[Tissue distribution of iso-metronidazole and metronidazole in tumor-bearing C3H inbred mice]. / Zur Gewebeverteilung von iso-Metronidazol und Metronidazol in tumortragenden C3H-Inzuchtmäusen.

Among the group of nitroimidazole radiosensitizers, predominantly misonidazole and metronidazole have so far been submitted to an extensive clinical testing. However, neurotoxic side effects have limited the dose of the substance necessary to obtain a maximal effect of sensibilization. Therefore, extensive efforts are being undertaken in the search for new compounds of equally good radiosensitizing action but with less side effects. One approach is to use substances of lower lipophilicity which will reduce penetration into the cerebral tissue. Proceeding from these considerations, comparative investigations were carried out with metronidazole (1-(2'-hydroxyethyl)-2-methyl-5-nitroimidazole) and iso-metronidazole (1-(2'-hydroxyethyl)-2-methyl-4-nitroimidazole), since in vitro but also in animal experiments the both substances showed an equally good radiosensitizing action while the lipophilicity of iso-metronidazole is much lower. Whereas for the metronidazole about the same distribution of the substance was found in all the organs investigated and also in the tissue of the mammary adenocarcinoma of C3H mice, the maximal concentration of iso-metronidazole in the cerebral tissue reached only about 50% of that in tumor tissue. This property, combined with the improved solubility, make the iso-metronidazole appear more appropriate for clinical testing than metronidazole.

[Combined use of radiosensitizing and protective agents in experimental radiotherapy]. / Sochetannoe primenenie radiosensibilizatorov i protektorov pri éksperimental'noi luchevoi terapii.

The appropriateness of the combined use of electron acceptor radiosensitizers: 4-nitroimidazole and metronidazole, and sulfhydryl protectors WR-2721 (gammaphos) and cysteamine was shown on the Chinese hamster cells V-79 and transplantable mouse tumors. The administration of the sensitizer 30-60 min and the protector 15-20 min before the irradiation of solid tumors weakens radiation reactions of the skin (metronidazole plus gammaphos) without weakening the effect of radiosensitization on transplantable animal tumors (metronidazole plus gammaphos or 4-nitroimidazole plus WR-2721).

[Skin reactions in the miniature pig following a single or fractionated local irradiation with 250 kVX-rays or 6.2 MeV neutron rays]. / Hautreaktionen beim Miniaturschwein nach einzeitiger oder fraktionierter Lokalbestrahlung mit 250-kV-Röntgen- oder 6,2-MeV-Neutronenstrahlen.

Skin areas of the miniature pig were irradiated locally with single fractionated (10 X Df in 12 days) doses of 250 kVX-rays or 6.2 MeV neutron rays. Depending on the neutron dose for single irradiations, the acute skin reactions up to 4 months following exposure yielded RBE values significantly less than 3.0, related to a neutron dose of 8 Gy and an X-ray dose of 24.2 Gy. When giving fractionated doses, RBE values greater than 3.1 were obtained, related to a neutron dose fraction of 1.2 Gy and an X-ray dose fraction of 3.7 Gy. For late effects 2 years after a single exposure, RBE values significantly greater than 2.3 were obtained, related to a neutron dose of 8 Gy and an X-ray dose of 18.6 Gy. Fractionated neutron irradiation yielded, as with the acute damage, RBE values greater than 3.1, related to a neutron dose fraction of 1.2 Gy and an X-ray dose fraction of 3.7 Gy. The tendency to higher RBE values for late against acute skin reactions could not be statistically verified by the present results.

[Light microscopic and histochemical findings on the mouse lung after neutron and 60 cobalt gamma-irradiation]. / Lichtmikroskopische und histochemische Befunde an der Mäuselunge nach Neutronen- und 60Kobalt-gamma-Bestrahlung.

The morphological changes on lungs of thorax irradiated mice, receiving a single dose of fast neutron and 60 cobalt radiation were investigated. Lungs were studied by histological and histochemical methods 2 weeks up to 10 months. Harvest changes were found after a time of 4-8 weeks. With histochemical methods more detailed damages are seen in contrast to routine histology. Two weeks post irradiation disturbances of phospholipid synthesis in alveolar epithelium cells of type II (AEC II) are found. Impairment of capillary endothelial cells are indicated by decreased activity of adenosine triphosphatase. Increased activity of beta-glucuronidase is seen in damaged bronchial epithelium.

[Age-related changes of cAMP and prostaglandin content in the brain and lymphocytes of spontaneously tumor-producing C3H mice]. / Altersbedingte Veränderungen des cAMP-und Prostaglandingehaltes im Gehirn und in den Lymphozyten von spontan mammakarzinombildenden C3H-Mäusen.

Age caused concurrent changes in the activation of the adenylate-cyclase activity by dopamine in the diencephalon and the stimulation of the basal level of cAMP by isoproterenol in the lymphocytes were demonstrated in the spontaneously tumor producing C3H mice. These changes may be related to the occurrence of tumors in these animals. The above-mentioned changes in the cAMP system were not found in AB mice. By treating the adult C3H mice with substances which increase the cAMP level, it was possible to achieve a renewed stimulation of the cAMP system as seen in young mice. With this treatment the spontaneous tumor-induction rate was also reduced. In the adenocarcinomas of the C3H mice a decrease in the level of prostaglandin E and an increase in the level of prostaglandin F2 alpha was observed.

[Comparative studies on the radiosensitizing action of 4-nitroimidazole and metronidazole (author's transl)]. / Vergleichende Untersuchungen zur strahlensensibilisierenden Wirkung von 4-Nitroimidazol und Metronidazol.

After the 2-nitroimidazole derivatives, misonidazole, and the 5-nitroimidazole derivative, metronidazole, had been tried in clinical radiotherapy, it seemed necessary to test substances from the group of 4-nitroderivatives of the imidazole on their effectiveness as hypoxic radiosensitizers. Therefore, the influence of 1-(2'-hydroxyethyl)-2-methyl-4-nitroimidazole vs. metronidazole on the semiconservative DNA synthesis prior to the following irradiation on leukemia cells L5178Y, on the reproductive capacity in V-70 cells on the Chinese hamster and on radiation-induced inhibition of tumour growth has been investigated in comparative experiments. The results showed a considerably lower inhibitory effect on DNA synthesis by 4-nitroimidazole compared with metronidazole. Neither substance has any influence on radiation-induced DNA synthesis under oxic conditions. Under hypoxia the 4-nitroimidazole derivative shows a little stronger radiosensitizing action than metronidazole. The radiation-induced decrease of the survival rate of V-79 cells is not influenced by either substance in well oxygenized cells, while being increased to approximately the same degree in hypoxic cultures. The radiation-induced inhibition of breast cancer growth in the 1st transplantation passage of C3H inbred mice is potentiated by 4-nitroimidazole in a similar way as by metronidazole.