• MeSH
• cisplatina analogy a deriváty   farmakologie   MeSH
• DNA metabolismus   účinky léků   MeSH
• genetická transkripce MeSH
• molekulární sekvence - údaje MeSH
• protinádorové látky farmakologie   MeSH
• sekvence nukleotidů MeSH
• skot MeSH
• zkřížené reakce MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH

Platinum-based complexes are important drugs for the treatment of cancer diseases. Compared to the commonly used Pt(II) compounds cisplatin and oxaliplatin, the recently reported complexes containing Pt(IV) seem to have several advantages; they are safer, can be used orally, have a higher scope of anticancer effect, and do not show cross-resistance to cisplatin. In the first part, cisplatin and oxaliplatin, and satraplatin and LA-12, the Pt(II) and Pt(IV) complexes, respectively, are characterised. Their structures, range of action and side effects are described. In the following part, the mechanisms of their effects are briefly explained, i.e., transport of the active agents to cells, adduct formation, biotransformation pathways, etc. The last part deals with protective mechanisms of the cell, differences in DNA repair mechanisms, and ideas concerning the development of resistance to these drugs.

• MeSH
• chemorezistence genetika   imunologie   účinky léků   MeSH
• cisplatina aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• farmakokinetika MeSH
• fenitrotion terapeutické užití   MeSH
• financování organizované MeSH
• glutathion škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• nežádoucí účinky léčiv komplikace   MeSH
• organokovové sloučeniny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• organoplatinové sloučeniny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• sloučeniny platiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

• MeSH
• cisplatina analýza   MeSH
• elektroforéza kapilární MeSH
• karboplatina analýza   MeSH
• palladium analýza   MeSH
• platina analýza   MeSH
• protinádorové látky analýza   MeSH
• thiokyanatany analýza   MeSH

The new platinum(IV) complex cis,trans,cis-[PtCl(2)(CH(3)COO)(2)-(NH(3))(1-adamantylamine)] [adamplatin(IV)] seems promising for the perspective application in therapy of corresponding tumors. It is therefore of great interest to understand details of mechanisms underlying its biological efficacy. Cellular uptake of the drug, alterations in the target DNA induced by platinum drugs along with processing of platinum-induced damage to DNA and drug inactivation by sulfur-containing compounds belong to major pharmacological factors affecting antitumor effects of platinum compounds. We examined in the present work the significance of these factors in the mechanism of antitumor effects of adamplatin(IV) and compared the results with those of the parallel studies performed with "conventional" cisplatin. The results show that deactivation of adamplatin(IV) by sulfur-containing compounds (such as glutathione or metallothioneins) is likely to play a less significant role in the mechanism of resistance of tumor cells to adamplatin(IV) in contrast to the role of these reactions in the effects of cisplatin. Moreover, the treatment of tumor cells with adamplatin(IV) does not result in DNA modifications that would be markedly different from those produced by cisplatin. In contrast, the effects of other factors, such as enhanced accumulation of the drug in cells, strong inhibition of DNA polymerization by these adducts, lowered DNA repair, and DNA-protein cross-linking are different from the effects of these factors in the mechanism underlying activity of cisplatin. Hence, the differences between effects of adamplatin(IV) and cisplatin observed in the present work on molecular level may help understand the unique activity of adamplatin(IV).

• MeSH
• adukty DNA účinky léků   MeSH
• bezbuněčný systém MeSH
• DNA řízené RNA-polymerasy metabolismus   MeSH
• DNA biosyntéza   MeSH
• financování organizované MeSH
• HeLa buňky MeSH
• HIV-1 enzymologie   MeSH
• krysa rodu rattus MeSH
• kyselina askorbová metabolismus   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• oprava DNA imunologie   MeSH
• organoplatinové sloučeniny terapeutické užití   MeSH
• platina metabolismus   MeSH
• plazmidy genetika   MeSH
• proteiny s vysokou pohyblivostí MeSH
• protinádorové látky terapeutické užití   MeSH
• reagencia zkříženě vázaná MeSH
• reverzní transkriptasa metabolismus   MeSH
• sekvence nukleotidů MeSH
• sloučeniny síry metabolismus   MeSH
• virové proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH

A new hydrophobic platinum(IV) complex, LA-12, a very efficient anticancer drug lacking cross-resistance with cisplatin (CDDP), is now being tested in clinical trials. Here we investigated the apoptogenic activity of LA-12 and its effect on gap-junctional intercellular communication (GJIC) in the rat liver epithelial cell line WB-F344. LA-12 induced apoptosis much more efficiently than did CDDP due to a combination of rapid penetration into the cell and attack on DNA, leading to fast activation of p53 and caspase-3. Exposure of WB-F344 cells to LA-12 led to rapid induction of the time- and dose-dependent decrease in GJIC. On the molecular level, loss of GJIC induced by LA-12 was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated by the use of inhibitors of ERK activation. Inhibition of GJIC was linked to rapid hyperphosphorylation of connexin-43 and disappearance of connexon clusters from membranes, which was not observed in the case of CDDP.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• apoptóza MeSH
• buněčné linie MeSH
• cisplatina farmakologie   MeSH
• epitelové buňky metabolismus   MeSH
• financování organizované MeSH
• fosforylace MeSH
• hydrofobní a hydrofilní interakce MeSH
• konexin 43 metabolismus   MeSH
• krysa rodu rattus MeSH
• mezerový spoj účinky léků   MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• sloučeniny platiny chemie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• adukty DNA chemická syntéza   MeSH
• DNA chemie   MeSH
• finanční podpora výzkumu jako téma MeSH
• guanin chemie   MeSH
• protinádorové látky chemie   MeSH
• sloučeniny platiny chemie   MeSH

PURPOSE: This study compared the pharmacokinetics, tissue distribution, and urinary excretion of platinum in rats after single oral doses of LA-12 and satraplatin. METHODS: Both platinum derivatives were administered to male Wistar rats as suspensions in methylcellulose at four equimolar doses within the range of 37.5-300 mg LA-12/kg body weight. Blood sampling was performed until 72 h, and plasma and plasma ultrafiltrate were separated. Moreover, urine was collected until 72 h, and kidney and liver tissue samples were obtained at several times after administration. Platinum was measured by atomic absorption spectrometry. The pharmacokinetics of platinum was analyzed by population modelling and post hoc Bayesian estimation as well as using non-compartmental pharmacokinetic analysis of the mean concentration-time curves. RESULTS: Platinum was detected in all plasma and ultrafiltrate samples 15 min after oral administration of both compounds and peaked between 3-4 h and 1-3 h, respectively. Similar for LA-12 and satraplatin, the C (max) and AUC values of plasma and ultrafiltrate platinum increased less than in proportion to dose. The mean C (max) and AUC values of plasma platinum observed after administration of LA-12 were from 0.84 to 2.5 mg/l and from 20.2 to 75.9 mg h/l. For ultrafiltrate platinum, the corresponding ranges were 0.16-0.78 mg/l and 0.63-1.8 mg h/l, respectively. The AUC of plasma platinum was higher after satraplatin (P < 0.001). However, administration of LA-12 resulted in significantly higher AUC values of ultrafiltrate platinum after the doses of 150 mg and 300 mg/kg (P < 0.01), respectively, and the C (max) values were significantly higher starting from the dose of 75 mg/kg LA-12 and upward (P < 0.01). Cumulative 72-h urinary recovery of platinum dose was below 5% for both compounds, and it decreased with the dose of satraplatin (P < 0.01), while a numerical decrease was observed after administration of LA-12 that did not reach statistical significance (P = 0.41). The renal clearance of free platinum was similar regardless of the dose and compound administered. Platinum concentrations in the liver homogenate exceeded those in the kidney. Distribution of platinum to tissues was higher after LA-12 compared to satraplatin. The difference in kidney platinum increased with dose and was twofold after 350 mg/kg LA-12. Liver platinum was twofold higher after LA-12 across all four doses. CONCLUSIONS: In conclusion, this first comparative pharmacokinetic study with LA-12 and satraplatin shows that characteristics of platinum exposure evaluated in the plasma, plasma ultrafiltrate and kidney and liver tissues increase less than in proportion to dose following a single-dose administration of 37.5-300 mg/kg to Wistar rats. These findings together with the dose-related elevation in the pharmacokinetic characteristics V/F and CL/F of platinum and ultrafiltrate platinum as well as a drop in platinum urinary recovery are consistent with a dose-related decrease in the extent of oral bioavailability most likely due to saturable intestinal absorption.

• MeSH
• amantadin aplikace a dávkování   analogy a deriváty   farmakokinetika   moč   MeSH
• aplikace orální MeSH
• Bayesova věta MeSH
• biologické modely MeSH
• krysa rodu rattus MeSH
• organoplatinové sloučeniny aplikace a dávkování   farmakokinetika   moč   MeSH
• potkani Wistar MeSH
• protinádorové látky aplikace a dávkování   farmakokinetika   moč   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Platinum(IV) complexes generally require reduction to reactive Pt(II) species to exert their chemotherapeutic activity. The process of reductive activation of (15)N-labeled (OC-6-43)-bis(acetato)diamminedichloridoplatinum(IV), in the presence of nicotinamide adenine dinucleotide (NADH) and horse heart cytochrome c (cyt c), was monitored by (1)H,(15)N-HSQC NMR spectroscopy and protein digestion experiments. It has been shown that cyt c plays a catalytic role in the transfer of two reducing equivalents from NADH to Pt(IV) species. Noncovalent interactions between reduced monoaqua cisplatin (cis-[PtCl((15)NH3)2(H2O)](+)) and the protein, in the proximity of the heme cofactor, and also covalent binding of platinum to the protein region around Met65 and Met80 take place.

• MeSH
• cisplatina chemie   metabolismus   MeSH
• cytochromy c chemie   metabolismus   MeSH
• hmotnostní spektrometrie MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární struktura MeSH
• NAD chemie   metabolismus   MeSH
• platina chemie   metabolismus   MeSH
• prekurzory léčiv chemie   metabolismus   MeSH
• protinádorové látky chemie   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Platinum (IV) derivative with adamantylamine-LA-12-represents a new generation of highly efficient anti-cancer drug derived from cisplatin and is currently in the final stage of phase I clinical trials. Understanding the specific mechanisms of its effects on cell cycle is necessary for defining the mode of action of LA-12. In this study, we characterized the ability of LA-12 to induce cell cycle perturbations in ovarian cancer cell line A2780 as compared to equitoxic cisplatin treatment. LA-12 induced a permanent accumulation of A2780 cells in S phase while cisplatin caused G2/M arrest at 24-h time point, where we also detected an increased expression of Gadd45alpha protein. Although both derivatives induced a rapid increase of p53 expression, this was not associated with a down-regulation of Mdm2 protein. Increased expression of p21(Cip1/WAF1) protein and its association with cyclins A and B1 suggested that this cyclin-dependent kinase inhibitor might contribute significantly to the observed perturbations of cell cycle. The results of this study provide insight into the mechanism of action of platinum-based derivative with adamantylamine on cell cycle in ovarian cancer cells. The differences between effects of LA-12 and cisplatin suggest that more attention should be paid to elucidation of modes of action of novel platinum(IV) complexes at cellular level.

• MeSH
• amantadin aplikace a dávkování   farmakologie   MeSH
• buněčný cyklus účinky léků   MeSH
• cisplatina farmakologie   MeSH
• financování organizované MeSH
• karcinom farmakoterapie   metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory vaječníků farmakoterapie   metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protein X asociovaný s bcl-2 metabolismus   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-mdm2 metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• srovnávací studie MeSH

The oral anti-tumor activity of a novel platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand was evaluated and compared with another platinum(IV) complex satraplatin. The human carcinoma xenografts of colon HCT116, prostate PC3, and ovarian A2780 and A2780/cisR (resistant to cisplatin) were used to evaluate the in-vivo anti-tumor activity. The daily x 5 repeated dose regimen in equimolar doses of LA-12 and satraplatin, administered in 2 cycles, was selected for this evaluation. All doses of LA-12 and satraplatin were significantly effective in comparison with the control. The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin. The highest effect was reached with LA-12 at a dose of 60 mg/kg. The shapes of growth curves of ovarian carcinoma A2780 and its subline resistant to cisplatin after therapy with LA-12 were very similar. This shows that LA-12 is able to overcome resistance to cisplatin.

• MeSH
• amantadin analogy a deriváty   terapeutické užití   MeSH
• chemorezistence MeSH
• cisplatina škodlivé účinky   MeSH
• financování organizované MeSH
• ligandy MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   patologie   prevence a kontrola   MeSH
• nádory tračníku farmakoterapie   patologie   prevence a kontrola   MeSH
• nádory vaječníků farmakoterapie   patologie   prevence a kontrola   MeSH
• organoplatinové sloučeniny terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• transplantace heterologní MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH