"IZ1893" Dotaz Zobrazit nápovědu
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il. ; 30 cm
Odkrytí změn chromosomů a jejich vazeb nebo asociací molekulárně biologickými mechanismy účinnosti komplexů kovů platinové skupiny na různé tyy buněk.
- MeSH
- antitumorózní látky MeSH
- mutační analýza DNA MeSH
- platina analogy a deriváty MeSH
- poškození DNA MeSH
- Konspekt
- Biologické vědy
- NLK Obory
- biologie
- embryologie a teratologie
- genetika, lékařská genetika
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
- MeSH
- adukty DNA chemická syntéza metabolismus MeSH
- denaturace nukleových kyselin MeSH
- deoxyguanosin chemie MeSH
- DNA chemie metabolismus MeSH
- fluorescenční barviva MeSH
- organoplatinové sloučeniny chemická syntéza metabolismus MeSH
- skot MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- MeSH
- antitumorózní látky farmakologie chemie MeSH
- denaturace nukleových kyselin účinky léků MeSH
- DNA chemie účinky léků MeSH
- molekulární sekvence - údaje MeSH
- organoplatinové sloučeniny farmakologie chemie MeSH
- osmolární koncentrace MeSH
- sekvence nukleotidů MeSH
- skot MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
Recognition and processing by cellular proteins of DNA modified by platinum complexes have been suggested to be relevant to the mechanism of their antitumor activity. Platinum complexes form on DNA various mono- and bifunctional adducts. It has already been described by other authors that intrastrand cross-links formed on DNA by antitumor cis-diamminedichloroplatinum(II) (cisplatin) between neighboring purine residues are recognized by several DNA-binding proteins. In contrast, these proteins do not recognize the intrastrand cross-links formed on DNA by cisplatin or its clinically ineffective trans isomer (transplatin) between nonadjacent base residues. An eventuality heretofore not addressed is that DNA interstrand cross-links (ICLs) of platinum compounds may be recognized by and bound to DNA-binding proteins. DNA probes of 110 base pairs (bp) were constructed containing five equally spaced ICLs of cisplatin or transplatin. These ICLs were formed at specific sites at which these adducts are preferentially formed in natural DNA. Gel electrophoresis mobility shift and competition assays with these probes were used to investigate the specific recognition and binding of the calf thymus HMG1 protein to the DNA ICLs of both platinum isomers. The ICL of antitumor cisplatin was recognized by and bound to the HMG1 protein with a similar affinity as the 1,2-intrastrand d(GpG) cross-link of this drug. The protein binding to the ICL is selective for the DNA modification by cisplatin, but not by chemotherapeutically inactive transplatin.(ABSTRACT TRUNCATED AT 250 WORDS)
- MeSH
- adukty DNA * metabolismus MeSH
- antitumorózní látky * metabolismus MeSH
- cisplatina * metabolismus MeSH
- DNA footprinting MeSH
- DNA vazebné proteiny * metabolismus MeSH
- endodeoxyribonukleasy metabolismus MeSH
- kompetitivní vazba MeSH
- konformace nukleové kyseliny MeSH
- molekulární sekvence - údaje MeSH
- poškození DNA MeSH
- proteiny s vysokou pohyblivostí metabolismus MeSH
- reagencia zkříženě vázaná * metabolismus MeSH
- sekvence nukleotidů MeSH
- substrátová specifita MeSH
- vazba proteinů MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The cytotoxicity of chloropolypyridyl ruthenium complexes of structural formulas [Ru(terpy)-(bpy)Cl]Cl, cis-[Ru(bpy)2Cl2], and mer-[Ru(terpy)Cl3] (terpy = 2,2':6'2"-terpyridine, bpy = 2,2'-bipyridyl) has been studied in murine and human tumor cell lines. The results show that mer-[Ru(terpy)Cl3] exhibits a remarkably higher cytotoxicity than the other complexes. Moreover, investigations of antitumor activity in a standard tumor screen have revealed the highest efficiency for mer-[Ru(terpy)Cl3]. In a cell-free medium, the ruthenium complexes coordinate to DNA preferentially at guanine residues. The resulting adducts can terminate DNA synthesis by thermostable VentR DNA polymerase. The reactivity of the complexes to DNA, their efficiency to unwind closed, negatively supercoiled DNA, and a sequence preference of their DNA adducts (studied by means of replication mapping) do not show a correlation with biological activity. On the other hand, the cytotoxic mer-[Ru(terpy)Cl3] exhibits a significant DNA interstrand cross-linking, in contrast to the inactive complexes which exhibit no such efficacy. The results point to a potential new class of metal-based antitumor compounds acting by a mechanism involving DNA interstrand cross-linking.
- MeSH
- 2,2'-dipyridyl * analogy a deriváty toxicita MeSH
- adukty DNA * MeSH
- antitumorózní látky farmakologie toxicita MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- HeLa buňky MeSH
- konformace nukleové kyseliny MeSH
- leukemie L1210 MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- myši MeSH
- organokovové sloučeniny * toxicita MeSH
- reagencia zkříženě vázaná MeSH
- replikace DNA účinky léků MeSH
- sekvence nukleotidů MeSH
- superhelikální DNA účinky léků MeSH
- testy toxicity MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
