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
• biofyzikální jevy * MeSH
• cisplatina metabolismus   MeSH
• DNA chemie   genetika   metabolismus   MeSH
• kalorimetrie MeSH
• konformace nukleové kyseliny MeSH
• oligodeoxyribonukleotidy chemie   genetika   metabolismus   MeSH
• reagencia zkříženě vázaná metabolismus   MeSH
• sekvence nukleotidů MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• DNA MeSH
• oligodeoxyribonukleotidy MeSH
• reagencia zkříženě vázaná MeSH
• transplatin MeSH Prohlížeč

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
• adukty DNA chemie   účinky léků   MeSH
• anthraceny chemie   MeSH
• chybné párování bází * účinky léků   MeSH
• cymeny MeSH
• DNA chemie   účinky léků   MeSH
• Escherichia coli chemie   MeSH
• ethylendiaminy chemie   MeSH
• interkalátory chemie   farmakologie   MeSH
• molekulární struktura MeSH
• monoterpeny chemie   MeSH
• organokovové sloučeniny chemie   farmakologie   MeSH
• poškození DNA MeSH
• ruthenium chemie   MeSH
• sekvence nukleotidů MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vazebný protein MutS opravné syntézy DNA chemie   účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-cymene MeSH Prohlížeč
• adukty DNA MeSH
• anthraceny MeSH
• cymeny MeSH
• DNA MeSH
• ethylendiaminy MeSH
• ethylenediamine MeSH Prohlížeč
• interkalátory MeSH
• monoterpeny MeSH
• organokovové sloučeniny MeSH
• ruthenium MeSH
• vazebný protein MutS opravné syntézy DNA 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
• adukty DNA chemie   metabolismus   MeSH
• cisplatina chemie   toxicita   MeSH
• DNA biosyntéza   MeSH
• konformace nukleové kyseliny MeSH
• oprava DNA MeSH
• organoplatinové sloučeniny chemie   toxicita   MeSH
• proteiny s vysokou pohyblivostí metabolismus   MeSH
• protinádorové látky chemie   toxicita   MeSH
• reagencia zkříženě vázaná chemie   toxicita   MeSH
• thiazoly chemie   toxicita   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adukty DNA MeSH
• cisplatina MeSH
• DNA MeSH
• organoplatinové sloučeniny MeSH
• proteiny s vysokou pohyblivostí MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH
• thiazoly MeSH
• trans-(PtCl2(NH3)(thiazole)) MeSH Prohlížeč
• transplatin MeSH Prohlížeč