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 chemie   účinky léků   MeSH
• fotochemické procesy účinky záření   MeSH
• karboplatina chemie   farmakologie   účinky záření   toxicita   MeSH
• kinetika MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• plazmidy MeSH
• poškození DNA účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemie   farmakologie   účinky záření   toxicita   MeSH
• screeningové testy protinádorových léčiv MeSH
• skot MeSH
• ultrafialové záření MeSH
• vazebná místa účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• karboplatina MeSH
• protinádorové látky MeSH

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
• adukty DNA chemie   metabolismus   MeSH
• CHO buňky MeSH
• cisplatina analogy a deriváty   chemie   farmakologie   MeSH
• DNA-dependentní DNA-polymerasy metabolismus   MeSH
• DNA chemie   účinky léků   metabolismus   MeSH
• domény HMG-Box MeSH
• HeLa buňky MeSH
• konformace nukleové kyseliny účinky léků   MeSH
• křečci praví MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• makromolekulární látky MeSH
• oligonukleotidy chemie   metabolismus   MeSH
• protein HMGB1 chemie   metabolismus   MeSH
• reagencia zkříženě vázaná chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• cisplatina MeSH
• DNA-dependentní DNA-polymerasy MeSH
• DNA MeSH
• makromolekulární látky MeSH
• oligonukleotidy MeSH
• protein HMGB1 MeSH
• reagencia zkříženě vázaná MeSH