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Modifications of Cellular Radiation Damage
Published in Kedar N. Prasad, Handbook of RADIOBIOLOGY, 2020
Among newly developed hypoxic cell radiosensitizers, fluorinated 2-nitroimidazole derivatives, KU-2285, is an effective radiosensitizer in vitro and in vivo at both high and low radiation doses.151 The sensitization enhancement ratio (SER) for 100–400 mg/kg of KU-2285 was between 1.12 and 1.42. RK-28, a 2-nitroimidazole nucleoside analog, is another newly developed hypoxic cell radiosensitizer.152,153 Pimonidazole and etanidazole are two recently developed hypoxic cell radiosensitizers.154 The clinical results of most of these radiosensitizing agents remained disappointing.
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 difficulty of achieving sufficiently large clinical doses of misonidazole led to a search for better radiosensitizing drugs. Of the many compounds synthesized and tested, two of the most promising were etanidazole and pimonidazole. Etanidazole was selected as being superior to misonidazole for two reasons. First, although it has a sensitizing efficiency equivalent to that of misonidazole, it has a shorter half-life in vivo, which should lead to reduced toxicity. Second, it also has a reduced lipophilicity (a lower octanol/water partition coefficient) and therefore is less readily taken up in neural tissue, leading to less neurotoxicity (6). Etanidazole was tested in two large head and neck cancer trials, one in the United States and the other in Europe. In neither case was there a significant therapeutic benefit although in a later subgroup analysis a positive benefit was reported. Pimonidazole contained a side chain with a weakly basic piperidine group. This compound is more electron affinic than misonidazole and thus is more effective as a radiosensitizer; it is also uncharged at acid pH, thus promoting its accumulation in ischaemic regions of tumours. A pimonidazole trial was started in uterine cervix, but was stopped when it became evident that those patients who received pimonidazole showed a poorer response.
Chemical radiosensitizers: the Journal history
Published in International Journal of Radiation Biology, 2019
In 1968, the Journal published the first papers (Foster 1968; Hornsey et al. 1968; Scott and Sturrock 1968) that I can identify that dealt explicitly with radiosensitization of hypoxic cells. These three studies, published back-to-back, were motivated by the then-recent discovery that tumors contained hypoxic cells that were resistant to radiation (Thomlinson and Gray 1955). The studies used an agent with ‘high electronic affinity’ as suggested by Adams and Dewey (1963). Specifically, they chose indanedione (ninhydrin), based, according to Hornsey et al. (1968) on the personal suggestion of Ged Adams. These three papers (along with a later paper by Barnes et al. (1969) showed that indanedione could differentially sensitize hypoxic cells to radiation. While mentions of indanedione soon dropped out of the Journal, these papers lead directly to the development of the next generations of ‘hypoxic cell sensitizers’. These nitroimidazole sensitizers (e.g. metronidazole, misonidazole, etanidazole) would feature heavily in the Journal in the 70s and 80s (e.g. Willson et al. 1974; Adams, Clarke, Flockhart, et al. 1979; Adams, Clarke, Gray, et al. 1979; Dennis et al. 1985; Shenoy and Singh 1985; Shibamoto et al. 1987; Overgaard 1989; Stratford et al. 1989).
Targeting of radio-enhancing drugs
Published in International Journal of Radiation Biology, 2022
Results are shown in Table 1. Both etanidazole and tirapazamine potentiated the effects of acute and fractionated radiation in the intra-muscular tumors but neither drug was effective in sub-cutaneous tumors. Since both drugs target hypoxic cells, it was hypothesized that the lack of effect in the subcutaneous tumor was attributable to the smaller size of the hypoxic fraction in this tumor model. This was confirmed using the hypoxia marker EF5 (Yapp et al. 1999).