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BACKGROUND: The transforming growth factor beta-1 (TGF ß-1) cytokine exerts both pro-tumor and anti-tumor effects in carcinogenesis. An increasing body of literature suggests that TGF ß-1 signaling outcome is partially dependent on the regulatory targets of downstream receptor-regulated Smad (R-Smad) proteins Smad2 and Smad3. However, the lack of Smad-specific antibodies for ChIP-seq hinders convenient identification of Smad-specific binding sites. RESULTS: In this study, we use localization and affinity purification (LAP) tags to identify Smad-specific binding sites in a cancer cell line. Using ChIP-seq data obtained from LAP-tagged Smad proteins, we develop a convolutional neural network with long-short term memory (CNN-LSTM) as a deep learning approach to classify a pool of Smad-bound sites as being Smad2- or Smad3-bound. Our data showed that this approach is able to accurately classify Smad2- versus Smad3-bound sites. We use our model to dissect the role of each R-Smad in the progression of breast cancer using a previously published dataset. CONCLUSIONS: Our results suggests that deep learning approaches can be used to dissect binding site specificity of closely related transcription factors.
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Aprendizaje Profundo , Sitios de Unión , Línea Celular , Transducción de Señal , Proteína Smad2/química , Proteína Smad2/metabolismo , Proteína smad3/química , Proteína smad3/genética , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g., L-783,277) that have a ß-resorcylic acid as the core structure. The designed compounds contain three types of Michael acceptors (acrylamide, vinylsulfonamide and maleimide) as potential covalent traps of a cysteine residue at the binding site of kinases. A variety of functional substitutions were also introduced to maximize the binding interactions. Biological evaluations revealed that compound 17, despite the presence of a highly reactive maleimide Michael acceptor, is a potent covalent FLT3 inhibitor which shows some specificity in cellular assays. On the other hand, compounds 2 and 6 containing acrylamide or vinylsulfonamide groups are reversible towards FLT3 binding, and are potent and selective inhibitors of mutant FLT3-ITD versus wt-FLT3. They also inhibit cell proliferation in FLT3-ITD expressing cell line MV-4-11 as compared to wt-FLT3 expressing cell line THP-1 and non-FLT3 cell lines (K562, HL60 and Hek-293T).
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Antineoplásicos/farmacología , Diseño de Fármacos , Hidroxibenzoatos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Resorcinoles/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Células HL-60 , Humanos , Hidroxibenzoatos/síntesis química , Hidroxibenzoatos/química , Células K562 , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Resorcinoles/síntesis química , Resorcinoles/química , Relación Estructura-Actividad , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
The BioPhorum Development Group is an industry collaboration enabling the sharing of common practices for the development of biopharmaceuticals. Bioassays are an important part of an analytical control system. Utilization of ready-to-use cells can increase operational flexibility and improve efficiency by providing frozen cell banks uniform stock while removing challenges associated with maintaining cultured cells. The BioPhorum Development Group-Bioassay workstream conducted an intercompany benchmarking survey and group discussions around the use of ready-to-use cells for bioassays. The results of the collaboration provide alignment on nomenclature, production, qualification and implementation of ready-to-use cells to support the assay life cycle.
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Productos Biológicos , Bioensayo/métodosRESUMEN
Staphylococcus aureus is the main aetiological agent responsible for the majority of human skin infections. Of particular concern is the methicillin-resistant variety, commonly known as MRSA. The extensive use of the first-line topical antibiotic of choice, mupirocin, has inevitably resulted in the emergence of resistant strains, signalling an urgent need for the development of new antibacterials with new mechanisms of action. In this work, we describe how we designed a novel cationic nonapeptide, containing only leucine and two lysine residues, with potent anti-MRSA activity and a rapid bactericidal mode of action. Coupled to a favourable safety profile towards human skin fibroblasts, we believe nonapeptide 11 has high potential for further development as a mupirocin replacement candidate to treat skin infections caused by MRSA.
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Antibacterianos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Nanoestructuras/química , Péptidos/química , Secuencia de Aminoácidos , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Mupirocina/farmacología , Péptidos/farmacología , Relación Estructura-ActividadRESUMEN
Molybdenum disulfide (MoS2) is traditionally grown at a high temperature and subsequently patterned to study its electronic properties or make devices. This method imposes severe limitations on the shape and size of MoS2 crystals that can be patterned precisely at required positions. Here, we describe a method of direct nanoscale patterning of MoS2 at room temperature by exposing a molybdenum thiocubane single-source precursor to a beam of electrons. Molybdenum thiocubanes with various alkylxanthate moieties [Mo4S4(ROCS2)6, where R = alkyl] were prepared using a "self-assembly" approach. Micro-Raman and micro-FTIR spectroscopic studies suggest that exposure to a relatively smaller dose of electrons results in the breakdown of xanthate moieties, leading to the formation of MoS2. High-resolution transmission electron micrographs suggest that the growth of MoS2 most likely happens along (100) planes. An electron-beam-induced chemical transformation of a molybdenum thiocubane resist was exploited to fabricate sub-10 nm MoS2 lines and dense dots as small as 13 nm with a pitch of 33 nm. Since this technique does not require the liftoff and etching steps, patterning of MoS2 with interesting shapes, sizes, and thicknesses potentially leading to tunable band gap is possible.
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Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold. The compounds possess promising in vitro and in vivo pharmacokinetic profiles and show potent on target inhibition of eIF4E phosphorylation in cells.
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Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Línea Celular Tumoral , Cristalografía por Rayos X , Descubrimiento de Drogas , Factor 4E Eucariótico de Iniciación/antagonistas & inhibidores , Humanos , Modelos Moleculares , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-ActividadRESUMEN
Staphylococcus aureus is the pathogen responsible for the majority of human skin infections. In particular, the methicillin-resistant variety, MRSA, has become a global clinical concern. The extensive use of mupirocin, the first-line topical antibacterial drug of choice, has led to the emergence of mupirocin-resistant MRSA globally, resulting in the urgent need for a replacement. Antimicrobial peptides are deemed plausible candidates. Herein, we describe a structure-activity relationship approach in the design of an ultra-short peptide with potent anti-MRSA activity with a rapid, bactericidal mode of action. Coupled to a low cytotoxic activity, we believe our lead compound can be developed into a topical antibacterial agent to replace mupirocin as the first-line drug for treating MRSA skin infections.
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Antibacterianos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Péptidos/química , Secuencia de Aminoácidos , Antibacterianos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Mupirocina/farmacología , Péptidos/farmacología , Relación Estructura-ActividadRESUMEN
The atypical protein kinase C-iota (PKC-ι) enzyme is implicated in various cancers and has been put forward as an attractive target for developing anticancer therapy. A high concentration biochemical screen identified pyridine fragment weakly inhibiting PKC-ι with IC50 = 424 µM. Driven by structure-activity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-ι (IC50= 270 nM). Through the course of the optimization, an intermediate compound was crystallized with the protein, and careful analysis of the X-ray crystal structure revealed a unique binding mode involving the post-kinase domain (C-terminal tail) of PKC-ι.
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[This corrects the article DOI: 10.1021/acsmedchemlett.9b00170.].
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SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.
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Vulvovaginal candidiasis (VVC) is a genital fungal infection afflicting approximately 75% of women globally and is primarily caused by the yeast Candida albicans. The extensive use of fluconazole, the first-line antifungal drug of choice, has led to the emergence of fluconazole-resistant C. albicans, creating a global clinical concern. This, coupled to the lack of new antifungal drugs entering the market over the past decade, has made it imperative for the introduction of new antifungal drug classes. Peptides with antifungal properties are deemed potential drug candidates due to their rapid membrane-disrupting mechanism of action. By specifically targeting and rapidly disrupting fungal membranes, they reduce the chances of resistance development and treatment duration. In a previous screening campaign involving an antimicrobial peptide library, we identified an octapeptide (IKIKIKIK-NH2) with potent activity against C. albicans. Herein, we report a structure-activity relationship study on this peptide with the aim of designing a more potent peptide for further development. The lead peptide was then tested against a panel of fluconazole-resistant C. albicans, subjected to a fungicidal/static determination assay, a human dermal fibroblast viability assay and a homozygous profiling assay to gain insights into its mechanism of action and potential for further development as a topical antifungal agent.
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Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Farmacorresistencia Fúngica/efectos de los fármacos , Fluconazol/farmacología , Péptidos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos/síntesis química , Péptidos/química , Relación Estructura-ActividadRESUMEN
Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι.
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Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Isoenzimas/antagonistas & inhibidores , Neoplasias Hepáticas/tratamiento farmacológico , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patología , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Células Tumorales CultivadasRESUMEN
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.
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Crisis Blástica/tratamiento farmacológico , Proliferación Celular , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Crisis Blástica/patología , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Ratones SCID , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nanostructures of metal sulfides are conventionally prepared via chemical techniques and patterned using self-assembly. This poses a considerable amount of challenge when arbitrary shapes and sizes of nanostructures are desired to be placed at precise locations. Here, we describe an alternative approach of nanoscale patterning of zinc sulfide (ZnS) directly using a spin-coatable and electron beam sensitive zinc butylxanthate resist without the lift-off or etching step. Time-resolved electron beam damage studies using micro-Raman and micro-FTIR spectroscopies suggest that exposure to a beam of electrons leads to quick disappearance of xanthate moieties most likely via the Chugaev elimination, and further increase of electron dose results in the appearance of ZnS, thereby making the exposed resist insoluble in organic solvents. Formation of ZnS nanocrystals was confirmed by high-resolution transmission electron microscopy and selected area electron diffraction. This property was exploited for the fabrication of ZnS lines as small as 6 nm and also enabled patterning of 10 nm dots with pitches as close as 22 nm. The ZnS patterns fabricated by this technique showed defect-induced photoluminescence related to sub-band-gap optical transitions. This method offers an easy way to generate an ensemble of functional ZnS nanostructures that can be arbitrarily patterned and placed in a precise way. Such an approach may enable programmable design of functional chalcogenide nanostructures.
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Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure-activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.
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Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Factor 4E Eucariótico de Iniciación/metabolismo , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones SCID , Terapia Molecular Dirigida/métodos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications for their potential use as therapeutic agents.
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Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Partículas Ribonucleoproteicas en Bóveda/metabolismo , eIF-2 Quinasa/metabolismo , Sustitución de Aminoácidos , Línea Celular Tumoral , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/metabolismo , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Partículas Ribonucleoproteicas en Bóveda/química , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/genéticaRESUMEN
The lack of new antibacterial drugs entering the market and their misuse have resulted in the emergence of drug-resistant bacteria, posing a major health crisis worldwide. In particular, meticillin-resistant Staphylococcus aureus (MRSA), a pathogen responsible for numerous human infections, has become endemic in hospitals worldwide. Drug repurposing, the finding of new therapeutic indications for approved drugs, is deemed a plausible solution to accelerate drug discovery and development in this area. Towards this end, we screened 1163 drugs approved by the Food and Drug Administration (FDA) for bioactivities against MRSA in a 10 µM single-point assay. After excluding known antibiotics and antiseptics, six compounds were identified and their MICs were determined against a panel of clinical MRSA strains. A toxicity assay using human keratinocytes was also conducted to gauge their potential for repurposing as topical agents for treating MRSA skin infections.
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3-Deazaneplanocinâ A (DzNep) is a potential epigenetic drug for the treatment of various cancers. DzNep has been reported to deplete histone methylations, including oncogenic EZH2 complex, giving rise to epigenetic modifications that reactivate many silenced tumor suppressors in cancer cells. Despite its promise as an anticancer drug, little is known about the structure-activity relationships of DzNep in the context of epigenetic modifications and apoptosis induction. In this study, a number of analogues of DzNep were examined for DzNep-like ability to induce synergistic apoptosis in cancer cells in combination with trichostatinâ A, a known histone deacetylase (HDAC) inhibitor. The structure-activity relationship data thus obtained provide valuable information on the structural requirements for biological activity. The studies identified three compounds that show similar activities to DzNep. Two of these compounds show good pharmacokinetics and safety profiles. Attempts to correlate the observed synergistic apoptotic activities with measured S-adenosylhomocysteine hydrolase (SAHH) inhibitory activities suggest that the apoptotic activity of DzNep might not be directly due to its inhibition of SAHH.
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Adenosina/análogos & derivados , Adenosina/química , Adenosina/uso terapéutico , Adenosina/toxicidad , Adenosilhomocisteinasa/antagonistas & inhibidores , Adenosilhomocisteinasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/toxicidad , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Recent biological and computational advances in drug design have led to renewed interest in targeted covalent inhibition as an efficient and practical approach for the development of new drugs. As part of our continuing efforts in the exploration of the therapeutic potential of resorcylic acid lactones (RALs), we report herein the design, synthesis, and biological evaluation of conveniently accessible RAL enamide analogues as novel covalent inhibitors of MAP kinase interacting kinases (MNKs). In this study, we have successfully demonstrated that the covalent binding ability of RAL enamides can be tuned by attaching an electron-withdrawing motif, such as an acyl group, to enhance its reactivity toward the cysteine residues at the MNK1/2 binding sites. We have also shown that ¹Hâ NMR spectroscopy is a convenient and effective tool for screening the covalent binding activities of enamides using cysteamine as a mimic of the key cysteine residue in the enzyme, whereas mass spectrometric analysis confirms covalent modification of the kinases. Preliminary optimization of the initial hit led to the discovery of enamides with low micromolar activity in MNK assays. Cancer cell line assays have identified RAL enamides that inhibit the growth of cancer cells with similar potency to the natural product L-783,277.
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Amidas/química , Diseño de Fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Lactonas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Amidas/síntesis química , Amidas/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isomerismo , Cinética , Lactonas/síntesis química , Lactonas/toxicidad , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/toxicidad , Proteínas Serina-Treonina Quinasas/metabolismo , Resorcinoles/química , Resorcinoles/toxicidadRESUMEN
BACKGROUND: Chemoradiotherapy for treatment of advanced head and neck cancer (HNC) is used to achieve organ preservation without compromising survival. Because chemoradiotherapy usually impacts adversely on nutritional and functional status, feeding by percutaneous endoscopic gastrostomy (PEG) is often part of the management regimen for these patients, but the presence of a PEG tube can also be associated with reduced quality of life (QOL). This study aimed to examine the factors associated with PEG insertion and the effects of PEG use on QOL and functional outcomes in HNC patients receiving chemoradiotherapy. METHOD: Survey of 36 consecutive patients treated by primary chemoradiotherapy for HNC. Patient weight, age, tumour type, details of PEG insertion, feeding regimens and treatment were noted. The survey comprised the Performance Status Scale, the Functional Measure for Swallowing, Nutritional Mode and a self-assessment of QOL. RESULTS: PEG insertion within 1 month of treatment was associated with smaller fall in body mass index at 12 months than PEG insertion 1 month or more after the start of the treatment (P < 0.05). Body mass index change was inversely correlated with health-related quality of life and significantly related to lower speech and swallowing function scores. Longer PEG duration correlated with poorer performance status and swallowing function (P < 0.01). Longer PEG duration also predicted poorer overall QOL (P < 0.01) and poorer swallowing (P < 0.01) and speech (P < 0.05). Nutritional mode was related to overall QOL (P < 0.01). CONCLUSIONS: Nutritional support for HNC patients undergoing chemoradiotherapy is an essential component of patient care. Early PEG insertion and shorter PEG duration are associated with more favourable QOL-related outcomes.