Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
M.Rosemann, Radiation effects on cells, tissues and organisms Radiation-effects on cells and tissues M.Rosemann National Center for Radiation Sciences Helmholtz-Center for Health and Environment M.Rosemann, Radiation effects on cells, tissues and organisms Radiation - Carcinogenesis initial medical and epidemiological observations 1902: A.Frieben: Demonstration lines cancroides of the upper side of the hand, that developed after long-term exposure to diagnostic X-rays. in: Fortschritte auf dem Gebiet der Röntgenstrahlung 6, 106ff 16th century: unusual high incidence of fatal lung diseases among silver and tin miners in the Erz Mountains of Saxonia (report of the local physician G.Agricola) was termed: Schneeberger Lung Disease 1937: lung cancer in miners was associated with Radon exposure of lung epithelium (B. Rajewski) since 1947: Radiation Effects Research Foundation (RERF) monitoring cancer incidenc in A-bomb survivors of Hiroshima and Nagasaki (RERF Foundation, Preston and Pierce, Radiation Research 160, 2003) M.Rosemann, Radiation effects on cells, tissues and organisms Excess cancer in Hiroshima A-bomb survivors 50 years follow-up study of approx. 60 000 person Leukaemia per 1Sv • Gamma- and neutron irradiation, single acute exposure, 0.2 – 3 Sv • allmost all organs affected • highest risk for continuously proliferating tissues (breast, skin, colon, juvenil thyroid, haematopoeitic system) M.Rosemann, Radiation effects on cells, tissues and organisms DNA – the primary target of radiation damage A - dose of about 2 Gy deposits in the entire exposed human body about 150 Joule energy (less than the thermal energy of a cup of hot coffee). Why than has ionizing radiation such a sever biological effect ? The energy of ionizing radiation is deposited in living matter in the form of discret ionisations. Their spatial pattern match the structure of the DNA double-helix. Ionizing radiation thus has a high efficiancy to produce DNA breaks DNA is a single-copy molecule Chromosomal DNA with a Mr > 6x104 kDa is several hundred times larger than the largest protein and has thus the biggest target size. M.Rosemann, Radiation effects on cells, tissues and organisms DNA – lesions are specific for the genotoxic agent DNA double strand break is the most severe DNA lesion M.Rosemann, Radiation effects on cells, tissues and organisms Initial radiation effect causes DNA fragmentation by double-strand breaks Dose [Gy] 0 0.2 0.5 1 2 5 10 20 intact, chromosomale DNA fragmented DNA M.Rosemann, Radiation effects on cells, tissues and organisms DNA double-strand breaks can result in fixed genetic alterations such as Chromosomal translocation V79 cells (Chin. Hamsters ovary cells) 2 Gy gamma-Irradiation, 6 h or deletions/losses of DNA (micronuclei) ROS17/2.8 cells (Osteoblasten, Ratte) 4 Gy gamma-irradiation, 12 h M.Rosemann, Radiation effects on cells, tissues and organisms Ionizing radiation causes loss of clonogenic cell survival 0 Gy 1 Gy (Mouse fibroblast-cells 230kVp-X) 2 Gy 4 Gy M.Rosemann, Radiation effects on cells, tissues and organisms Dose / Gy 0 1 2 3 4 5 0 -0.5 -1 -1.5 Log S/So -2 -2.5 -3 -3.5 -4 -4.5 -5 230kV-Xray M.Rosemann, Radiation effects on cells, tissues and organisms Dose / Gy 0 1 2 3 4 5 0 -0.5 -1 -1.5 Log S/So -2 -2.5 -3 -3.5 -4 -4.5 -5 230kV-Xray 3MeV-De M.Rosemann, Radiation effects on cells, tissues and organisms Dose / Gy 0 1 2 3 4 5 0 -0.5 -1 -1.5 Log S/So -2 -2.5 -3 -3.5 -4 -4.5 -5 4MeV-α 230kV-Xray 3MeV-De M.Rosemann, Radiation effects on cells, tissues and organisms Dose / Gy 0 1 2 3 4 0 -0.5 -1 -1.5 Log S/So -2 -2.5 -3 -3.5 -4 140MeV-Ne -4.5 -5 4MeV-α 5 M.Rosemann, Radiation effects on cells, tissues and organisms Dose / Gy 0 1 2 3 4 0 -0.5 -1 -1.5 1200MeV-Xe Log S/So -2 -2.5 -3 -3.5 -4 140MeV-Ne -4.5 -5 4MeV-α 5 M.Rosemann, Radiation effects on cells, tissues and organisms Relative biological effectiveness (RBE) for clonogenic cell survival depending on LET RBE (S/Sx) 8 7 6 5 4 3 2 1 0 2 4 7 10 14 25 64 110 140 170 180 300 420 700 LET (kev/µm) 230kV-Xray 3MeV-De 4MeV-α 140MeV/u-Ne 1200MeV-Xe M.Rosemann, Radiation effects on cells, tissues and organisms Relative biological effectiveness (RBE) for clonogenic cell survival depending on LET RBE (S/Sx) 8 7 6 Resonance ? 5 4 3 2 1 0 2 4 7 10 14 25 64 110 140 170 180 300 420 700 LET (kev/µm) 230kV-Xray 3MeV-De 4MeV-α 140MeV/u-Ne 1200MeV-Xe M.Rosemann, Radiation effects on cells, tissues and organisms Relative biological effectiveness (RBE) for clonogenic cell survival depending on LET RBE (S/Sx) 8 7 6 5 4 3 2 1 0 2 4 7 10 14 25 64 110 140 170 180 300 420 700 LET (kev/µm) 230kV-Xray 3MeV-De 4MeV-α 140MeV/u-Ne 1200MeV-Xe M.Rosemann, Radiation effects on cells, tissues and organisms Radiation mutagenesis and the prediction of DNA target N. Timmofeev-Ressovsky (working at Kaiser-Wilhelm Institute in BerlinBuch, 1928-1945) tested various radiation qualities for their mutagenic potential on Drosophila. Measuring mutation and the ionisation pattern in parallel, he concluded 1935 (together with Zimmer and Delbrueck) that the sensitive target in the cell is a single molecule of about 5 – 20 nm in diameter (cross-section) Their monography „On the natur of gene-mutations and the structure of genes“ inspired E. Schröder („what is life“) and prompted J.Watson and F.Crick discovering DNA as the molecular base of inheritance. M.Rosemann, Radiation effects on cells, tissues and organisms Radiation-induced changes at Chromosomes If an essential gene is lost, cell dies. Chromatid type Aberration Chromosome type Aberration S-Phase Deletion If no essential gene is lost, cell might survive (but might have lost Tumor-Suppressor-Genes) Mitosis Deletion If a stable translocation is generated, cell survives (but might acquire an activated Oncogens ) Loss of acentric fragments Translocation M.Rosemann, Radiation effects on cells, tissues and organisms Drosophila-Mutations discovered in offspring of X-irradiated parental flies wildtype fruit-fly mutant (albino) mutant (white eye) mutant (inverted body segment) M.Rosemann, Radiation effects on cells, tissues and organisms Initial radiation effect causes DNA fragmentation by double-strand breaks Living cells can repair most of these damages Dose [Gy] 0 0.2 0.5 1 2 5 10 20 intact, chromosomale DNA fragmented DNA Repair following 20Gy 0 20’ 40’ 60’ 90’ 2h 3h 5h M.Rosemann, Radiation effects on cells, tissues and organisms The Radium-Dial Painters (US Radium Corporation) painting of aircraft-instruments with radioactive-fluorescence ink accidental oral uptake of Ra226 (10-1000µCi/year, T1/2=1600 y) accumulation in all skeletal regions (earth alkaline metal incorporated into bone similar to calcium) http://www.lastfm.de/music/Kraftwerk/_/Radioaktivit%C3%A4t M.Rosemann, Radiation effects on cells, tissues and organisms Radiation-induced Osteosarcoma in mice 224 Ra Primary Osteosarcoma M.Rosemann, Radiation effects on cells, tissues and organisms Th227 induced Osteosarcomas in mice: radiological and histological appearance Histology using EvG staining Murine radiogenic osteosarcomas resemble human spontaneous bone tumours (Gössner et al 1976). M.Rosemann, Radiation effects on cells, tissues and organisms Synopsis: Radiation acts primarily on the cellular DNA. It causes with high efficiancy DNA breaks Long persistant effects are • Cell killing • Chromosomal damage • Mutations • Cancer