Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(2)(cis-1,4-DACH)] (DACH=diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum-DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4-5.4-fold) of [PtCl(2)(cis-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (approximately 1.5-fold) of [PtCl(2)(cis-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(2)(cis-1,4-DACH)] with glutathione (approximately 1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media (approximately 2-fold); (v) similar sequence preference of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand cross-linking efficiency (6%); (vii) similar bending (32 degrees) and enhanced local unwinding (approximately 1.5-fold) induced in DNA by the major 1,2-GG-intrastrand cross-link; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(2)(cis-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(2)(cis-1,4-DACH)] from DNA.

• MeSH
• antitumorózní látky farmakologie   chemie   metabolismus   MeSH
• buněčná membrána metabolismus   účinky léků   MeSH
• cyklohexylaminy farmakologie   chemie   metabolismus   MeSH
• DNA nádorová metabolismus   MeSH
• glutathion metabolismus   MeSH
• HeLa buňky MeSH
• králíci MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nosiče léků chemie   metabolismus   toxicita   MeSH
• oprava DNA fyziologie   účinky léků   MeSH
• organoplatinové sloučeniny metabolismus   toxicita   MeSH
• skot MeSH
• sloučeniny platiny chemie   metabolismus   toxicita   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• srovnávací studie MeSH

In early studies of empirical structure-activity relationships, monodentate Pt(II) complexes were considered to be biologically inactive. Examples of such inactive monodentate Pt(II) compounds are [PtCl(dien)]+ (dien=diethylenetriamine) and [PtCl(NH3)3]+. DNA is considered the major biological target of platinum compounds. Thus, monodentate DNA binding of Pt(II) compounds was previously expected to display insignificant biological effects because it was assumed to affect DNA conformation and downstream cellular processes markedly less than the cross-links of bifunctional Pt(II) complexes. More recently it was shown that some monodentate Pt(II) complexes do exhibit biological effects; the active monodentate Pt(II) complexes commonly feature bulkier amine ligands than the hitherto used dien or NH(3) groups. We were therefore interested in determining whether a simple but marked enhancement of the bulkiness of the dien ligand in monodentate [Pt(NO3)(dien)]+ by multiple methylation of this ligand affects the early phases in which platinum compounds exert their biological activity. More specifically, the goals of this study, performed in cell-free media, were to determine how the modification of DNA duplexes by methylated analogues of [Pt(NO3)(dien)]+ affects their energetics and how the alterations of this biophysical parameter are reflected by the recognition of these duplexes by DNA polymerases and the DNA repair system. We have found that the impact of the methylation of [Pt(NO3)(dien)]+ on the biophysical properties of DNA (thermodynamic, thermal, and conformational properties) and its biochemical processes (DNA polymerization and the repair of DNA adducts) is remarkable. Hence, we conclude that monodentate DNA binding of Pt(II) compounds may considerably affect the biophysical properties of DNA and consequently downstream cellular processes as a result of a large increase in the bulkiness of the nonleaving ligands in this class of metal complex.

• MeSH
• DNA-dependentní DNA-polymerasy chemie   MeSH
• DNA chemie   MeSH
• kalorimetrie MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• metylace MeSH
• molekulární sekvence - údaje MeSH
• molekulární struktura MeSH
• oprava DNA genetika   MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   MeSH
• sekvence nukleotidů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.

• MeSH
• adukty DNA chemie   MeSH
• amantadin analogy a deriváty   farmakologie   chemie   metabolismus   MeSH
• antitumorózní látky farmakologie   chemie   metabolismus   MeSH
• cirkulární dichroismus MeSH
• DNA chemie   MeSH
• financování organizované MeSH
• hypoxanthinfosforibosyltransferasa genetika   účinky léků   MeSH
• lidé MeSH
• mutageny farmakologie   chemie   metabolismus   MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemie   metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH

We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(eta(6)-arene)Ru(en)Cl](+), where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical "piano-stool" geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.

• MeSH
• antitumorózní látky * farmakologie   chemie   MeSH
• denaturace nukleových kyselin MeSH
• DNA chemie   metabolismus   účinky léků   MeSH
• guanin metabolismus   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   patologie   MeSH
• organokovové sloučeniny farmakokinetika   farmakologie   metabolismus   MeSH
• ruthenium * MeSH
• spektrální analýza MeSH
• superhelikální DNA MeSH
• terfenylové sloučeniny farmakologie   chemie   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Using biochemical methods, we have examined the effect of two factors that might play a role in the mechanism of the biological activity of cisplatin at elevated temperatures (>37 degrees C). We show that increased temperatures result in distinct alterations in the modification of the target DNA by cisplatin, and in the repair of these modifications. Our in vitro results support the view that the enhanced DNA-cross-linking efficiency of cisplatin and the lower efficiency of native DNA repair mechanisms at higher temperature play at least a partial role in the potentiation of the antitumor effects of cisplatin under conditions of mild hyperthermia.

• MeSH
• antitumorózní látky farmakologie   chemie   MeSH
• časové faktory MeSH
• cisplatina farmakologie   chemie   MeSH
• DNA řízené RNA-polymerasy antagonisté a inhibitory   chemie   MeSH
• DNA chemie   účinky léků   MeSH
• financování organizované MeSH
• HeLa buňky MeSH
• lidé MeSH
• oprava DNA MeSH
• RNA chemická syntéza   chemie   účinky léků   MeSH
• skot MeSH
• teplota MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH

We report in the present work new analogues of clinically ineffective transplatin in which one ammine group was replaced by aliphatic and the other by a planar heterocyclic ligand, namely trans-[PtCl(2)(isopropylamine)(3-(hydroxymethyl)-pyridine)], 1, and trans-[PtCl(2)(isopropylamine)(4-(hydroxymethyl)-pyridine)], 2. The new compounds, in comparison with parent transplatin, exhibit radically enhanced activity in tumor cell lines both sensitive and in particular resistant to cisplatin. Concomitantly, the DNA binding mode of 1 and 2 compared to parent transplatin and other antitumor analogues of transplatin in which only one ammine group was replaced is also different. The results also suggest that the reactions of glutathione and metallothionein-2 with compounds 1 and 2 do not play a crucial role in their overall biological effects. In addition, the monofunctional adducts of 1 and 2 are quenched by glutathione considerably less than the adducts of transplatin, which may potentiate cytotoxic effects of these new platinum complexes.

• MeSH
• aminy chemie   MeSH
• cirkulární dichroismus MeSH
• cisplatina farmakologie   chemická syntéza   chemie   MeSH
• DNA chemie   účinky léků   MeSH
• financování organizované MeSH
• heterocyklické sloučeniny monocyklické farmakologie   chemická syntéza   chemie   MeSH
• krystalografie rentgenová MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• molekulární sekvence - údaje MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• sekvence nukleotidů MeSH
• thiomočovina chemie   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH