371 research outputs found
Proteolysis of microtubule associated protein 2 and sensitivity of pancreatic tumours to docetaxel
We have studied the state of microtubule associated protein 2 (MAP2) in the pancreatic ductal adenocarcinomas P03 and P02 (sensitive and refractory to docetaxel respectively) since they express the corresponding mRNA and MAP2-related peptides. Immunohistochemical localization showed that in tumour P03 the MAP2-related peptides are highly expressed and confined to the epithelial malignant cells while in P02 the intensity of the immunostaining is lower. However, anti α-tubulin staining followed a similar pattern suggesting that the net amount of macromolecular structures in the sensitive tumour is higher than in the refractory one. This may explain its higher sensitivity to docetaxel, because tubulin assembled into microtubules is the target of the drug. We found that protein extracts from both tumours differed in their proteolytic activity on rat brain MAP2. Since the proteolysis pattern obtained was similar to the one produced by Cathepsin D, we studied the effect of MAP2 proteolysed by this enzyme on microtubule formation in vitro. Proteolysis was found to increase the tendency of tubulin to assemble into macromolecular structures (microtubules and aggregates) in the presence of docetaxel. This suggests that in vivo proteolysis of MAP2 might increase microtubule alterations and potentiate the antitumour effect of docetaxel. © 2000 Cancer Research Campaig
Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SMâ406/ATâ406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer
The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SMâ406/ATâ406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPKâPD) model was developed to predict the tissue concentrationâtime profiles of SMâ406, the related oncoâprotein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rateâlimited) model was used to describe SMâ406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rateâlimited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SMâ406 concentration in tumor to the cIAP1 degradation, proâcaspase 8 decrease, CLâPARP accumulation and tumor growth inhibition. The PBPKâPD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SMâ406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100147/1/bdd1850.pd
A positioning pillow to improve lumbar puncture success rate in paediatric haematology-oncology patients: a randomized controlled trial
<p>Abstract</p> <p>Background</p> <p>Lumbar punctures (LPs) are common in children with cancer. Although pain management during the lumbar puncture has been well standardized, dealing with stress and anxiety is not well addressed yet. Our objective was to evaluate the potential improvement of the LP success rate using a positioning pillow, to ensure maximum lumbar flexion, and allow paravertebral muscles to relax, in children who are awake, with either conscious sedation or no sedation.</p> <p>Methods</p> <p>Children aged 2â18 years undergoing LP were randomly assigned to a positioning pillow or no intervention. The primary outcome was the rate of success, i.e. achieving the LP (sampling or injection) at the first attempt, without bleeding (RBC < 50/mm<sup>3</sup>). The secondary outcomes included: the child's pain, assessed by a self-administered visual analogical scales (VAS) for children over 6 years of age; the parents' and caregivers' perception of the child's pain; the satisfaction of the children, the parents, the caregivers and the physician. The child's cooperation and the occurrence of post-LP syndrome were also evaluated.</p> <p>Results</p> <p>124 children (62 in each group) were included. The LP pillow tended to increase the success rate of LPs (67% vs. 57%, p = 0.23), and decreased the post-LP syndromes (15% vs. 24%, p = 0.17) but the differences were not statistically significant. In children over 6-year of age (n = 72), the rate of success was significantly higher in the pillow group (58.5% vs. 41.5%, p = 0.031), with a tendency to feel less pain (median VAS 25 vs. 15 mm, p = 0.39) and being more satisfied (84.4% vs. 75.0%, p = 0.34).</p> <p>Conclusion</p> <p>Overall results do not demonstrate a benefit in using this pillow for lumbar punctures. This study results also suggest a benefit in the sub group of children over 6-year of age; this result needs confirmation.</p> <p>Trial Registration</p> <p>The trial was registered with Clinical Trials.gov (number NCT00775112).</p
A novel enzymatically-mediated drug delivery carrier for bone tissue engineering applications: combining biodegradable starch-based microparticles and differentiation agents
In many biomedical applications, the performance
of biomaterials depends largely on their degradation
behavior. For instance, in drug delivery applications, the
polymeric carrier should degrade under physiological
conditions slowly releasing the encapsulated drug. The aim
of this work was, therefore, to develop an enzymaticmediated
degradation carrier system for the delivery of
differentiation agents to be used in bone tissue engineering
applications. For that, a polymeric blend of starch with
polycaprolactone (SPCL) was used to produce a microparticle
carrier for the controlled release of dexamethasone
(DEX). In order to investigate the effect of enzymes on the
degradation behavior of the developed system and release
profile of the encapsulated osteogenic agent (DEX), the
microparticles were incubated in phosphate buffer solution
in the presence of a-amylase and/or lipase enzymes (at
physiological concentrations), at 37 C for different periods
of time. The degradation was followed by gravimetric
measurements, scanning electron microscopy (SEM) and
Fourier transformed infrared (FTIR) spectroscopy and the
release of DEX was monitored by high performance liquid
chromatography (HPLC). The developed microparticles
were shown to be susceptible to enzymatic degradation, as observed by an increase in weight loss and porosity with
degradation time when compared with control samples
(incubation in buffer only). For longer degradation times,
the diameter of the microparticles decreased significantly
and a highly porous matrix was obtained. The in vitro
release studies showed a sustained release pattern with
48% of the encapsulated drug being released for a period of
30 days. As the degradation proceeds, it is expected that
the remaining encapsulated drug will be completely
released as a consequence of an increasingly permeable
matrix and faster diffusion of the drug. Cytocompatibility
results indicated the possibility of the developed microparticles
to be used as biomaterial due to their reduced
cytotoxic effects
PluronicÂź block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances
YesThis mini-review highlights the latest advances in the chemistry and biology of PluronicÂź triblock copolymers. We focus on their applications in medicine, as drug delivery carriers, biological response modifiers, and pharmaceutical ingredients. Examples of drug delivery systems and formulations currently in clinical use, clinical trials or preclinical development are highlighted. We also discuss the role that PluronicÂź copolymers may play in the innovative design of new nanomedicines in the near future.We thank the Leverhulme Trust (Early Career Fellowship no. ECF-2013-414 to NPEB), the University of Warwick (Grant no. RDF 2013-14 to NPEB) and EPSRC (EP/G004897/1 to APB) for support
A phase II irinotecanâcisplatin combination in advanced pancreatic cancer
We report a cisplatin and irinotecan combination in patients with biopsy-proven advanced pancreatic adenocarcinoma. Patients were selected from a specialist centre and required good performance status (KPS>70%), measurable disease on CT scan, and biochemical and haematological parameters within normal limits. Based on a two-stage phase II design, we aimed to treat 22 patients initially. The study was stopped because of the death of the 19th patient during the first treatment cycle, with neutropenic sepsis and multiorgan failure. A total of 89 treatments were administered to 17 patients. Serious grade 3/4 toxicities were haematological (neutropenia) 6%, diarrhoea 6%, nausea 7% and vomiting 6%. Using the clinical benefit response (CBR) criteria, no patients had an overall CBR. For responses confirmed by CT examination, there was one partial response (5%), three stable diseases lasting greater than 6 weeks (16%), with an overall 22% with disease control (PR+SD). The median progression-free and overall survival was 3.1 months (95% CI: 1.3-3.7) and 5.0 (95% CI: 3.9-10.1) months, respectively. Although this synergistic combination has improved the response rates and survival of other solid tumours, we recommend caution when using this combination in the palliation of advanced pancreatic cancer, because of unexpected toxicity
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