Mechanism of action of some bioreducible 2-nitroimidazoles: comparison of in vitro cytotoxicity and ability to induce DNA strand breakage.
The interaction of a series of nitroimidazole-aziridine radiosensitisers, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH7 results in strand breakage. The efficiency of strand breakage substantially increases on reduction of the nitroimidazole analogues. The rate of production of strand breaks decreases on interaction with both parent and reduced nitroimidazole analogues as the aziridine moiety is deactivated through alkyl-substitution. These variations in efficiency are reflected in changes in the toxicity towards both oxic and hypoxic cells and in the decrease in toxicity with progressive substitution of the aziridine moiety. The stabilities of these nitroimidazoles in aqueous solution at pH7 have also been determined. However, these stabilities do not parallel the variations in the alkylating efficiency of DNA by the aziridine moiety. These results have been discussed in terms of the relative reactivities of the nitroimidazoles with plasmid DNA and their ability to act as cytotoxic agents, especially following bioreduction and how the findings may relate to the radiosensitising properties of these agents.
O'Neill
P
P
MRC Radiobiology Unit, Didcot, Oxon, UK.
Jenkins
T C
TC
Stratford
I J
IJ
Silver
A R
AR
Ahmed
I
I
McNeil
S S
SS
Fielden
E M
EM
Adams
G E
GE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010957:Plasmids; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D004247:DNA