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71.
Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines 总被引:2,自引:0,他引:2
A. E. Wakeling A. J. Barker D. H. Davies D. S. Brown L. R. Green S. A. Cartlidge J. R. Woodburn 《Breast cancer research and treatment》1996,38(1):67-73
Summary Since the mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGFR), and EGFR is commonly overexpressed in solid human tumours, inhibitors of receptor tyrosine kinase activity (RTK) could prove to be effective antitumour agents. Screening of a compound library using an EGF-RTK enzyme prepared from human tumour derived A431 cells identified a series of potent (IC50<1µM) enzyme inhibitors. These inhibitors are quinazolines bearing a variety of substituted anilines at the 4-position. The most potent 4-anilinoquinazolines (IC50 20nM) have small non-polar meta substituents on the aniline ring, and are competitive with ATP and non-competitive with substrate. The growth inhibitory activity of these agents was assessed in vitro using KB cells (human oral squamous tumour) grown in the absence or presence of EGF. A selected compound, 4-(3-chloroanilino)quinazoline (CAQ), inhibited EGF-stimulated growth in a concentration dependent manner and complete blockade was observed at concentrations (1–10 µM) which had no effect on basal growth. Selectivity of growth inhibition by CAQ was further exemplified in IGF1-stimulated KB cells where no effect was detected at concentrations which completely blocked EGF-stimulated growth. Similarly, CAQ blocked TGF-stimulated growth in MCF-7 human breast cancer cells without affecting insulin-stimulated growth. These studies define a novel class of EGF-RTK inhibitors which are also potent and selective inhibitors of EGF-stimulated human tumour cell growthin vitro.
Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb. 相似文献
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G. M. Barker S. Radley A. Davis K. D. R. Setchell N. O'Connell I. A. Donovan M. R. B. Keighley J. P. Neoptolemos 《International journal of colorectal disease》1993,8(4):188-192
Previous studies have suggested that patients with familial adenomatous polyposis (FAP) have increased faecal excretion of cholesterol but a reduction in cholesterol metabolites. It was consequently proposed that the degree of faecal cholesterol degradation could be used as a means of diagnosis. Developments in the extraction and analysis of faecal neutral sterols as well as the accurate means of diagnosing FAP by DNA analysis and indirect ophthalmoscopy has necessitated a re-examination of this proposal. Faecal neutral sterols were analysed in 10 patients with untreated FAP following a complete 5-day stool collection and compared with 9 healthy control subjects (including 4 siblings) closely matched for age and sex. The median [25 and 75, percentiles] stool wet weights were similar between the FAP (97.5 [69, 192] g · 24 h-1) and the control (116 [61.5, 137] g · 24 h-1) groups. Faecal cholesterol concentration was similar in the two groups (FAP=2.3 [1.4, 4.2]; control=3.5 [1.0, 6.0] mol · g-1 dry wt) as was the concentration of total neutral sterols not including plant sterols (FAP=17.2 [13.4, 21.0]; control=18.2 [7.4, 21.6] mol · g-1 dry wt). There were no significant differences in the proportions of cholesterol metabolised between the FAP (82.3 [74.2, 93.5]%) and control (72.1 [5.7, 81.3]%) groups. This study does not support the notion that faecal neutral sterol metabolism is uniquely different in patients with FAP.
Résumé Des études précedentes avaient suggéré que les malades avec polypose adénomateuse familiale (PAF) avaient une excrétion fécale augmentée de choléstérol mais une réduction des métabolìtes du choléstérol. On a donc proposé que les degrés de dégradation fécale du choléstérol puisse être utilisée comme moyen de diagnostic. Le développement dans l'extraction et l'analyse des stérols neutres fécaux aussi bien que des moyens appropriés de diagnostiquer la PAF par analyse du DNA et ophthalmoscopie indirecte a nécessité un ré-examen de cette proposition. Les stérols neutres fécaux, ont été analysés chez 10 patients avec une PAF non traitée après une collection complète des matières de 5 jours et comparés avec 9 sujets contrôles sains (comprenant 4 enfants de mêmes parents) étroitement appareillés pour l'âge et le sexe. Les poids moyens (25 et 75 percentiles) de selles humides étaient similaires chez les PAF (97.5 (69, 192) g · 24 h-1) et les contrôles (116 (61.5, 137) g · 24 h-1). La concentration de choléstérol fecal était similaire dans les deux groupes (PAF=2.3 (1.4, 4.2); controle=3.5 (1.0, 6.0) mol · g poids sec) de même que la concentration de stérols neutres totaux stéroïdes végétaux exclus (PAF=17.2 (13.4, 21.0); controle 18.2 (7.4, 21.6) mol · g poids sec). Il n'y avait pas de différence significative dans les proportions de choléstérol métabolisé entre les PAF (82.3 (74.2, 93.5)%) et les contrôles (72.1 (5.7, 81.3)%). Cette étude ne confirme pas la notion que le métabolisme des stérols neutres fécaux est uniquement différent chez les patients avec une PAF.相似文献
74.
Barker C 《Health and social service journal》1981,91(4735):315-318
Ten years ago the Worcester Development Project was launched as a model reorganisation of mental illness services. Charles Barker, senior nursing officer, department of psychiatry, Worcester Royal Infirmary, looks at the progress of the project. 相似文献
75.
Two children presented with Ph1-positive leukemia, confirmed by Giemsa banding as 22q-. One child showed an initial presentation characteristic of acute lymphoblastic leukemia, followed by development of chronic myelocytic leukemia 2 yr later. A second child presented in blast crisis. Both patients showed blast cells possessing both lymphoid and myeloid characteristics, as demonstrated by histochemical, biochemical, or surface receptor properties of each cell series. The evidence provided supports the assumption of mixed lymphoid-myeloid properties of blast cells in chronic myelocytic leukemia in children. Detailed study of the leukemic cells may aid in the understanding of complex stem cell relationships and suggest more effective therapeutic approaches. 相似文献
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78.
Carruthers I Williams PA Elsigood T Stoker J Orros G Hancock C Barker C 《The Health service journal》1992,102(5311):suppl 1-suppl 8
79.
Dietary behaviour and health in Northern Ireland: an exploration of biochemical and haematological associations. 下载免费PDF全文
M E Barker S I McClean J J Strain K A Thompson 《Journal of epidemiology and community health》1992,46(2):151-156
STUDY OBJECTIVE--The aim was to determine the relationships between dietary behaviour and biochemical and haematological measures. DESIGN--This was a cross sectional population study. SETTING--The study took place in the general community within Northern Ireland. SUBJECTS--522 randomly selected adults aged 18-64 years took part (65% of the eligible sample). MEASUREMENTS AND MAIN RESULTS--Four dietary behaviours were identified using principal components analysis from 7 d weighed dietary records described in terms of mean intake of 41 food groups. Haematological and biochemical analyses were carried out on non-fasting blood samples. Social, personal, and lifestyle information was ascertained through interviewer administered questionnaires. Partial correlations controlled for age and smoking behaviour were calculated. There were significant negative associations between iron status measures and the "traditional" behaviour, while the "meat and two veg" behaviour showed positive associations. There were positive associations between the "cosmopolitan" and "convenience" behaviours and folate status in women. White cell count and platelet levels in women were negatively associated with the "traditional" and "cosmopolitan" behaviours. Total cholesterol levels showed significant negative associations with the "cosmopolitan" behaviour in women and HDL cholesterol levels were positively associated with the "cosmopolitan", "convenience" and "meat and two veg" behaviours. CONCLUSIONS--Through a multivariate approach to dietary assessment it is possible to identify food combinations that cluster and interact to influence biochemical and haematological indices of health status. 相似文献
80.