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BACKGROUND: Major urological complications (MUCs) after kidney transplantation contribute to patient morbidity and compromise graft function. The majority arise from vesicoureteric anastomosis and present early after transplantation. Ureteric stents have been successfully used to treat such complications. A number of centres have adopted a policy of universal prophylactic stenting at the time of graft implantation to reduce the incidence of urine leaks and ureteric stenosis. Stents are associated with specific complications, and some centres advocate a policy of only stenting selected anastomoses. This is an update of our review, first published in 2005 and last updated in 2013. OBJECTIVES: To examine the benefits and harms of routine ureteric stenting to prevent MUCs in kidney transplant recipients. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant's Specialised Register (up to 19 June 2024) using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Our meta-analysis included all randomised controlled trials (RCTs) and quasi-RCTs designed to examine the impact of using stents for kidney transplant recipients. We aimed to include studies regardless of the type of graft, the technique of ureteric implantation, or the patient group. DATA COLLECTION AND ANALYSIS: Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Twelve studies (1960 patients) were identified. One study was deemed to be at low risk of bias across all domains. The remaining 11 studies were of low or medium quality, with a high or unclear risk of bias in at least one domain. Universal prophylactic ureteric stenting versus control probably reduces major urological complications (11 studies: 1834 participants: RR 0.30, 95% CI 0.16 to 0.55; P < 0.0001; I2 = 16%; moderate certainty evidence; number needed to treat (17)); this benefit was confirmed in the only study deemed to be at low risk of bias across all domains. This benefit was also seen for the individual components of urine leak and ureteric obstruction. Universal prophylactic ureteric stent insertion reduces the risk of MUC in the subgroup of studies with short duration (≤ 14 days) of stenting (2 studies, 480 participants: RR 0.39, 95% CI CI 0.21 to 0.72; P = 0.003; I2 = 0%) and where stenting was continued for > 14 days (8 studies, 124 participants: RR 0.22, 95% CI 0.08 to 0.61; P = 0.004; I2 = 29%). It is uncertain whether stenting has an impact on the development of urinary tract infection (UTI) (10 studies, 1726 participants: RR 1.32, 95% CI 0.97 to 1.80; P = 0.07; I² = 60%; very low certainty evidence due to risk of bias, heterogeneity and imprecision). Subgroup analysis showed that the risk of UTI did not increase if short-duration stenting was used (9 days) and that there was no impact on UTI risk when the prophylactic antibiotic regime co-trimoxazole 480 mg/day was used. Stents appear generally well tolerated, although studies using longer stents (≥ 20 cm) for longer periods (> 6 weeks) had more problems with encrustation and migration. There was no evidence that the presence of a stent resulted in recurrent or severe haematuria (8 studies, 1546 participants: RR 1.09, 95% CI 0.59 to 2.00; P = 0.79; I2 = 33%). The impact of stents on graft and patient survival and other stent-related complications remains unclear as these outcomes were either poorly reported or not reported at all. AUTHORS' CONCLUSIONS: Routine prophylactic stenting probably reduces the incidence of MUCs, even when the duration of stenting is short (≤ 14 days). Further high-quality studies are required to assess optimal stent duration. Studies comparing selective stenting and universal prophylactic stenting, whilst difficult to design and analyse, would address the unresolved quality of life and economic issues.
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Trasplante de Riñón , Complicaciones Posoperatorias , Ensayos Clínicos Controlados Aleatorios como Asunto , Stents , Uréter , Humanos , Stents/efectos adversos , Trasplante de Riñón/efectos adversos , Uréter/cirugía , Complicaciones Posoperatorias/prevención & control , Obstrucción Ureteral/prevención & control , Cuidados Intraoperatorios/métodosRESUMEN
The Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the ß3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvß3 and αIIbß3 are important anticancer targets, most integrin antagonists developed to target the ß3 integrins are highly selective for αvß3 or αIIbß3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic ß3 integrin antagonist. These new antagonists combine a high activity against αvß3 with a moderate affinity for αIIbß3, providing the first evidence for a new approach to integrin targeting in cancer.
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The hypoxic tumour microenvironment (hTME), arising from inadequate and chaotic vascularity, can present a major obstacle for the treatment of solid tumours. Hypoxic tumour cells compromise responses to treatment since they can generate resistance to radiotherapy, chemotherapy and immunotherapy. The hTME impairs the delivery of a range of anti-cancer drugs, creates routes for metastasis and exerts selection pressures for aggressive phenotypes; these changes potentially occur within an immunosuppressed environment. Therapeutic strategies aimed at the hTME include targeting the molecular changes associated with hypoxia. An alternative approach is to exploit the prevailing lack of oxygen as a principle for the selective activation of prodrugs to target cellular components within the hTME. This review focuses on the design concepts and rationale for the use of unidirectional Hypoxia-Activated Prodrugs (uHAPs) to target the hTME as exemplified by the uHAPs AQ4N and OCT1002. These agents undergo irreversible reduction in a hypoxic environment to active forms that target DNA topoisomerase IIα (TOP2A). This nuclear enzyme is essential for cell division and is a recognised chemotherapeutic target. An activated uHAP interacts with the enzyme-DNA complex to induce DNA damage, cell cycle arrest and tumour cell death. uHAPs are designed to overcome the shortcomings of conventional HAPs and offer unique pharmacodynamic properties for effective targeting of TOP2A in the hTME. uHAP therapy in combination with standard of care treatments has the potential to enhance outcomes by co-addressing the therapeutic challenge presented by the hTME.
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Neoplasias , Profármacos , Humanos , Profármacos/farmacología , Profármacos/uso terapéutico , Microambiente Tumoral , Hipoxia de la Célula , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Hipoxia/tratamiento farmacológico , ADN-Topoisomerasas/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia-induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia-activated prodrug of lidocaine. EXPERIMENTAL APPROACH: The rat Langendorff-perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. KEY RESULTS: In isolated hearts, OCT2013 and lidocaine prevented ischaemia-induced VF equi-effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi-effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg-1 i.v., whereas lidocaine reduced it even at 1 mg·kg-1 . In adult rat ventricular myocytes, OCT2013 had no effect on Ca2+ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate-dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi-effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013-perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. CONCLUSIONS AND IMPLICATIONS: OCT2013 is inactive but is bio-reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia-activated and ischaemia-selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity.
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Isquemia Miocárdica , Profármacos , Animales , Antiarrítmicos/farmacología , Isquemia , Lidocaína/farmacología , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/tratamiento farmacológico , Profármacos/farmacología , Ratas , Ratas Wistar , Fibrilación VentricularRESUMEN
Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.
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Antineoplásicos/farmacología , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Citocromo P-450 CYP1B1/antagonistas & inhibidores , Familia 2 del Citocromo P450/antagonistas & inhibidores , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Estudios de Cohortes , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Familia 2 del Citocromo P450/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/patología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Ratones , Profármacos/farmacología , Profármacos/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.
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Antineoplásicos/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Duocarmicinas/farmacología , Indoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Duocarmicinas/síntesis química , Duocarmicinas/química , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Polysialic acid (polySia) is a linear polysaccharide comprised of N-acetylneuraminic acid residues and its over-expression in cancer cells has been correlated with poor clinical prognosis. An assay has been developed for quantitative analysis of cellular polySia expression. This was achieved by extracting and purifying released polySia from glycoproteins by mild acid hydrolysis and optimised organic extraction. The polySia was further hydrolysed into Sia monomers, followed by fluorescent labelling and quantitative analysis. The assay was qualified utilising endoneuraminidase-NF to remove polySia from the surface of C6-ST8SiaII cancer cells (EC50 = 2.13 ng/mL). The result was comparable to that obtained in a polySia-specific cellular ELISA assay. Furthermore, the assay proved suitable for evaluation of changes in polySia expression following treatment with a small molecule inhibitor of polysialylation. Given the importance of polySia in multiple disease states, notably cancer, this is a potentially vital tool with applications in the fields of drug discovery and glycobiology.
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Cromatografía de Fase Inversa , Ácidos Siálicos/análisis , Animales , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Cromatografía por Intercambio Iónico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Glicósido Hidrolasas/metabolismo , Ratas , Ácidos Siálicos/metabolismo , Sialiltransferasas/antagonistas & inhibidores , Sialiltransferasas/metabolismoRESUMEN
The polysialyltransferases (polySTs) catalyse the polymerisation of polysialic acid, which plays an important role in tumour metastasis. While assays are available to assess polyST enzyme activity, there is no methodology available specifically optimised for identification and quantitative evaluation of potential polyST inhibitors. The development of an HPLC-fluorescence-based enzyme assay described within includes a comprehensive investigation of assay conditions, including evaluation of metal ion composition, enzyme, substrate and acceptor concentrations, temperature, pH, and tolerance to DMSO, followed by validation using known polyST inhibitors. Thorough analysis of each of the assay components provided a set of optimised conditions. Under these optimised conditions, the experimentally observed Ki value for CMP, a competitive polyST inhibitor, was strongly correlated with the predicted Ki value, based on the classical Cheng-Prusoff equation [average fold error (AFE) = 1.043]. These results indicate that this assay can provide medium-throughput analysis for enzyme inhibitors with high accuracy, through determining the corresponding IC50 values with substrate concentration at the KM, without the need to perform extensive kinetic studies for each compound. In conclusion, an in vitro cell-free assay for accurate assessment of polyST inhibition is described. The utility of the assay for routine identification of potential polyST inhibitors is demonstrated, allowing quantitative measurement of inhibition to be achieved, and exemplified through assessment of full competitive inhibition. Given the considerable and growing interest in the polySTs as important anti-metastatic targets in cancer drug discovery, this is a vital tool to enable preclinical identification and evaluation of novel polyST inhibitors.
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Pruebas de Enzimas/métodos , Inhibidores Enzimáticos/análisis , Sialiltransferasas/antagonistas & inhibidores , Cromatografía Líquida de Alta Presión , Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Humanos , Cinética , Quinoxalinas/síntesis química , Quinoxalinas/química , Sialiltransferasas/química , Trisacáridos/síntesis química , Trisacáridos/químicaRESUMEN
Polysialic acid (polySia) is a unique, well-characterised carbohydrate polymer highly-expressed on the cell surface of neurons in the early stages of mammalian brain development. Post-embryogenesis, it is also re-expressed in a number of tumours of neuroendocrine origin. It plays important roles in modulating cell-cell, and cell-matrix adhesion and migration, tumour invasion and metastasis. Techniques for structural and quantitative characterisation of polySia from tumours and cancer cells are thus essential in exploring the relationship between polySia expression levels and structural and functional changes associated with cancer progression and metastasis. A variety of techniques have been developed to structurally and quantitatively analyse polySia in clinical tissues and other biological samples. In this review, analytical approaches used for the determination of polySia in biological matrices in the past 20 years are discussed, with a particular focus on chemical approaches, and quantitative analysis.
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Pruebas de Química Clínica/métodos , Ácidos Siálicos/análisis , Animales , Humanos , Ácidos Siálicos/química , Ácidos Siálicos/aislamiento & purificaciónRESUMEN
NLG919 is an effective small molecule inhibitor of indoleamine 2, 3-dioxygenase-1 (IDO-1) in anti-tumour immunotherapy, but the poor aqueous solubility limits its application for effective intravenous dosing. In this study a cyclodextrin (CD) complexation strategy has been systematically evaluated to achieve a simple and feasible method to prepare an NLG919 injectable formulation. From a series of CDs, HP-ß-CD proved to be the most conducive for NLG919 solubilization (approx 800-fold increase). Characterization studies using DSC, 1H NMR, XRPD and molecular simulation demonstrated that the NLG919/HP-ß-CD loading mechanism involved an increasing pH-dependent binding affinity. Importantly cell-based studies in vitro and anti-tumour activity in vivo demonstrated that the pharmacological activity of NLG919 as an IDO-1 inhibitor was not influenced by HP-ß-CD complexation. Furthermore, the combination of NLG919/HP-ß-CD with paclitaxel (PTX) significantly improved anti-tumour chemotherapy compared to PTX alone. In summary, NLG919/HP-ß-CD is shown to highly enhance the aqueous solubility of NLG919 with activity unaffected, greatly facilitating the intravenous use of this small molecule immunotherapeutic to improve the efficacy of PTX.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclodextrinas/uso terapéutico , Imidazoles/uso terapéutico , Isoindoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Paclitaxel/uso terapéutico , Animales , Rastreo Diferencial de Calorimetría/métodos , Línea Celular Tumoral , Femenino , Células HeLa , Humanos , Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Espectroscopía de Resonancia Magnética/métodos , Ratones , Ratones Endogámicos BALB C , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Solubilidad/efectos de los fármacosRESUMEN
BACKGROUND: OCT1002 is a unidirectional hypoxia-activated prodrug (uHAP) OCT1002 that can target hypoxic tumor cells. Hypoxia is a common feature in prostate tumors and is known to drive disease progression and metastasis. It is, therefore, a rational therapeutic strategy to directly target hypoxic tumor cells in an attempt to improve treatment for this disease. Here we tested OCT1002 alone and in combination with standard-of-care agents in hypoxic models of castrate-resistant prostate cancer (CRPC). METHODS: The effect of OCT1002 on tumor growth and vasculature was measured using murine PC3 xenograft and dorsal skin fold (DSF) window chamber models. The effects of abiraterone, docetaxel, and cabazitaxel, both singly and in combination with OCT1002, were also compared. RESULTS: The hypoxia-targeting ability of OCT1002 effectively controls PC3 tumor growth. The effect was evident for at least 42 days after exposure to a single dose (30 mg/kg) and was comparable to, or better than, drugs currently used in the clinic. In DSF experiments OCT1002 caused vascular collapse in the PC3 tumors and inhibited the revascularization seen in controls. In this model OCT1002 also enhanced the anti-tumor effects of abiraterone, cabazitaxel, and docetaxel; an effect which was accompanied by a more prolonged reduction in tumor vasculature density. CONCLUSIONS: These studies provide the first evidence that OCT1002 can be an effective agent in treating hypoxic, castrate-resistant prostate tumors, either singly or in combination with established chemotherapeutics for prostate cancer.
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Antraquinonas/farmacología , Etilenodiaminas/farmacología , Profármacos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Animales , Antraquinonas/farmacocinética , Procesos de Crecimiento Celular/efectos de los fármacos , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Etilenodiaminas/farmacocinética , Humanos , Masculino , Ratones , Ratones Desnudos , Profármacos/farmacocinética , Neoplasias de la Próstata Resistentes a la Castración/irrigación sanguínea , Neoplasias de la Próstata Resistentes a la Castración/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and ß1 subunits has been explored relatively extensively and linked to tumour progression and metastasis. Individual receptors αvß3 and αvß5 have proved popular targets for diagnostic and therapeutic agents but lesser studied receptors, such as αvß6, αvß8, and ß1 subfamily members, also show promise. This review presents the current knowledge of integrin expression and function in squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on the arginine-glycine-aspartate (RGD)-binding integrins, in order to highlight the potential of integrins as targets for personalised tumour-specific identification and therapy.
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PURPOSE: Nipple secretions are protein-rich and a potential source of breast cancer biomarkers for breast cancer screening. Previous studies of specific proteins have shown limited correlation with clinicopathological features. Our aim, in this pilot study, was to investigate the intra- and interpatient protein composition of nipple secretions and the implications for their use as liquid biopsies. EXPERIMENTAL DESIGN: Matched pairs of nipple discharge/nipple aspirate fluid (NAF, n = 15) were characterized for physicochemical properties and SDS-PAGE. Four pairs were selected for semiquantitative proteomic profiling and trypsin-digested peptides analyzed using 2D-LC Orbitrap Fusion MS. The resulting data were subject to bioinformatics analysis and statistical evaluation for functional significance. RESULTS: A total of 1990 unique proteins were identified many of which are established cancer-associated markers. Matched pairs shared the greatest similarity (average Pearson correlation coefficient of 0.94), but significant variations between individuals were observed. CONCLUSIONS AND CLINICAL RELEVANCE: This was the most complete proteomic study of nipple discharge/nipple aspirate fluid to date providing a valuable source for biomarker discovery. The high level of milk proteins in healthy volunteer samples compared to the cancer patients was associated with galactorrhoea. Using matched pairs increased confidence in patient-specific protein levels but changes relating to cancer stage require investigation of a larger cohort.
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Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Líquido Aspirado del Pezón/metabolismo , Proteómica , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Biopsia LíquidaRESUMEN
Cyclodextrins (CD) are widely used bitter taste masking agents, for which the binding equilibrium constant (K) for the drug-CD complex is a conventional parameter for quantitating the taste masking effects. However, some exceptions have been reported to the expected relationship between K and bitterness reduction and the relationship between kinetic parameters of a drug-CD interaction, including association rate constant (Ka) and disassociation rate constant (Kd), and taste masking remains unexplored. In this study, based upon a database of kinetic parameters of drugs-HP-ß-CD generated by Surface Plasmon Resonance Imaging for 485 drugs, the host-guest kinetic interactions between drugs and HP-ß-CD for prediction of taste masking effects have been investigated. The taste masking effects of HP-ß-CD for 13 bitter drugs were quantitatively determined using an electronic gustatory system (α-Astree e-Tongue). Statistical software was used to establish a model based on Euclidean distance measurements, Ka and Kd of the bitter drugs/HP-ß-CD-complexes (R2=0.96 and P<0.05). Optimized parameters, Ka3, Kd, KaKd, Kd3, Ka2 and Ka/Kd with notable influence, were obtained by stepwise regression from 12 parameters derived from Ka, Kd and K (Ka/Kd). 10-fold cross-validation was used to verify the reliability of the model (correlation coefficient of 0.84, P<0.05). The established model indicated a relationship between Ka, Kd, K and taste masking by HP-ß-CD and was successful in predicting the extent of taste masking by HP-ß-CD of 44 bitter drugs, which was in accordance with the literature reported. In conclusion, the relationship between kinetics of drug-CD interactions and taste masking was established and providing a new strategy for predicting the cyclodextrin mediated bitter taste masking.
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Gusto , 2-Hidroxipropil-beta-Ciclodextrina , Cinética , Reproducibilidad de los ResultadosRESUMEN
Purpose: To understand the role of hypoxia in prostate tumor progression and to evaluate the ability of the novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the antitumor effect of bicalutamide.Experimental Design: The effect of OCT1002 on prostate cancer cells (LNCaP, 22Rv1, and PC3) was measured in normoxia and hypoxia in vitroIn vivo, tumor growth and lung metastases were measured in mice treated with bicalutamide, OCT1002, or a combination. Dorsal skin fold chambers were used to image tumor vasculature in vivo Longitudinal gene expression changes in tumors were analyzed using PCR.Results: Reduction of OCT1002 to its active form (OCT1001) decreased prostate cancer cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone, or with bicalutamide, showed significantly greater tumor growth control and reduced lung metastases compared with controls. Reestablishment of the tumor microvasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the upregulation of RUNX2 and its targets caused by bicalutamide alone was blocked by OCT1002.Conclusions: OCT1002 selectively targets hypoxic tumor cells and enhances the antitumor efficacy of bicalutamide. Furthermore, bicalutamide caused changes in gene expression, which indicated progression to a more malignant genotype; OCT1002 blocked these effects, emphasizing that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumor growth and malignant progression. This is of importance for the design and refinement of existing androgen-deprivation regimens in the clinic. Clin Cancer Res; 23(7); 1797-808. ©2016 AACR.
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Antraquinonas/administración & dosificación , Etilenodiaminas/administración & dosificación , Proteínas de Neoplasias/genética , Profármacos/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Anilidas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Nitrilos/administración & dosificación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Compuestos de Tosilo/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Fused cyclobutanes are found in a range of natural products and formation of these motifs in a straightforward and easy manner represents an interesting synthetic challenge. To this end we investigated an intramolecular variant of the thermal enamine [2 + 2] cyclisation, developing a diastereoselective intramolecular enamine [2 + 2] cyclisation furnishing δ lactone and lactam fused cyclobutenes in good yield and excellent diastereoselectivity.
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The polysialyltransferases are biologically important glycosyltransferase enzymes responsible for the biosynthesis of polysialic acid, a carbohydrate polymer that plays a critical role in the progression of several diseases, notably cancer. Having improved the chemical synthesis and purification of the fluorescently-labelled DMB-DP3 acceptor, we report optimisation and validation of a highly sensitive cell-free high-throughput HPLC-based assay for assessment of human polysialyltransferase activity.
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Cromatografía Líquida de Alta Presión , Ensayos Analíticos de Alto Rendimiento/métodos , Sialiltransferasas/análisis , Colorantes Fluorescentes , HumanosRESUMEN
Non-invasive methods to monitor tumour growth are an important goal in cancer drug development. Thermographic imaging systems offer potential in this area, since a change in temperature is known to be induced due to changes within the tumour microenvironment. This study demonstrates that this imaging modality can be applied to a broad range of tumour xenografts and also, for the first time, the methodology's suitability to assess anti-cancer agent efficacy. Mice bearing subcutaneously implanted H460 lung cancer xenografts were treated with a novel vascular disrupting agent, ICT-2552, and the cytotoxin doxorubicin. The effects on tumour temperature were assessed using thermographic imaging over the first 6 hours post-administration and subsequently a further 7 days. For ICT-2552 a significant initial temperature drop was observed, whilst for both agents a significant temperature drop was seen compared to controls over the longer time period. Thus thermographic imaging can detect functional differences (manifesting as temperature reductions) in the tumour response to these anti-cancer agents compared to controls. Importantly, these effects can be detected in the first few hours following treatment and therefore the tumour is observable non-invasively. As discussed, this technique will have considerable 3Rs benefits in terms of reduction and refinement of animal use.
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Alternativas al Uso de Animales/métodos , Neoplasias/tratamiento farmacológico , Termografía , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Doxorrubicina/uso terapéutico , Humanos , Ratones , Oligopéptidos/uso terapéutico , Tiourea/análogos & derivados , Tiourea/uso terapéuticoRESUMEN
The identification and quantification of functional cytochromes P450 (CYPs) in biological samples is proving important for robust analyses of drug efficacy and metabolic disposition. In this study, a novel CYP activity-based probe was rationally designed and synthesised, demonstrating selective binding of CYP isoforms. The dependence of probe binding upon the presence of NADPH permits the selective detection of functionally active CYP. This allows the detection and analysis of these enzymes using biochemical and proteomic methodologies and approaches.
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Sistema Enzimático del Citocromo P-450/metabolismo , Sondas Moleculares/metabolismo , Benzofuranos/química , Benzofuranos/metabolismo , Sistema Enzimático del Citocromo P-450/química , Humanos , Immunoblotting , Cinética , Hígado/metabolismo , Espectrometría de Masas , Sondas Moleculares/química , NADP/metabolismo , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , ProteómicaRESUMEN
The structure of solid drug delivery systems has considerable influence on drug release behaviors from particles and granules and also impacts other properties relevant to release characteristics such as taste. In this study, lipid-based microspheres of acetaminophen were prepared to mask the undesirable taste of drug and therefore to identify the optimal formulation for drug release. Synchrotron radiation X-ray computed microtomography (SR-µCT) was used to investigate the fine structural architectures of microspheres non-destructively at different sampling times during drug release test, which were simultaneously determined to quantitatively correlate the structural data with drug release behaviors. The results demonstrated that the polymeric formulation component, namely, cationic polymethacrylate (Eudragit E100), was the key factor to mask the bitter taste of acetaminophen by inhibiting immediate drug release thereby reducing the interaction intensity of the bitter material with the oral cavity taste buds. The structure and morphology of the microspheres were found to be influenced by the shape and particle size of the drug, which was also an important factor for taste-masking performance. The quantitative analysis generated detailed structural information which was correlated well with drug release behaviors. Thus, SR-µCT has been proved as a powerful tool to investigate the fine microstructure of particles and provides a new approach in the design of particles for taste masking.