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DNA interactions of antitumor platinum(IV) complexes
O Nováková1, O Vrána, V I Kiseleva
1Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno.
Abstract:
Modifications of natural DNA and synthetic double-stranded oligodeoxyribonucleotides by cis-diamminedichloro-trans-dihydroxyplatinum(IV) (oxoplatin) were studied by means of ELISA, Maxam-Gilbert footprinting techniques, HPLC of enzymically digested DNA, and transcription assay. It was found that oxoplatin can bind DNA directly without addition of a reducing agent. In addition, the antibodies elicited against DNA modified by cisplatin were not competitively inhibited by DNA modified by oxoplatin. However, DNA containing the adducts of oxoplatin became a strong inhibitor of these antibodies, if it was subsequently treated with ascorbic acid, which is a reducing agent. These results were interpreted to mean that oxoplatin can form DNA adducts containing the platinum moiety in the quadrivalent state. The direct irreversible binding of the platinum(IV) drug is, however, slow as compared to the reaction of its platinum(II) counterpart. It was also found that oxoplatin preferentially binds to guanine residues and can form DNA intrastrand and interstrand cross-links containing platinum(IV). The DNA adducts containing platinum(IV) can inhibit in vitro transcription by a prokaryotic DNA-dependent RNA polymerase. We find that the platinum(IV) complex binds to DNA at similar sites as its platinum(II) counterpart. On the other hand, the DNA adducts containing the platinum(II) or platinum(IV) analogues differ in the number of ligands and the formal charge on their platinum center. We suggest that these differences could be responsible for distinct conformational features and stability of DNA modified by platinum(II) or platinum(IV) complexes.
Insights
Oxoplatin, a platinum(IV) drug, directly binds DNA, forming adducts that differ from platinum(II) counterparts. These platinum(IV) DNA adducts can inhibit transcription and may alter DNA structure.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Platinum-based drugs are crucial in cancer chemotherapy.
- Understanding the DNA-binding mechanisms of platinum complexes is vital for drug development.
Purpose of the Study:
- To investigate the DNA modification by cis-diamminedichloro-trans-dihydroxyplatinum(IV) (oxoplatin).
- To compare the DNA adducts formed by oxoplatin (platinum(IV)) with those of cisplatin (platinum(II)).
Main Methods:
- Enzyme-Linked Immunosorbent Assay (ELISA)
- Maxam-Gilbert footprinting
- High-Performance Liquid Chromatography (HPLC)
- In vitro transcription assays
Main Results:
- Oxoplatin directly binds DNA, forming platinum(IV) adducts, preferentially at guanine residues.
- DNA adducts of oxoplatin differ from cisplatin adducts and can inhibit transcription.
- Oxoplatin forms intrastrand and interstrand DNA cross-links.
Conclusions:
- Oxoplatin forms unique platinum(IV)-DNA adducts that differ in stability and conformation from platinum(II) adducts.
- These differences may influence the biological activity and therapeutic potential of platinum(IV) complexes.