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Item Open Access Nervous-system-specific carcinogenesis by ethylnitrosourea in the rat: molecular and cellular aspects(1977) Rajewsky, Manfred F.; Augenlicht, Leonard H.; Biessmann, Harald; Goth, Regine; Hülser, Dieter F.; Laerum, Ole D.; Lomakina, L. Ya.A lead in the search for cellular determinants favoring neoplastic transformation may be provided by the pronounced tissue specificity of the oncogenic effect of certain carcinogens which do not require enzymatic metabolic activation, i.e., in cases where this specificity cannot be due to tissue differences in the activity of enzymes involved in the formation of the ultimate reactants. A carcinogen that fulfills this condition is the ethylating agent N-ethyl-N-nitrosourea (EtNU). Alkylation of nucleic acid constituents by N-nitroso compounds in relation to mutagenesis and carcinogenesis has received considerable attention recently.Item Open Access Molecular and cellular mechanisms in nervous system-specific carcinogenesis by N-ethyl-N-nitrosourea(1976) Rajewsky, Manfred F.; Goth, Regine; Laerum, Ole D.; Biessmann, Harald; Hülser, Dieter F.A single pulse of N-ethyl-N-nitrosourea (ENU), applied to BDIX rats during the perinatal age, specifically results in a high incidence of neuroectodermal neoplasms in the central and peripheral nervous system (NS). The pronounced sensitivity of the developing NS suggests a dependence of the carcinogenic effect on the proliferative and/or differentiative state of the target cells at the time of the ENU pulse. The specificity of ENU for the NS cannot be due to tissue variations in the degree of carcinogen-cell interactions, since the reactive, electrophilic ethyl cation is produced by rapid, nonenzymatic decomposition of ENU indiscriminately in all tissues. Correspondingly, the initial molar fractions of ethylated purine bases are similar in the DNA of "high-risk" (perinatal brain) and "low-risk" tissues (e.g., liver; adult brain). However, while the respective half lives in DNA of N7-ethylguanine and N3-ethyladenine show only minor differences for both types of tissues, the mutagenic ethylation product 06-ethylguanine is removed from brain DNA very much more slowly than from the DNA of other tissues. Together with their high rate of DNA replication during the perinatal age, the incapacity of rat brain cells for enzymatic elimination of 06-alkylguanine from their DNA could account for an increased probability of neoplastic conversion, and hence for the NS specificity of ENU in the rat.Item Open Access Untersuchungen zur Synchronisation in vivo: temporäre Inhibition der DNA-Synthese durch Hydroxyharnstoff in normalen und malignen Säugerzellsystemen(1971) Rajewsky, Manfred F.; Hülser, Dieter F.; Fabricius, ErikaDie Bearbeitung einer Reihe von Problemstellungen der experimentellen und klinischen Krebsforschung setzt die Möglichkeit einer Synchronisation proliferierender Zellsysteme in vivo voraus. Dies gilt z. B. für die Frage, ob bei Säugerzellen als Funktion ihrer Position im Zellcyclus Empfindlichkeitsunterschiede vorhanden sind, und zwar sowohl hinsichtlich der Auslösbarkeit des Prozesses der malignen Transformation durch Cancerogene, als auch in bezug auf die Inaktivierbarkeit maligner Zellen durch cytocide Agentien oder ionisierende Strahlung. In der vorliegenden Arbeit wird über Untersuchungen zur in vivo-Synchronisation verschiedener Gewebe (Embryo; Leber; Milz; transplantabler BICR/M1R-Tumor) der Ratte durch temporäre Blockade der DNA-Synthese mit Hydroxyharnstoff (HU) berichtet.Item Open Access Elektronenmikroskopische Autoradiogramme: unterschiedliche Empfindlichkeit von Photoemulsionen gegenüber Tritium(1971) Hülser, Dieter F.; Rajewsky, Manfred F.The sensitivity of the photographic emulsion is an important factor in the resolution of autoradiographs at the electron microscopic level. In a number of recent publications, single hit processes have been considered sufficient for the production of developable latent images by tritium electrons. However, since the absorbed energy required or latent image formation in AgBr crystals of commercially available emulsions is of the order of 800 eV, onIy low energy tritium electrons (up to 3 keV) will produce latent images by single hit processes in small AgBr crystals of about 400 A diameter. In emulsions with larger AgBr crystals (about 1000 A diameter), electrons with an energy of up to about 6 keV can be regisiered by single hit processes. Evidently, latent image formation may also result from multiple hits by electrons of higher energy. Since the energy absorption required for latent image formation is constant, the sensitivity of photographic emulsions must be considered proportional to the diameter of the respective AgBr crystals, unless methods become available for specific sensitization of emulsions with small AgBr crystals.Item Open Access Synchronisation in vivo: temporary inhibition of DNA synthesis in the rat embryo with hydroxyurea(1971) Rajewsky, Manfred F.; Fabricius, Erika; Hülser, Dieter F.As part of experimental studies on the synchronisation of mammalian cell populations in vivo, the proliferative response of rat embryo cells (18th day of gestation) was investigated following transplacental administration of hydroxyurea (HU). DNA synthesis was strongly inhibited by i.p. injection of a single dose of 0.25 or 0.5 mg HU/g body weight, for periods of 2.5 and 4.5 h, respectively. Reversal of blocks occurred rapidly due to the short half-life (45 min) of the inhibitor in the embryo. The resulting synchronizing effects were analysed in terms of mitotic indices and rate of 3H-TdR incorporation for a period of 18 h after administration of HU.Item Open Access Electrophysiological properties of ethylnitrosourea-induced, neoplastic neurogenic rat cell lines cultured in vitro and in vivo(1976) Laerum, Ole D.; Hülser, Dieter F.; Rajewsky, Manfred F.A comparative analysis was performed on the electrophysiological properties of 11 neoplastic neurogenic cell culture lines and five other cell lines of different origin (HV1C, rat bile duct carcinoma; BICR/M1 RK , rat mammary tumor; HeLa, human cervix carcinoma; 3T3, mouse embryo; REe, rat embryo). Neurogenic lines were derived either from N-ethyl-N-nitrosourea-induced neoplasms of the nervous system or from cultured fetal rat brain cells that had undergone neoplastic transformation in vitro after exposure to Nethyl-N-nitrosourea in vivo. Electrical membrane excitability was lacking in all neurogenic cells analyzed. Their membrane potential and input resistance values were similar to those of the nonneurogenic lines. Intercellular ionic coupling was consistently observed between cells of a fibroblastoid shape or cells bearing multiple cytoplasmic processes (i.e., all neurogenic lines HV1C, BICR/M1RK , and 3T3). Epithelioid cells (i.e., HeLa, REe, an NV1C subpopulation, and a GV1C1 variant) showed no such intercellular communication. In vivo monolayer cultures on glass coverslips were obtained by a modified i.p. diffusion chamber technique. Under these conditions, the cells (with the exception of a glioma-derived cell line) retained the morphological appearance and electrophysiological properties observed in vitro.