Inactivation and repair of double-stranded DNA damaged by the aziridinyl nitroimidazole RSU 1069.

Incubation of RSU 1069 in the presence of biologically active double-stranded phi X174 DNA resulted in, depending on pH, ionic strength and concentration of drug, inactivation of the DNA. A variety of lesions are induced including a high number of single-strand breaks and alkali-labile lesions, which are at most partly lethal. The main inactivating damage consists probably of base damage, induced by alkylation.

Mutational specificity of gamma-rays differs for the same target in plasmid DNA and double-stranded (RF) M13 bacteriophage DNA.

In the lacZ alpha gene of a pUC plasmid a 144 bp insert was cloned as target for mutagenesis. Irradiation of the plasmid in a diluted aqueous solution by 60Co gamma-rays under oxic conditions leads to a very specific mutation spectrum. The predominant type of mutation was a C/G to A/T transversion (29 out of 47 mutants) whereas C/G to G/C transversions were found 7 times and C/G to T/A transitions 10 times.

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.

Mutations induced by 60Co gamma-irradiation in double-stranded M13 bacteriophage DNA in nitrous-oxide saturated solutions are characterized by a high specificity.

Irradiation of double-stranded M13 mp10 DNA in a diluted aqueous solution under N2O leads to a very specific mutation spectrum. Fifteen of 28 mutations induced in a 144 base pair (bp) target are C/G to G/C transversions, the other five bp substitutions are C/G to A/T transversions. Six mutations were single bp deletions, one is a large deletion of 180 bp and one is a 10 bp duplication which is probably from spontaneous origin.

Kinetics and mechanism of electron transfer between purines and pyrimidines, their dinucleotides and polynucleotides after reaction with hydrated electrons; a pulse radiolysis study.

The radical spectra of mixtures of thymidine 5'-monophosphate (TMP) or uridine 5'-monophosphate (UMP) with adenine 5'-monophosphate (AMP) after hydrated electron attack, measured from 5 to 3000 microsecond after pulse radiolysis, can only be described in terms of the radical spectra of the nucleotides if an electron transfer is taken into account from the purine radical anion to the pyrimidine, resulting in the formation of a pyrimidine radical anion. From analysis of the spectra of the dinucleoside phosphates ApU, dApT and dCpdA after eaq- attack it follows that the electron-donating species is the purine radical anion (A-.) rather than the protonated purine radical.