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
- Precursor Cell Lymphoblastic Leukemia-Lymphoma * drug therapy MeSH
- Acute Disease MeSH
- Child MeSH
- Progression-Free Survival MeSH
- Inotuzumab Ozogamicin MeSH
- Calicheamicins * MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Child, Preschool MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Research Support, Non-U.S. Gov't 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.
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
- Alkynes chemistry MeSH
- Amides chemical synthesis MeSH
- Amino Acids chemistry MeSH
- Amines chemistry MeSH
- Cyclization MeSH
- Diynes chemistry MeSH
- Catalysis MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Solid-Phase Synthesis Techniques methods MeSH
- Thermodynamics MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
- Ataxia Telangiectasia Mutated Proteins genetics MeSH
- DNA-Binding Proteins genetics MeSH
- DNA Breaks, Double-Stranded drug effects MeSH
- DNA Repair Enzymes genetics MeSH
- Histones genetics MeSH
- Meiosis genetics MeSH
- Metaphase genetics MeSH
- Mice MeSH
- Oocytes growth & development metabolism MeSH
- DNA Damage drug effects genetics MeSH
- Zinostatin administration & dosage MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
- Biopolymers chemistry classification therapeutic use MeSH
- Cytostatic Agents MeSH
- Ethylene Glycols chemistry therapeutic use MeSH
- Financing, Organized MeSH
- Genetic Therapy methods MeSH
- Pharmaceutical Preparations MeSH
- Humans MeSH
- Maleic Anhydrides therapeutic use MeSH
- Methacrylates chemistry therapeutic use MeSH
- Polymers history chemistry therapeutic use MeSH
- Polystyrenes therapeutic use MeSH
- Zinostatin therapeutic use MeSH
- Check Tag
- Humans 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
- Cell Line MeSH
- Cytostatic Agents chemical synthesis chemistry pharmacology MeSH
- Diynes chemistry MeSH
- Cobalt chemistry MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Nitriles chemistry MeSH
- Purines chemical synthesis chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
- Ataxia Telangiectasia Mutated Proteins MeSH
- Cell Line MeSH
- Chromatin * metabolism MeSH
- DNA-Binding Proteins physiology genetics metabolism MeSH
- Microscopy, Fluorescence MeSH
- Phosphorylation MeSH
- Nucleic Acid Synthesis Inhibitors MeSH
- Humans MeSH
- Mutation MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Proteins physiology genetics metabolism MeSH
- DNA Damage * MeSH
- Protein Serine-Threonine Kinases physiology genetics metabolism MeSH
- Cell Cycle Proteins physiology genetics metabolism MeSH
- Repressor Proteins physiology genetics metabolism MeSH
- Signal Transduction * physiology MeSH
- Cell Survival genetics drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Blotting, Western MeSH
- Zinostatin pharmacology MeSH
- Check Tag
- Humans MeSH
