Enhancement of melphalan (L-PAM) toxicity by reductive metabolites of 1-methyl-2-nitroimidazole, a model nitroimidazole chemosensitizing agent.
Chemosensitization of bifunctional alkylators by misonidazole (MISO) and related nitroimidazoles in vitro has 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 (t-PAM) in HT-29 human colon cancer cells. INO2 was a modest chemosensitizing agent, enhancing L-PAM only under hypoxic conditions. The 2-electron reduction product, 1-methyl-2-nitrosoimidazole (INO), was a potent chemosensitizer, enhancing L-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 by L-PAM even at millimolar concentration. These results suggest that nitrosoimidazoles may be the active chemosensitizing species generated upon the reductive metabolism of nitroimidazoles.
Mulcahy
R T
RT
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Gipp
J J
JJ
Ublacker
G A
GA
McClelland
R A
RA
D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008558:Melphalan / Q000633:toxicity*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000378:metabolism; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D009593:Nitroimidazoles; C042596:1-methyl-2-nitroimidazole; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan