Misonidazole radiosensitizer

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

Fig. 1. Radiosensitization of hypoxic V79 cells by 5 pM cisplatin compared to 1 mM misonidazole. The enhancement ratio for the cisplatin (5 iiM) in this experiment was 1.15. Adapted from Stratford et al. (153).

Stratford IJ, Williamson C, Adams GE. Combination studies with misonidazole and a cis-platinum complex cytotoxicity and radiosensitization in vitro. BrJ Cancer 1980 41 517-522. 

Denison L, Haigh A, D Cunha G, Martin RF (1992) DNA ligands as radioprotectors Molecular studies with Hoechst 33342 and Hoechst 33258. Int J Radiat Biol 61 69-81 Deschavanne PJ, Debieu D, Chavaudra N, Malaise EP (1985) Radiosensitizing and cytotoxic properties of misonidazole on glutathione synthetase deficient human fibroblasts. Int J Radiat Biol 48 213-221... 

Whillans DW, Hunt JW (1978) Rapid-mixing studies of the mechanisms of chemical radiosensitization and protection in mammalian cells. Br J Cancer 37 38-41 Whillans DW, Hunt JW (1982) A rapid-mixing comparison of the mechanisms of radiosensitization by oxygen and misonidazole in CHO cells. Radiat Res 90 126-141 Whillans DW, Adams GE, Neta P (1975) Electron-affinic sensitization. VI. Pulse radiolysis and ESR comparison of some 2- and 5-nitroimidazoles. Radiat Res 62 407-421... 

Whillans DW, Hunt JW (1982) A rapid-mixing comparison of the mechanisms of radiosensitization by oxygen and misonidazole in CHO cells. Radiat Res 90 126-141... 

The ESR spectra of radical ions of known radiosensitizers metronidazole, misonidazole, omidazole, and other nitroimidazoles have been investigated in the conditions of photolysis [856, 857], pulse radiolysis [849, 856, 858-865], and in the presence of other donors of free electrons [866-872], Radical anions of 2-nitroimi-dazole [849] and 4(5)-nitroimidazole [860] depending on medium pH can exist in three forms (Scheme 3.21) ... 

One-electron reduction of misonidazole - 2-nitroimidazole radiosensitizer [891], (nitroimidazolyl)succinic esters [892] and nitroindazoles [893, 894] has been studied by ESR and polarography. Misonidazole is participated in the determination of potentiation degree of the anticancer agent cytotoxicity [891],... 

High-performance liquid chromatography (HPLC) has been used to analyze metronidazole [1435-1437], misonidazole [1309,1438], and other nitroimidazoles [1435, 1439] in body fluids or pharmaceutical dosage forms. HPLC analysis of effect of hypoxic-cell radiosensitizer misonidazole on the radiation-induced reduction of DNA bases (thymine, cytosine, and adenine) has been carried out [1440, 1441], HPLC was employed to characterize different nitroimidazoles [327, 366, 388,409, 450, 1442-1444], nitropyrazoles [246, 301], nitrothiazoles [366], l-aryl(hetaryl)-4-nitro-l,2,3-triazoles [601], nitrobenzimidazoles [707], nitrobenzofurazans [774, 1445-1449], nitrobenzotriazoles [1450],... 

RSU-1069, 6141-43, and pomonizadole (Ro-03-8799), 6244,45, are electron-affinic radiosensitizers less toxic than misonidazole 63. The aziridine 61 exhibits also greater selective toxicity towards hypoxic cells than 6346-48.61 and 62 have been deuterium- and... 

When it was recognized that the clastogenic effect of this phorbol diester involved the release of superoxide, clastogenicity was suppressed and cell survival increased by concomitant incubation with Cu-Zn SOD [497-499]. Pretreatment with Cu-Zn SOD also reduced X-ray and phorbol diester promoted transformations and increased survival of culture hamster embryo cells [493, 500]. In still another study it was found that Cu-Zn SOD reduced transformation of lOTl/2 cells produced by concomitant X-ray irradiation and exposure to misonidazole, a hypoxic cell radiosensitizer [501]. These observations were most pronounced when Cu-Zn SOD was present during fixation and expression periods [502], consistent with the observation that Cu-Zn SOD protects DNA [503] and proteins [474] against ionizing radiation. Effective radiation protection as a result of superoxide removal does offer anticlastogenic activity as well. 

The reduction potentials of metronidazole, nimorazole, misonidazole, and nitrofurantoin (Figure 1, 8, 9, 10 and 11 respectively) and analogues of these nitroarene radiosensitizers were thus measured and compared with the concentrations C of the compounds needed to achieve a defined radiosensitizing effect in mammalian cells. QSARs of the form ... 

M.E. Watts, M.F. Dennis and I.J. Roberts, Radiosensitization by misonidazole, pimonidazole and azomycin and intracellular uptake in human tumour cell lines, Int. J. Radiat. Biol., 57 (1990) 361. 

J.M. Brown and P. Workman, Partition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole, Radiat. Res., 82 (1980) 171. 

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