Abstract
Double-stranded oligonucleotides containing cisplatin adducts, with and without a mismatched region, were exposed to hydrated electrons generated by gamma-rays. Gel electrophoresis analysis demonstrates the formation of cisplatin-interstrand crosslinks from the cisplatin-intrastrand species. The rate constant per base for the reaction between hydrated electrons and the double-stranded oligonucleotides with and without cisplatin containing a mismatched region was determined by pulse radiolysis to be 7 × 109 and 2 × 109 M−1 s−1, respectively. These results provide a better understanding of the radiosensitizing effect of cisplatin adducts in hypoxic tumors and of the formation of interstrand crosslinks, which are difficult for cells to repair.
Highlights
Platinum-based chemotherapeutic agents, including cisplatin, are used for the treatment of several tumors, including ovary, lung, testicular, head and neck cancer [1,2,3], often in combination with radiotherapy, either sequentially or concomitantly
Previous water-radiolysis studies have shown that the presence of cisPt adducts sensitizes single-stranded oligonucleotides to e−aq, leading to the formation of base damage and loss of the platinum [13, 14]
We demonstrate that, in the presence of cisPt adducts, e−aq produces interstrand crosslinks (ICLs) in double-stranded DNA
Summary
Platinum-based chemotherapeutic agents, including cisplatin (cisPt), are used for the treatment of several tumors, including ovary, lung, testicular, head and neck cancer [1,2,3], often in combination with radiotherapy, either sequentially or concomitantly (chemo-radiotherapy). The reaction of e−aq with double-stranded oligonucleotide–cisPt complexes containing a mismatched region is investigated and the rate constant for the reaction of e−aq with platinated DNA is determined by pulse radiolysis.
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