[en] Nitro compunds are activated by coupled enzyme reactions to oxygen reactive intermediates leading to the formation of peroxide, under aerobic conditions, and to the depletion of thiols, under anaerobic conditions. Some nitro compounds as substrates for glutathione-S-transferase, show peroxide production without prior thiol removal. Other drugs reacting spontaneouly with glutathione also produce peroxide. Glutathione plays an important role in the metabolism of the nitrocompounds either by directly reacting with them or their reduced intermediates such as the nitroso, nitro and hydroxyl radical. In the case of misonidazole, protection against their cytotoxic effects can be achieved by the addition of exogenous thiols such as glutathione or cysteamine. Results indicate that oxygen and peroxide electrodes provide convenient means for measuring the products of metabolic activation of nitro compounds. Mechanisms are proposed whereby protein, nonprotein and glutathione thiols can interact with drug radicals or with DNA radicals. 60 references, 14 figures, 5 tables

[en] There have been reports in the literature that neutron energies higher than those currently in use may result in a lower OER; reports of experiments at the University of Maryland cyclotron indicated OER values of 1.3 and 1.2 for neutrons generated by 80 MeV deuterons and 101 MeV protons beryllium respectively. Because of the practical importance of this subject, the present communication reports the results of experiments with the 101 MeV and proton beam also with a beam generated by 80 MeV deuterons on a thin combination target of beryllium and tantalum. The results of this series of experiments are in direct conflict with the published data. We see no indication of a reduced OER for higher neutron energies

[en] The effectiveness of misonidazole as a hypoxic radiosensitizer of mammalian cells is increased by prolonged exposure of hypoxic cells to the drug. It was found that drug intermediates might react with endogenous non-protein thiols (NPSH). These thiols function to protect the cell against deleterious intermediates that could otherwise attach and modify critical macromolecules such as DNA, RNA and protein. This paper presents studies on the effects of misonidazole, as well as newly developed hypoxic cell radiosensitizers, in an attempt to (1) identify the alterations in the NPSH, and (2) elucidate the role that the changes in NPSH play in cytotoxic and radiosensitizing effects of nitro compounds

[en] Experiments designed to compare the two 2-nitroimidazoles Ro-07-0582 and Ro-07-0741 in terms of their radiosensitizing and cytotoxic properties are reported. A standardized in vitro cell culture test system was used. Ro-07-0741 has been shown to be a more effective radiosensitizer of hypoxic cells than is Ro-07-0582 but this may be offset by the increased toxicity shown by this drug. Whether this increased toxicity is seen in animals and presents a problem remains to be seen, but from first reports (Brown, personal communication) in vivo, Ro-07-0741 is indeed more toxic to animals than Ro-07-0582. Because of in vivo toxicity the doses of Ro-07-0741 administered to mice have been reduced approximately by a factor of two in respect to Ro-07-0582

[en] This paper describes experiments with mammalian cells in vitro to compare the radiosensitizing and cytotoxic properties of five newly synthesized hypoxia mediated drugs with the current drug in use, misonidazole. Attention has focused on the need to synthesize or identify compounds with equal or greater effectiveness but at the same time exhibiting less serious side effects

[en] It was previously shown that the radiosensitizing effectiveness of misonidazole was enhanced if cells were incubated with the drug under hypoxic conditions for several hours at 37.5⁰C prior to irradiation compared with the more usual situation where radiation is delivered immediately or soon after the addition of the drug. This paper describes experiments using Chinese hamster V79 cells designed to compare several different nitroimidazoles for their ability to produce this preincubation effect, with special reference to the mechanisms involved

[en] When misonidazole is used in clinical radiotherapy it is common practice to irradiate 4 hours after oral administration, when drug concentration has reached a maximum in the tumor. If irradiation were further delayed, the drug concentration would decrease due to drug excretion, and the effective radiosensitizing ability of the remaining drug would increase. This paper describes experiments in which V79 cells, cultured in vitro, were used to simulate the in vivo situation and investigate the effect of prolonged preincubation prior to irradiation for a range of simulated drug half-lives. The results indicate that, when drug concentration decays exponentially with a 4 hour half-life, the same amount of radiosensitization is obtained whether the radiation is delivered immediately after the addition of the drug or if it is delayed for 4-1/2 hours

[en] Clinical trials of misonidazole are already well underway, but no definitive conclusions are likely for several years. Meanwhile, attention in the laboratory is directed toward identifying or synthesizing alternative compounds, which equal misonidazole in radiosensitizing efficiency, while at the same time exhibiting less troublesome side effects. Two of the most promising contenders are desmethylmisonidazole and SR 2508. The present communication describes experiments with cells cultured in vitro designed to compare the properties of misonidazole with these two potential replacements

[en] Many strategies have been suggested to overcome the resistance of hypoxic cells to x- and γ-rays, the most recent of which involves the use of electron affinic agents which mimic oxygen by differentially sensitizing hypoxic cells to the lethal effect of x-rays. Two of these compounds, Metronidazole and Misonidazole, have already entered phase III clinical trials; however, the dose of Misonidazole that can be used is limited due to the appearance of neurotoxicity. Consequently, attention has focussed on the need to synthesize or identify compounds with equal or greater effectiveness but at the same time exhibiting less troublesome side effects. This paper describes experiments with mammalian cells in vitro to compare the radiosensitizing and cytotoxic properties of five newly synthesized hypoxia-mediated drugs with the current drug in use, Misonidazole

[en] Misonidazole is an electron affinic compound that selectively sensitizes mammalian cells to the lethal effects of x and gamma rays, and is already in use in clinical trials as an adjunct to radiotherapy. MTDQ (6,6-methylene-bis-2,2,4 trimethyl-1,2-dihydroquinoline) is an antioxidant that was initially developed as a food additive but has recently been the subject of preliminary clinical investigations in Hungary and limited in vitro experimentation in the United States. The present communication describes experiments involving the testing of MTDQ as a hypoxic cell radiosensitizer alone and in combination with misonidazole in order to determine the sensitizing properties of the two widely different agents