Enhancement of melphalan (L-PAM) toxicity by reductive metabolites of 1-methyl-2-nitroimidazole, a model nitroimidazole chemosensitizing agent.
Enhancement of melphalan (L-PAM) toxicity by reductive metabolites of 1-methyl-2-nitroimidazole, a model nitroimidazole chemosensitizing agent.
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通过 1-甲基-2-硝基咪唑（一种模型硝基咪唑化学增敏剂）的还原代谢物增强美法仑 (L-PAM) 毒性。
DOI：
10.1016/0006-2952(90)90585-9
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发表时间：
1990
影响因子：
5.8
通讯作者：
McClelland,RA
中科院分区：
文献类型：
--
作者：
Mulcahy,RT;Gipp,JJ;Ublacker,GA;McClelland,RA
Chemosensitization of bifunctional alkylators by misonidazole (MISO) and related nitroimidazolesin vitrohas been shown to require hypoxic exposures. Presumably, reductive metabolism of the nitroimidazole under hypoxic conditions results in generation of a chemosensitizing intermediate(s) in a manner analogous to that described for the hypoxic toxicity of these compounds. In an attempt to identify these intermediates, we examined the ability of reductive metabolites of a model 2-nitroimidazole compound, 1-methyl-2-nitroimidazole (INO2), to enhance the toxicity of melphalan (l-PAM) in HT-29 human colon cancer cells. INO2was a modest chemosensitizing agent, enhancingl-PAM only under hypoxic conditions. The 2-electron reduction product, 1-methyl-2-nitrosoimidazole (INO), was a potent chemosensitizer, enhancingl-PAM toxicity at micromolar concentrations under either aerobic or hypoxic conditions. In contrast, the 4- and 6-electron reduction products, 1-methyl-2-[hydroxylamino]imidazole and 1-methyl-2-aminoimidazole, respectively, failed to modify cell kill byl-PAM even at millimolar concentrations. These results suggest that nitrosoimidazoles may be the active chemosensitizing species generated upon the reductive metabolism of nitroimidazoles.
