Clinically ineffective transplatin [trans-diamminedichloridoplatinum(II)] is used in the studies of the structure-pharmacological activity relationship of platinum compounds. In addition, a number of transplatin analogs exhibit promising toxic effects in several tumor cell lines including those resistant to conventional antitumor cisplatin. Moreover, transplatin-modified oligonucleotides have been shown to be effective modulators of gene expression. Owing to these facts and because DNA is also considered the major pharmacological target of platinum complexes, interactions between transplatin and DNA are of great interest. We examined, using biophysical and biochemical methods, the stability of 1,3-GNG intrastrand cross-links (CLs) formed by transplatin in short synthetic oligodeoxyribonucleotide duplexes and natural double-helical DNA. We have found that transplatin forms in double-helical DNA 1,3-GNG intrastrand CLs, but their stability depends on the sequence context. In some sequences the 1,3-GNG intrastrand CLs formed by transplatin in double-helical DNA readily rearrange into interstrand CLs. On the other hand, in a number of other sequences these intrastrand CLs are relatively stable. We show that the stability of 1,3-GNG intrastrand CLs of transplatin correlates with the extent of conformational distortion and thermodynamic destabilization induced in double-helical DNA by this adduct.

• MeSH
• Biophysical Phenomena * MeSH
• Cisplatin metabolism   MeSH
• DNA chemistry   genetics   metabolism   MeSH
• Calorimetry MeSH
• Nucleic Acid Conformation MeSH
• Oligodeoxyribonucleotides chemistry   genetics   metabolism   MeSH
• Cross-Linking Reagents metabolism   MeSH
• Base Sequence MeSH
• Thermodynamics MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cisplatin MeSH
• DNA MeSH
• Oligodeoxyribonucleotides MeSH
• Cross-Linking Reagents MeSH
• transplatin MeSH Browser

The present study was performed to examine the affinity of Escherichia coli mismatch repair (MMR) protein MutS for DNA damaged by an intercalating compound. We examined the binding properties of this protein with various DNA substrates containing a single centrally located adduct of ruthenium(II) arene complexes [(eta(6)-arene)Ru(II)(en)Cl][PF(6)] [arene is tetrahydroanthracene (THA) or p-cymene (CYM); en is ethylenediamine]. These two complexes were chosen as representatives of two different classes of monofunctional ruthenium(II) arene compounds which differ in DNA-binding modes: one that involves combined coordination to G N7 along with noncovalent, hydrophobic interactions, such as partial arene intercalation (tricyclic-ring Ru-THA), and the other that binds to DNA only via coordination to G N7 and does not interact with double-helical DNA by intercalation (monoring Ru-CYM). Using electrophoretic mobility shift assays, we examined the binding properties of MutS protein with various DNA duplexes (homoduplexes or mismatched duplexes) containing a single centrally located adduct of ruthenium(II) arene compounds. We have shown that presence of the ruthenium(II) arene adducts decreases the affinity of MutS for ruthenated DNA duplexes that either have a regular sequence or contain a mismatch and that intercalation of the arene contributes considerably to this inhibitory effect. Since MutS initiates MMR by recognizing DNA lesions, the results of the present work support the view that DNA damage due to intercalation is removed from DNA by a mechanism(s) other than MMR.

• MeSH
• DNA Adducts chemistry   drug effects   MeSH
• Anthracenes chemistry   MeSH
• Base Pair Mismatch * drug effects   MeSH
• Cymenes MeSH
• DNA chemistry   drug effects   MeSH
• Escherichia coli chemistry   MeSH
• Ethylenediamines chemistry   MeSH
• Intercalating Agents chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Monoterpenes chemistry   MeSH
• Organometallic Compounds chemistry   pharmacology   MeSH
• DNA Damage MeSH
• Ruthenium chemistry   MeSH
• Base Sequence MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• MutS DNA Mismatch-Binding Protein chemistry   drug effects   MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 4-cymene MeSH Browser
• DNA Adducts MeSH
• Anthracenes MeSH
• Cymenes MeSH
• DNA MeSH
• Ethylenediamines MeSH
• ethylenediamine MeSH Browser
• Intercalating Agents MeSH
• Monoterpenes MeSH
• Organometallic Compounds MeSH
• Ruthenium MeSH
• MutS DNA Mismatch-Binding Protein MeSH

Replacement of one ammine in clinically ineffective trans-[PtCl2(NH3)2] (transplatin) by a planar N-heterocycle, thiazole, results in significantly enhanced cytotoxicity. Unlike 'classical' cisplatin {cis-[PtCl2(NH3)2]} or transplatin, modification of DNA by this prototypical cytotoxic transplatinum complex trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) leads to monofunctional and bifunctional intra or interstrand adducts in roughly equal proportions. DNA fragments containing site-specific bifunctional DNA adducts of trans-PtTz were prepared. The structural distortions induced in DNA by these adducts and their consequences for high-mobility group protein recognition, DNA polymerization and nucleotide excision repair were assessed in cell-free media by biochemical methods. Whereas monofunctional adducts of trans-PtTz behave similar to the major intrastrand adduct of cisplatin [J. Kasparkova, O. Novakova, N. Farrell and V. Brabec (2003) Biochemistry, 42, 792-800], bifunctional cross-links behave distinctly differently. The results suggest that the multiple DNA lesions available to trans-planaramine complexes may all contribute substantially to their cytotoxicity so that the overall drug cytotoxicity could be the sum of the contributions of each of these adducts. However, acquisition of drug resistance could be a relatively rare event, since it would have to entail resistance to or tolerance of multiple, structurally dissimilar DNA lesions.

• MeSH
• DNA Adducts chemistry   metabolism   MeSH
• Cisplatin chemistry   toxicity   MeSH
• DNA biosynthesis   MeSH
• Nucleic Acid Conformation MeSH
• DNA Repair MeSH
• Organoplatinum Compounds chemistry   toxicity   MeSH
• High Mobility Group Proteins metabolism   MeSH
• Antineoplastic Agents chemistry   toxicity   MeSH
• Cross-Linking Reagents chemistry   toxicity   MeSH
• Thiazoles chemistry   toxicity   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• DNA Adducts MeSH
• Cisplatin MeSH
• DNA MeSH
• Organoplatinum Compounds MeSH
• High Mobility Group Proteins MeSH
• Antineoplastic Agents MeSH
• Cross-Linking Reagents MeSH
• Thiazoles MeSH
• trans-(PtCl2(NH3)(thiazole)) MeSH Browser
• transplatin MeSH Browser