(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC50 values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA.

• MeSH
• antitumorózní látky * farmakologie   metabolismus   MeSH
• cisplatina farmakologie   MeSH
• difosfáty farmakologie   MeSH
• DNA metabolismus   MeSH
• nádory * MeSH
• organoplatinové sloučeniny farmakologie   metabolismus   MeSH
• oxaliplatin farmakologie   MeSH
• platina farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Lenvatinib, a small molecule tyrosine kinase inhibitor (TKI), exhibits good inhibitory effect in several types of carcinomas. Specifically, it is the most effective TKI used for treatment of thyroid cancer. To extend pharmacokinetics data on this anticancer agent, we aimed to identify the metabolites of lenvatinib formed during in vitro incubation of lenvatinib with human hepatic microsomes or recombinant cytochromes P450 (CYPs) by using high performance liquid chromatography and mass spectrometry. The role of CYPs in the oxidation of lenvatinib was initially investigated in hepatic microsomes using specific CYP inhibitors. CYP-catalytic activities in each microsomal sample were correlated with the amounts of lenvatinib metabolites formed by these samples. Further, human recombinant CYPs were employed in the metabolic studies. Based on our data, lenvatinib is metabolized to O-desmethyl lenvatinib, N-descyclopropyl lenvatinib and lenvatinib N-oxide. In the presence of cytochrome b5, recombinant CYP3A4 was the most efficient to form these metabolites. In addition, CYP1A1 significantly contributes to the lenvatinib metabolism. It was even more efficient in forming of O-desmethyl lenvatinib than CYP3A4 in the absence of cytochrome b5. The present study indicates that further research focused on drug-drug interactions, in particular on CYP3A4 and CYP1A1 modulators, is needed. This will pave new avenues towards TKIs-mediated personalized therapy.

• MeSH
• antitumorózní látky metabolismus   MeSH
• chinoliny metabolismus   MeSH
• fenylmočovinové sloučeniny metabolismus   MeSH
• hmotnostní spektrometrie MeSH
• inhibitory cytochromu P450 farmakologie   MeSH
• inhibitory proteinkinas metabolismus   MeSH
• jaterní mikrozomy enzymologie   metabolismus   MeSH
• králíci MeSH
• krysa rodu rattus MeSH
• lékové interakce MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• oxidace-redukce MeSH
• potkani Wistar MeSH
• systém (enzymů) cytochromů P-450 účinky léků   metabolismus   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cardiovascular diseases remain the leading cause of death worldwide; hence there is an increasing focus on developing physiologically relevant in vitro cardiovascular tissue models suitable for studying personalized medicine and pre-clinical tests. Despite recent advances, models that reproduce both tissue complexity and maturation are still limited. We have established a scaffold-free protocol to generate multicellular, beating human cardiac microtissues in vitro from hiPSCs-namely human organotypic cardiac microtissues (hOCMTs)-that show some degree of self-organization and can be cultured for long term. This is achieved by the differentiation of hiPSC in 2D monolayer culture towards cardiovascular lineage, followed by further aggregation on low-attachment culture dishes in 3D. The generated hOCMTs contain multiple cell types that physiologically compose the heart and beat without external stimuli for more than 100 days. We have shown that 3D hOCMTs display improved cardiac specification, survival and metabolic maturation as compared to standard monolayer cardiac differentiation. We also confirmed the functionality of hOCMTs by their response to cardioactive drugs in long-term culture. Furthermore, we demonstrated that they could be used to study chemotherapy-induced cardiotoxicity. Due to showing a tendency for self-organization, cellular heterogeneity, and functionality in our 3D microtissues over extended culture time, we could also confirm these constructs as human cardiac organoids (hCOs). This study could help to develop more physiologically-relevant cardiac tissue models, and represent a powerful platform for future translational research in cardiovascular biology.

• MeSH
• antitumorózní látky * metabolismus   MeSH
• buněčná diferenciace fyziologie   MeSH
• indukované pluripotentní kmenové buňky * MeSH
• kardiomyocyty metabolismus   MeSH
• kardiovaskulární látky * metabolismus   MeSH
• lidé MeSH
• srdce fyziologie   MeSH
• tkáňové inženýrství metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process. Therefore, repurposing drugs with already established clinical application offers an attractive, fast-track approach for novel treatment options. In this study, we show that the anti-cancer drug candidate MitoTam, a mitochondria-targeted analog of tamoxifen, efficiently eliminates a wide range of evolutionarily distinct pathogens in vitro, including pathogenic fungi, Plasmodium falciparum, and several species of trypanosomatid parasites, causative agents of debilitating neglected tropical diseases. MitoTam treatment was also effective in vivo and significantly reduced parasitemia of two medically important parasites, Leishmania mexicana and Trypanosoma brucei, in their respective animal infection models. Functional analysis in the bloodstream form of T. brucei showed that MitoTam rapidly altered mitochondrial functions, particularly affecting cellular respiration, lowering ATP levels, and dissipating mitochondrial membrane potential. Our data suggest that the mode of action of MitoTam involves disruption of the inner mitochondrial membrane, leading to rapid organelle depolarization and cell death. Altogether, MitoTam is an excellent candidate drug against several important pathogens, for which there are no efficient therapies and for which drug development is not a priority.

• MeSH
• antitumorózní látky * metabolismus   farmakologie   MeSH
• membránový potenciál mitochondrií MeSH
• Plasmodium falciparum MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• Trypanosoma brucei brucei * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Pharmacological inhibition of cyclin-dependent kinases has emerged as a possible treatment option for various cancer types. We recently identified substituted imidazo[1,2-c]pyrimidin-5(6H)-ones as inhibitors of cyclin-dependent kinase 2 (CDK2). Here, we report the synthesis of derivatives modified at positions 2, 3, 6 or 8 prepared using Suzuki-Miyaura cross-coupling, halogenation, Dimroth-type rearrangement and alkylation as the main synthetic methods. The compounds displayed micro- to submicromolar inhibition of CDK2/cyclin E activity. Binding of the most potent compound 3b to CDK2 was determined using isothermal titration calorimetry. The co-crystal structure of 3b in complex with fully active CDK2 was solved, revealing the binding mode of 3b in the ATP pocket and a hydrogen bonding interaction with hinge region residue Leu83. Evaluation against leukaemia cell lines revealed low cytotoxicity, which is in line with the high selectivity towards CDK2. This study demonstrates that substituted imidazo[1,2-c]pyrimidines can be exploited for future kinase inhibitor development.

• MeSH
• antitumorózní látky chemická syntéza   metabolismus   farmakologie   MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   metabolismus   MeSH
• imidazoly chemie   metabolismus   farmakologie   MeSH
• inhibitory proteinkinas chemická syntéza   metabolismus   farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• pyrimidiny chemie   metabolismus   farmakologie   MeSH
• simulace molekulární dynamiky MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vodíková vazba MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Ophthalmic disorders are amid the most common pathologies worldwide. In this regard, hyaluronan (HA) has gained widespread use in eye surgeries and treatment of eye diseases. HA-based materials are well tolerated and show excellent biocompatibility. Therefore, HA is a sought-after component of ophthalmic formulations. However, several parameters have to be adjusted to reach an optimal performance and effectiveness. The complexity of HA properties represents a major challenge for biological and structural characterization. This review covers fundamental aspects and recent developments in HA ophthalmic research. Biological mechanisms underlying the health benefits of HA and their potential therapeutic applications are elaborated. Furthermore, current pharmacokinetic and safety studies are discussed. Noticeably, the benefits of chemical modification and processed HA forms are described to broaden the applications of this unique polysaccharide. The current research challenges and prospects are also outlined and discussed.

• MeSH
• antitumorózní látky chemie   metabolismus   MeSH
• glaukom farmakoterapie   MeSH
• kyselina hyaluronová analogy a deriváty   terapeutické užití   MeSH
• lidé MeSH
• nosiče léků chemie   MeSH
• oční nemoci farmakoterapie   MeSH
• oční roztoky chemie   MeSH
• viskozita MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.

• MeSH
• antitumorózní látky metabolismus   MeSH
• chinazoliny metabolismus   MeSH
• jaterní mikrozomy MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• oxidace-redukce MeSH
• oxygenasy metabolismus   MeSH
• piperidiny metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

With the aim to develop a new anticancer agent, we prepared poly[N-(2-hydroxypropyl)methacrylamide-co-methyl 2-methacrylamidoacetate] [P(HP-MMAA)], which was reacted with hydrazine to poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-hydrazinyl-2-oxoethyl)methacrylamide] [P(HP-MAH)] to conjugate doxorubicin (Dox) via hydrazone bond. The resulting P(HP-MAH)-Dox conjugate was used as a coating of magnetic γ-Fe2 O3 nanoparticles obtained by the coprecipitation method. In vitro toxicity of various concentrations of Dox, P(HP-MAH)-Dox, and γ-Fe2 O3 @P(HP-MAH)-Dox nanoparticles was determined on somatic healthy cells (human bone marrow stromal cells hMSC), human glioblastoma line (GaMG), and primary human glioblastoma (GBM) cells isolated from GBM patients both at a short and prolonged exposition time (up to 7 days). Due to hydrolysis of the hydrazone bond in acid milieu of tumor cells and Dox release, the γ-Fe2 O3 @P(HP-MAH)-Dox nanoparticles significantly decreased the GaMG and GBM cell growth compared to free Dox and P(HP-MAH)-Dox in low concentration (10 nM), whereas in hMSCs it remained without effect. γ-F2 O3 @PHP nanoparticles alone did not affect the viability of any of the tested cells.

• MeSH
• akrylamidy chemie   MeSH
• antitumorózní látky chemie   metabolismus   farmakologie   MeSH
• doxorubicin chemie   metabolismus   farmakologie   MeSH
• glioblastom patologie   MeSH
• lidé MeSH
• magnetické nanočástice chemie   MeSH
• nádorové buněčné linie MeSH
• nosiče léků chemie   MeSH
• polymery chemie   MeSH
• proliferace buněk MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• uvolňování léčiv MeSH
• viabilita buněk účinky léků   MeSH
• železité sloučeniny chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

ultikinázový inhibitor midostaurin je novou léčivou látkou užívanou spolu se standardní chemoterapií v terapii pacientů s akutní myeloidní leukemií (AML) s mutací kinázy FLT3. Jedná se o přípravek první generace ze skupiny inhibitorů FLT3 a v současnosti je jedinou léčivou látkou z této skupiny, která má schválenu indikaci a úhradu v indukční a konsolidační léčbě pacientů s AML. Midostaurin je podáván ve formě perorálních tobolek dvakrát denně 8.–21. den cyklu chemoterapie. Prostřednictvím enzymu CYP3A4 je biotransformován na metabolity, které mají rovněž farmakologickou aktivitu. Zvýšené opatrnosti je nutno dbát při současné medikaci silnými inhibitory CYP3A4, které mohou vést ke zvýšení toxicity vlivem prodloužení expozice účinné látce. Midostaurin je pacienty obecně dobře tolerován, zvláště při podávání s jídlem, které redukuje dosažené vrcholové maximální koncentrace a snižuje četnost epizod nevolnosti a zvracení. Nejčastějším nežádoucím účinkem v klinických studiích byla febrilní neutropenie, specifickými nežádoucími účinky jsou prodloužení intervalu QTc a rozvoj intersticiálního plicního postižení. Ve studii RATIFY dosáhl medián celkového přežití při terapii midostaurinem se standardní chemoterapií 74,7 měsíce oproti 25,6 měsíce při léčbě standardní chemoterapií v kombinaci s placebem. Při terapii midostaurinem byla pozorována vyšší četnost dosažení kompletní remise onemocnění a delší interval přežití bez nemoci daný redukcí četnosti relapsů AML. Článek rovněž shrnuje klinické zkušenosti s midostaurinem a management nežádoucích účinků v praxi pracoviště autorů – ÚHKT.

The multi‑kinase inhibitor midostaurin is a new therapeutic agent used together with standard chemotherapy in the treatment of patients with acute myeloid leukemia (AML) and a FLT3‑kinase mutation. It is a first generation product from the FLT3‑inhibitor family and is currently the only therapeutic agent of this group approved and reimbursed for the treatment of patients in induction and consolidation of AML. Midostaurin is administered orally as capsules twice daily on days 8‑21 of the chemotherapy cycle and is metabolised by CYP3A4 to metabolites that also have pharmacological activity. Caution should be exercised if it is co‑administered with potent CYP3A4 inhibitors that may lead to increased toxicity due to prolonged exposure to the active substance. Midostaurin is generally well tolerated by patients, particularly when administered with food that lowers the peak of maximal concentrations and reduces the frequency of nausea and vomiting. The most common adverse event in clinical trials was febrile neutropenia and specific adverse events included QTc prolongation and development of interstitial lung involvement. In the RATIFY study, median overall survival for midostaurin in combination with standard chemotherapy was 74.7 months compared with 25.6 months for standard chemotherapy in combination with placebo. In the midostaurin arm, a higher rate of complete AML remissions and a long­er disease‑free interval due to a reduction in the frequency of relapses were observed. The article also summarizes the clinical expe­rience with midostaurin and the management of adverse reactions at the UHKT.

• Klíčová slova
• midostaurin, FLT3,
• MeSH
• akutní myeloidní leukemie * farmakoterapie   komplikace   MeSH
• analýza přežití MeSH
• antitumorózní látky aplikace a dávkování   ekonomika   farmakokinetika   farmakologie   metabolismus   škodlivé účinky   MeSH
• aplikace orální MeSH
• chemoterapie konsolidační MeSH
• dospělí MeSH
• homologní transplantace MeSH
• inhibitory proteinkinas * aplikace a dávkování   ekonomika   farmakokinetika   farmakologie   metabolismus   škodlivé účinky   MeSH
• kardiomyopatie MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nežádoucí účinky léčiv epidemiologie   klasifikace   prevence a kontrola   MeSH
• receptory vaskulárního endoteliálního růstového faktoru antagonisté a inhibitory   MeSH
• statistika jako téma MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

The literature reports on cationic and anionic phthalocyanines (Pcs) for photodynamic therapy suggest systematically significant differences in activity. In this work, ten different zinc(II) Pcs with carboxylate functions or quaternary nitrogens (hydrophilic anionic, hydrophilic cationic, amphiphilic anionic, and amphiphilic cationic) were investigated, with the aim of revealing reasons for such differences. In vitro assays on HeLa, MCF-7, and HCT-116 cells confirmed higher photoactivity for cationic Pcs (EC50 ∼ 3-50 nM) than for anionic Pcs (EC50 ∼ 0.3-10 μM), the latter being additionally significantly more active in serum-free medium. The environmental pH, binding to serum proteins, interaction with biomembranes, differences in subcellular localization, and relocalization after irradiation were found to be the main factors contributing to the generally lower photoactivity of anionic Pcs than that of the cationic derivatives. This result is not limited only to the presented derivatives and should be considered in the design of novel photosensitizers.

• MeSH
• antitumorózní látky chemická syntéza   metabolismus   farmakologie   účinky záření   MeSH
• fosfatidylcholiny chemie   metabolismus   MeSH
• fotochemoterapie MeSH
• fotosenzibilizující látky chemická syntéza   metabolismus   farmakologie   účinky záření   MeSH
• indoly chemická syntéza   metabolismus   farmakologie   účinky záření   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• liposomy chemie   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• sérový albumin hovězí metabolismus   MeSH
• singletový kyslík metabolismus   MeSH
• světlo MeSH
• zinek chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH