Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1-18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m2. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9-93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49-20.07). One year Event Free Survival was 36.7% (95% CI: 22.2-60.4%), and Overall Survival was 55.1% (95% CI: 39.1-77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.
- MeSH
- akutní lymfatická leukemie * farmakoterapie MeSH
- akutní nemoc MeSH
- dítě MeSH
- doba přežití bez progrese choroby MeSH
- inotuzumab ozogamicin MeSH
- kalicheamiciny * MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
Oplopanax elatus (Nakai) Nakai has a long history of use as an ethnomedicine by the people living in eastern Asia. However, its bioactive constituents and cancer chemopreventive mechanisms are largely unknown. The aim of this study was to prepare O. elatus extracts, fractions, and single compounds and to investigate the herb's antiproliferative effects on colon cancer cells and the involved mechanisms of action. Two polyyne compounds were isolated from O. elatus, falcarindiol and oplopandiol. Based on our HPLC analysis, falcarindiol and oplopandiol are major constituents in the dichloromethane (CH2Cl2) fraction. For the HCT-116 cell line, the dichloromethane fraction showed significant effects. Furthermore, the IC50 for falcarindiol and oplopandiol was 1.7 µM and 15.5 µM, respectively. In the mechanistic study, after treatment with 5 µg/ml for 48 h, dichloromethane fraction induced cancer cell apoptosis by 36.5% (p < 0.01% vs. control of 3.9%). Under the same treatment condition, dichloromethane fraction caused cell cycle arrest at the G2/M phase by 32.6% (p < 0.01% vs. control of 23.4%), supported by upregulation of key cell cycle regulator cyclin A to 21.6% (p < 0.01% vs. control of 8.6%). Similar trends were observed by using cell line HT-29. Data from this study filled the gap between phytochemical components and the cancer chemoprevention of O. elatus. The dichloromethane fraction is a bioactive fraction, and falcarindiol is identified as an active constituent. The mechanisms involved in cancer chemoprevention by O. elatus were apoptosis induction and G2/M cell cycle arrest mediated by a key cell cycle regulator cyclin A.
- MeSH
- diyny terapeutické užití MeSH
- kolorektální nádory * prevence a kontrola MeSH
- lidé MeSH
- mastné alkoholy terapeutické užití MeSH
- methylenchlorid terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
We present the application of a Glaser-Hay diyne coupling for the synthesis of conformationally constrained Nα-amino acid amides with different diyne ring sizes. Twelve-membered rings were the smallest rings that could be prepared by this approach. We observed the formation of triethylammonium adducts in the cases of smaller (10- and 11-membered) rings. Calculation of the conformational barriers for the cyclization reactions of various ring sizes demonstrated that the formation of amino acid-derived smaller rings by this reaction is thermodynamically unfavorable.
- MeSH
- alkyny chemie MeSH
- amidy chemická syntéza MeSH
- aminokyseliny chemie MeSH
- aminy chemie MeSH
- cyklizace MeSH
- diyny chemie MeSH
- katalýza MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- techniky syntézy na pevné fázi metody MeSH
- termodynamika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This study reports the first Co2 (CO)8 -catalyzed [2+2+2] polycyclotrimerization by the transformation of internal ethynyl groups of aromatic diyne monomers. The reaction yields polycyclotrimers of polyphenylene-type with either hyperbranched or partly crosslinked architecture. The homopolycyclotrimerization of the monomers with two ethynyl groups per one molecule, namely 1,4-bis(phenylethynyl)benzene, 4,4'-bis(phenylethynyl)biphenyl, and 4-(phenylethynyl)phenylacetylene, gives partly crosslinked, insoluble polyphenylenes. The soluble, hyperbranched polyphenylenes are generated via copolycyclotrimerization of 1,4-bis(phenylethynyl)benzene with 1,2-diphenylacetylene (average number of ethynyl groups per monomer molecule < 2). This one-step polycyclotrimerization path to hyperbranched or partly crosslinked polyphenylenes is an alternative to the synthesis of these polymers by Diels-Alder transformation of substituted cyclopentadienones. All polyphenylenes prepared exhibit photoluminescence with emission maxima ranging from 381 to 495 nm. Polyphenylenes with a less compact packing of segments are microporous (specific surface area up to 159 m2 g-1 ), which is particularly important in the case of soluble polyphenylenes because they can be potentially used to prepare microporous layers.
Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by γH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of γH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.
- MeSH
- ATM protein genetika MeSH
- DNA vazebné proteiny genetika MeSH
- dvouřetězcové zlomy DNA účinky léků MeSH
- enzymy opravy DNA genetika MeSH
- histony genetika MeSH
- meióza genetika MeSH
- metafáze genetika MeSH
- myši MeSH
- oocyty růst a vývoj metabolismus MeSH
- poškození DNA účinky léků genetika MeSH
- zinostatin aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Polymer therapeutics including polymer-drug conjugates, polymer-protein conjugates and polymer-modified gene delivery vectors are addressed in this review. Brief history of the polymer therapeutics is described with a focus on the pioneering work accomplished at the Institute of Macromolecular Chemistry in Prague. The advantages of polymer therapeutics compared with lowmolecular- weight drugs are outlined. Polymer cancerostatics, polymer-protein conjugates with anti-cancer activity and polymer-modified viruses based on N-(2-hydroxypropyl) methacrylamide copolymers and biodegradable multiblock poly(ethylene glycol) polymers are chosen as examples. The current status of clinical evaluation of the polymer therapeutics is also mentioned.
- MeSH
- biopolymery chemie klasifikace terapeutické užití MeSH
- cytostatické látky MeSH
- ethylenglykoly chemie terapeutické užití MeSH
- financování organizované MeSH
- genetická terapie metody MeSH
- léčivé přípravky MeSH
- lidé MeSH
- maleinanhydridy terapeutické užití MeSH
- methakryláty chemie terapeutické užití MeSH
- polymery dějiny chemie terapeutické užití MeSH
- polystyreny terapeutické užití MeSH
- zinostatin terapeutické užití MeSH
- Check Tag
- lidé MeSH
Transition metal complex catalysed cocyclotrimerization of 6-alkynylpurines 1 with various diynes 2 and 6-(diynyl)purines 4 with nitriles 5 enabled to synthesize series of substituted 6-arylpurines 3 and 6-heteroarylpurines 6 in good yields. The obtained 6-aryl- and 6-heteroarylpurines were tested for cytostatic activity.
- MeSH
- buněčné linie MeSH
- cytostatické látky chemická syntéza chemie farmakologie MeSH
- diyny chemie MeSH
- kobalt chemie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nitrily chemie MeSH
- puriny chemická syntéza chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The cellular DNA-damage response is a signaling network that is vigorously activated by cytotoxic DNA lesions, such as double-strand breaks (DSBs). The DSB response is mobilized by the nuclear protein kinase ATM, which modulates this process by phosphorylating key players in these pathways. A long-standing question in this field is whether DSB formation affects chromatin condensation. Here, we show that DSB formation is followed by ATM-dependent chromatin relaxation. ATM's effector in this pathway is the protein KRAB-associated protein (KAP-1, also known as TIF1beta, KRIP-1 or TRIM28), previously known as a corepressor of gene transcription. In response to DSB induction, KAP-1 is phosphorylated in an ATM-dependent manner on Ser 824. KAP-1 is phosphorylated exclusively at the damage sites, from which phosphorylated KAP-1 spreads rapidly throughout the chromatin. Ablation of the phosphorylation site of KAP-1 leads to loss of DSB-induced chromatin decondensation and renders the cells hypersensitive to DSB-inducing agents. Knocking down KAP-1, or mimicking a constitutive phosphorylation of this protein, leads to constitutive chromatin relaxation. These results suggest that chromatin relaxation is a fundamental pathway in the DNA-damage response and identify its primary mediators.
- MeSH
- ATM protein MeSH
- buněčné linie MeSH
- chromatin * metabolismus MeSH
- DNA vazebné proteiny fyziologie genetika metabolismus MeSH
- fluorescenční mikroskopie MeSH
- fosforylace MeSH
- inhibitory syntézy nukleových kyselin MeSH
- lidé MeSH
- mutace MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny fyziologie genetika metabolismus MeSH
- poškození DNA * MeSH
- protein-serin-threoninkinasy fyziologie genetika metabolismus MeSH
- proteiny buněčného cyklu fyziologie genetika metabolismus MeSH
- represorové proteiny fyziologie genetika metabolismus MeSH
- signální transdukce * fyziologie MeSH
- viabilita buněk genetika účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- western blotting MeSH
- zinostatin farmakologie MeSH
- Check Tag
- lidé MeSH
