elusive whether CDK9 targeting alters tumor cell radiosensitivity. Five human head and neck squamous cell carcinoma (HNSCC) cell lines (SAS, FaDu, HSC4, Cal33, UTSCC5) as well as SAS cells stably transfected with CDK9-EGFP-N1 plasmid or empty vector controls were used. Upon either CDK9 small interfering RNA knockdown or treatment with a pan-CDK inhibitor (ZK304709), colony formation, DNA double strand breaks (DSBs), apoptosis, cell cycling, and expression and phosphorylation of major cell cycle and DNA damage repair proteins were examined. While CDK9 overexpression mediated radioprotection, CDK9 depletion clearly enhanced the radiosensitivity of HNSCC cells without an induction of apoptosis. While the cell cycle and cell cycle proteins were significantly modulated by CDK9 depletion, no further alterations in these parameters were observed after combined CDK9 knockdown with irradiation. ZK304709 showed concentrationdependent cytotoxicity but failed to radiosensitize HNSCC cells. Our findings suggest a potential role of CDK9 in the radiation response of HNSCC cells. Additional studies are warranted to clarify the usefulness to target CDK9 in the clinic. Source

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