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Aim: The cellular damage of ionising radiation depends on dose, physical radiation quality (e. g. LET) and intracellular radionuclide uptake. The influence of two beta emitters (188Re and 131I) on the thyroid cell line PCCl3 was studied. Furthermore, we analysed the effect of intracellular accumulation., Methods: The thyroid cell line PCCl3 was irradiated with 188Re-perrhenate or 131I-sodium iodide in presence or absence of perchlorate. The initial DNA-damage was measured in the comet assay as olive tail moment (OTM). The colony forming assay detects the clonogenic cell survival as surviving fraction. Additional the intracellular radionuclide uptake was quantified., Results: Dose response curves were established for irradiation with 188Re-perrhenate or 131I-iodine under various extra- and intracellular activity distribution conditions. In the presence of perchlorate DNA-damage and clonogenic cell survival for both radionuclides were comparable. In the absence of perchlorate radionuclide uptake of 1.39% (131I) and 4.14% (188Re) were measured causing twofold higher radiotoxicity. Although 131I uptake was lower than 188Re uptake the OTM values were higher und surviving fractions were lower., Conclusions: 131I, compared to 188Re, has lower mean beta energy and a higher LET, and therefore, it induced a higher DNA-damage even at lower intracellular uptake. An additional explanation for the higher radiotoxicity of 131I could be the higher dose exposition caused by cross-fire through neighborhood cells.

Multiple organ failure remains the major cause of death in critically ill patients. In view of therapeutic strategies, current research activities focus on the cellular response to different kinds of cellular stress (hypoxia, oxidative damage and mechanical distress) in the pathogenic sequelae of organ failure. The cellular stress reactions are characterized by induction of adaptive programs of gene expression (e.g. acute phase proteins, heat shock proteins, hypoxia-associated proteins) to protect the cells from energy depletion and cell death. Generally, the mitochondria are early indicators of cellular stress showing a loss of cytochrome c and a breakdown of the transmembrane potential. Shortage of ATP and decrease of pH can be observed in the cytoplasm which leads to a disintegration of the cytoskeleton. As a consequence, the cell becomes spherical and separates from the surrounding cells. Depending on the acuity of the stressor, the cell dies due to necrosis or apoptosis. Dysregulation of the balance of apoptosis and necrosis in different organs seems to be an important mechanism in the development of organ failure. New insights into the cellular mechanisms during organ dysfunction promote the development of new diagnostic (e.g., optical and spectroscopic) and pharmacological tools leading to a better prevention and therapy of organ failure.

According to a considerable amount of publications apoptosis plays an important role for radio- and chemotherapy. The most important results related to this issue will be described in 2 independent articles, covering the following topics: Part I: I. definition, morphology, biochemical processes, II. clinical relevant detection assays, III. signal transduction. Part II: significance of apoptosis for radio- and chemotherapy.

In diseases leading to massive acute cell damage, e.g., myocardial infarction or spontaneous inflammation, increased amounts of hydroperoxides of unsaturated fatty acids (LOOH) are found. An even higher production of LOOH is observed in homogenized tissue. If cells are injured, dormant lipoxygenases (LOX) are inevitably activated. They oxidize unsaturated membrane fatty acids to LOOH. This process involves not only arachidonic acid - as tacitly assumed up to now - but also linoleic acid. LOOH are decomposed to chemically highly reactive species, some of which were previously unknown (e.g, alpha-hydroxyaldehydes). LOO. radicals can also transform any molecule with a double bond to an epoxide. Therefore, epoxides are found in injured tissue. The same degradation products of hydroperoxides have been observed in elevated amounts in acute cell injury and in chronic diseases, e.g., atherosclerosis, psoriasis, and rheumatoid diseases. Therefore, we conclude that in these cases too, increased generation of hydroperoxides is caused by gradual cell injury liberating lipoxygenases.

Some aspects of the effect of hyperthermia on mammalian cells are presented. Hyperthermia is an efficient means to kill cells or to reinforce the action of radiation. These effects depend on temperature. Between both effects exists a steep temperature gradient, making necessary an exact measurement of temperature. The cytotoxic effect prefers radioresistant cells such as hypoxic cells or cells in the late DNA synthesis phase. A combination will be favorable because both therapy methods supplement each other, but produce no interaction. If one wishes to take advantage of the radiosensitizing effect, hyperthermia intervenes in the processes of recovery after the radiation insult. It is therefore indicated especially in case of tumors presenting a great capacity of cells recovery. Here, a real interaction between hyperthermia and radiotherapy takes place at the same target. Cellular death after hyperthermia and radiotherapy is caused by different mechanisms. All these data suggest the following recommendations for clinical practice: The temperature should be chosen higher or lower than 42 degrees C depending on the desired effect (cytotoxic or radiosensitizing effect). Under the point of view of recovery, radiotherapy should be followed by hyperthermia. In order to avoid an induction of resistance against hyperthermal treatment, hyperthermia should be combined as often as possible with radiotherapy.

Pathohistological findings are playing an important role in the advice of toxic organ damages. After presentation of some details about the frequency of toxic organ damages, the pathways of toxic agents in the organism are discussed. In cells toxic damage may induce cell necrosis, functional disturbance, inhibition of cell proliferation or malignant transformation; in extracellular structures it may lead to degradation phenomena in the connective tissue matrix. As demonstrated in example of calciphylaxis, a combination of different noxes may not only add but even potentiate the effects of the single noxes. In intracellular reparation processes the lysosomal system is involved. In case of necrosis regeneration is possible in most kinds of tissues, if connective tissue rails are preserved. Otherwise an irreversible reparative fibrotic alteration of organ structure is induced which develops according to particular general and schematic rules. As mostly character and course of the tissue reaction is unspecific, pathohistological findings do not enable conclusions on the type of inducing toxic agent. The following presentation of some examples of toxic damages with pathognomonic histological appearance deals with asbestosis, silicosis, chloroquine-induced cardiomyopathy, aluminum-induced osteopathy and a recently described liver cirrhosis in early childhood induced by copper-containing drinking water. Some limits of traditional pathohistological evaluation of toxic organ damages have been overcome by application of new morphological techniques. Own investigations revealed that the immunocytochemical demonstration of the C5b-9-complement complex enables a better and earlier detection of irreversibly damaged cells. Discrimination of toxic and virus-induced tissue damage is facilitated by the technique of in-situ-hybridization. Sometimes a specific recognition and localization of toxic agents is achieved by X-ray microanalysis, electron-spectroscopic imaging (= ESI) resp. laser microprobe mass spectrometry (= LAMMA); comparing these techniques X-Ray microanalysis and ESI, both, enable specific identification of chemical elements, while LAMMA, in addition, offers some information about the involved molecules and isotopes.