Interaction of RSU 1069 and 1137 with DNA in vitro. Biological implications and mechanistic aspects.
We have examined the capacity of the nitroimidazole aziridine antitumour drug RSU 1069 to react with DNA in vitro in order to get a better understanding of its mechanism of action. Moreover, we have utilized biologically active phi X174 DNA to investigate the biological relevance of the chemical DNA modification induced by the drug. Incubation of RSU 1069 in the presence of single-stranded phi X174 DNA resulted in extensive inactivation of the DNA, which is dependent on the concentration of drug and temperature. Only about 2% of the inactivating damage can be attributed to strand breakage. The main damage most probably consists of base damage, of which a part is non-lethal and alkali-labile which in turn can be converted into lethal lesion and subsequently into a break applying a post-incubation alkali treatment. Furthermore, from the dependence of the inactivation and also the formation of breaks on pH and ionic strength, it is concluded that the reaction most probably takes place between a protonated RSU 1069 and a negative DNA coil and that the damage pattern reflects the difference in reactivity of RSU 1069 with the phosphate groups and the bases in DNA. Comparison between RSU 1069 and its ring-open hydrolysis product RSU 1137 revealed that (lethal) damage induced in the DNA must be ascribed to the alkylating properties of the aziridine moiety.
Lafleur
M V
MV
Department of Biophysics, Vrije Universiteit, Amsterdam, The Netherlands.
Westmijze
E J
EJ
Visser
O J
OJ
Wagenaar
N
N
Soetekouw
R
R
Loman
H
H
Retèl
J
J
D000468:Alkalies; D001388:Aziridines / Q000378:metabolism; D010584:Bacteriophage phi X 174 / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D013696:Temperature
D000468:Alkalies; D001388:Aziridines; D004277:DNA, Single-Stranded; C033132:aziridine; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D004247:DNA; C069174:RSU 1137