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Modifications of Cellular Radiation Damage
Published in Kedar N. Prasad, Handbook of RADIOBIOLOGY, 2020
Clinical trials of misonidazole: A recent study79 has reported the results of clinical trials of misonidazole using over 200 patients. Neurotoxicity, primarily peripheral neuropathy, was observed in 28% of those given two or more doses (12 g/m2). Randomized clinical trials in carcinoma of the bronchus, bladder, and breast have shown no advantage.79 Preliminary results suggest that misonidazole may be of some value in improving radiation therapy in carcinoma of the cervix.79
The oxygen effect and therapeutic approaches to tumour hypoxia
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Michael R. Horsman, J. Martin Brown, Albert J. van der Kogel, Bradly G. Wouters, Jens Overgaard
The first clinical studies of radiosensitizers were with metronidazole in brain tumours and together with encouraging laboratory studies of misonidazole they were followed by a boom in the late 1970s of trials exploring the potential of this latter agent as a radiosensitizer (31). Most of the trials with misonidazole were unable to demonstrate a significant improvement in radiation response, although benefit was seen in some trials in certain subgroups of treated patients. This was certainly true for the Danish head and neck cancer trial (DAHANCA 2), which found a highly significant improvement in pharynx tumours but not in the prognostically better glottic carcinomas (33). The generally disappointing clinical results with misonidazole may partly be because it was evaluated in unpromising tumour sites and with too few patients. However, the most likely explanation is the fact that the misonidazole doses were too low for adequate sensitization, being limited by the risk of neurotoxicity (3).
Spheroids in Radiobiology Research
Published in Rolf Bjerkvig, Spheroid Culture in Cancer Research, 2017
Although work with radiosensitizers and spheroids has recently been directed primarily toward the use of these compounds as markers of hypoxic regions (see below), there have been a few recent radiation studies with radiosensitizers and spheroids. Chary et al.111 showed that an imidazole, cimetidine, which is used clinically as a H2 blocker, could radiosensitize hypoxic cells in V79 spheroids. This compound was found to be antagonistic when used in combination with misonidazole. Durand and Olive112 have recently measured the effects of a radiosensitizer (BSO) and a radioprotector (WR-2721) on the radiosensitivity of cells in different regions of V79 spheroids. These agents act by altering the level of endogenous thiols in the cell. Their studies demonstrated that reduction or enhancement of thiols actually changed the radiosensitivity of the cells by altering the availability of oxygen. Finally, Mueller-Klieser et al.113 have demonstrated that a nonmetallic oxygen complex, tetrachlorodecaoxide, can significantly increase the oxygenation of spheroids, as determined with oxygen-sensitive microelectrodes. The effect of this complex on the radiation response of cells in spheroids has not been reported.
Interaction of drugs with gut microbiota modulators
Published in Drug Metabolism Reviews, 2023
Nitro compounds are metabolized by gut microbiota (Kim 2015). Of these, orally administered nitrazepam and clonazepam are metabolized to 7-amino-nitrazepam and 7-aminoclonazepam in vivo by the gut microbiota, respectively (Ochs et al. 1991; Takeno et al. 1993; Rafii et al. 1997; Zimmermann et al. 2019b). These metabolites are an active teratogenic substance (Takeno et al. 1990, 1993). The nitro-reductive metabolism can also occur in the liver (Takeno et al. 1993). Misonidazole, a radiosensitizing nitro-compound for clinical radiation therapy of cancer, is metabolized to 1-(2-aminoimidazol-1-yl)-3-methoxypropan-2-ol by gut microbiota (Koch et al. 1980). However, the production of these metabolites is significantly lower in germ-free mice than in conventional mice. These results suggest that the reductive reaction activity may be more potent in gut microbiota than in the liver and affect their pharmacological effects.