Chemosensitization at reduced nitroimidazole concentrations by mixed-function compounds combining 2-nitroimidazole and chloroethylnitrosourea.
A mixed-function compound (I-278) combining 2-nitroimidazole and chloroethylnitrosourea has been shown to be greater than 2-fold more toxic to hypoxic HeLa-MR cells than to cells similarly exposed under aerobic conditions, consistent with chemosensitization of nitrosourea toxicity by the 2-nitroimidazole Misonidazole (MISO). However, in the case of I-278, the enhancement resulted from micromolar concentrations of 2-nitroimidazole as opposed to the millimolar quantities required for a similar enhancement by MISO. These experiments provide evidence (1) that the enhanced hypoxic toxicity of I-278 is not attributable to additional, independent hypoxic cell killing by the nitroimidazole group and (2) that the interaction between the two functions under hypoxic conditions results in increased crosslink formation typical of chemosensitization. The data strongly suggest that the chemosensitizing efficiency of nitroimidazoles can be dramatically improved by covalent linkage to a chloroethylating species.
Mulcahy
R T
RT
Department of Human Oncology, University of Wisconsin, Madison 53792.
Gipp
J J
JJ
Carminati
A
A
Barascut
J L
JL
Imbach
J L
JL
D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents; D006367:HeLa Cells; D006801:Humans; D008920:Misonidazole / Q000008:administration & dosage / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D009607:Nitrosourea Compounds / Q000494:pharmacology*
D003432:Cross-Linking Reagents; D009593:Nitroimidazoles; D009607:Nitrosourea Compounds; C060623:I 278; D008920:Misonidazole