Carboplatin, an analogue of "classical" cis-diamminedichloridoplatinum(II) (cisplatin), is a widely used second-generation platinum anticancer drug. Cytotoxicity of cisplatin and carboplatin is mediated by platinum-DNA adducts. Markedly higher concentrations of carboplatin are required, and the rate of adduct formation is considerably slower. The reduced toxic effects in tumor cells and a more acceptable side-effect profile are attributable to the lower reactivity of carboplatin with nucleophiles, since the cyclobutanedicarboxylate ligand is a poorer leaving group than the chlorides in cisplatin. Recently, platinum complexes were shown to be particularly attractive as potential photochemotherapeutic anticancer agents. Selective photoactivation of platinum complexes by irradiation of cancer cells may avoid enhancement of toxic side-effects, but may increase toxicity selectively in cancer cells and extend the application of photoactivatable platinum complexes to resistant cells and to a wider range of cancer types. Therefore, it was of interest to examine whether carboplatin can be affected by irradiation with light to the extent that its DNA binding and cytotoxic properties are altered. We have found that carboplatin is converted to species capable of enhanced DNA binding by UVA irradiation and consequently its toxicity in cancer cells is markedly enhanced. Recent advances in laser and fiber-optic technologies make it possible to irradiate also internal organs with light of highly defined intensity and wavelength. Thus, carboplatin is a candidate for use in photoactivated cancer chemotherapy.

• MeSH
• DNA chemistry   drug effects   MeSH
• Photochemical Processes radiation effects   MeSH
• Carboplatin chemistry   pharmacology   radiation effects   toxicity   MeSH
• Kinetics MeSH
• Humans MeSH
• Tumor Cells, Cultured MeSH
• Plasmids MeSH
• DNA Damage drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemistry   pharmacology   radiation effects   toxicity   MeSH
• Drug Screening Assays, Antitumor MeSH
• Cattle MeSH
• Ultraviolet Rays MeSH
• Binding Sites drug effects   MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA MeSH
• Carboplatin MeSH
• Antineoplastic Agents 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

The structure-pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX(2)(amine)(2)] structure while the trans-[PtX(2)(amine)(2)] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl(2)(NH(3))(2)]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl(2)(NH(3))(2)]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl(2)(E-iminoether)(2)]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl(2)(E-iminoether)(2)] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] locally distort DNA, bend the DNA axis by 21 degrees toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA-protein ternary cross-links produced by trans-[PtCl(2)(E-iminoether)(2)] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl(2)(E-iminoether)(2)] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism from 'classical' cisplatin and its analogs.

• MeSH
• DNA Adducts chemistry   metabolism   MeSH
• CHO Cells MeSH
• Cisplatin analogs & derivatives   chemistry   pharmacology   MeSH
• DNA-Directed DNA Polymerase metabolism   MeSH
• DNA chemistry   drug effects   metabolism   MeSH
• HMG-Box Domains MeSH
• HeLa Cells MeSH
• Nucleic Acid Conformation drug effects   MeSH
• Cricetinae MeSH
• Rats MeSH
• Humans MeSH
• Macromolecular Substances MeSH
• Oligonucleotides chemistry   metabolism   MeSH
• HMGB1 Protein chemistry   metabolism   MeSH
• Cross-Linking Reagents chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA Adducts MeSH
• Cisplatin MeSH
• DNA-Directed DNA Polymerase MeSH
• DNA MeSH
• Macromolecular Substances MeSH
• Oligonucleotides MeSH
• HMGB1 Protein MeSH
• Cross-Linking Reagents MeSH

Recent findings that novel trans-dichloroplatinum(II) complexes exhibit antitumor activity violate the classical structure-activity relationships of platinum(II) complexes. These novel "nonclassical" trans platinum complexes also comprise those containing planar aromatic amines. Initial studies have shown that these compounds form a considerable amount of DNA interstrand cross-links (up to approximately 30%) with a rate markedly higher than clinically ineffective transplatin. The present work has shown, using Maxam-Gilbert footprinting, that trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3)(thiazole)], representatives of the group of new antitumor trans-dichloroplatinum complexes containing planar amines, preferentially form DNA interstrand cross-links between guanine residues at the 5'-GC-3' sites. Thus, DNA interstrand cross-linking by trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3)(thiazole)] is formally equivalent to that by antitumor cisplatin, but different from clinically ineffective transplatin which preferentially forms these adducts between complementary guanine and cytosine residues. This result shows for the first time that simple chemical modification of the structure of an inactive compound alters its DNA binding site into a DNA adduct of an active drug.

• MeSH
• DNA Adducts metabolism   MeSH
• Quinolines chemistry   MeSH
• Cisplatin metabolism   MeSH
• Cytosine chemistry   MeSH
• DNA Footprinting MeSH
• DNA chemistry   MeSH
• Guanine chemistry   MeSH
• Nucleic Acid Conformation MeSH
• Ligands MeSH
• Oligonucleotides chemical synthesis   chemistry   MeSH
• Antineoplastic Agents chemistry   MeSH
• Cross-Linking Reagents chemistry   MeSH
• Base Sequence MeSH
• Stereoisomerism MeSH
• Thiazoles chemistry   MeSH
• Structure-Activity Relationship 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
• Comparative Study MeSH
• Names of Substances
• DNA Adducts MeSH
• Quinolines MeSH
• Cisplatin MeSH
• Cytosine MeSH
• DNA MeSH
• Guanine MeSH
• Ligands MeSH
• Oligonucleotides MeSH
• Antineoplastic Agents MeSH
• quinoline MeSH Browser
• Cross-Linking Reagents MeSH
• Thiazoles MeSH