Abstract：
BACKGROUND:Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Glucocorticoids form a critical component of chemotherapy regimens and resistance to glucocorticoid therapy is predictive of poor outcome. We have previously shown that glucocorticoid resistance is associated with upregulation of the oncogene C-MYC and failure to induce the proapoptotic gene BIM. METHODS:A high-throughput screening (HTS) campaign was carried out to identify glucocorticoid sensitisers against an ALL xenograft derived from a glucocorticoid-resistant paediatric patient. Gene expression analysis was carried out using Illumina microarrays. Efficacy, messenger RNA and protein analysis were carried out by Resazurin assay, reverse transcription-PCR and immunoblotting, respectively. RESULTS:A novel glucocorticoid sensitiser, 2-((4,5-dihydro-1H-imidazol-2-yl)thio)-N-isopropyl-N-phenylacetamide (GCS-3), was identified from the HTS campaign. The sensitising effect was specific to glucocorticoids and synergy was observed in a range of dexamethasone-resistant and dexamethasone-sensitive xenografts representative of B-ALL, T-ALL and Philadelphia chromosome-positive ALL. GCS-3 in combination with dexamethasone downregulated C-MYC and significantly upregulated BIM expression in a glucocorticoid-resistant ALL xenograft. The GCS-3/dexamethasone combination significantly increased binding of the glucocorticoid receptor to a novel BIM enhancer, which is associated with glucocorticoid sensitivity. CONCLUSIONS:This study describes the potential of the novel glucocorticoid sensitiser, GCS-3, as a biological tool to interrogate glucocorticoid action and resistance.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Toscan CE,Jing D,Mayoh C,Lock RBdoi
10.1038/s41416-020-0824-8subject
Has Abstractpub_date
2020-06-01 00:00:00pages
1769-1781issue
12eissn
0007-0920issn
1532-1827pii
10.1038/s41416-020-0824-8journal_volume
122pub_type
杂志文章abstract：:The aim of this study was to assess the cost-effectiveness of combination chemotherapy with paclitaxel/cisplatin, compared with standard etoposide/cisplatin in patients with advanced non-small cell lung cancer (NSCLC). We obtained the primary survival and resource utilization data from a large three-arm randomized tri...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1038/sj.bjc.6690426
更新日期：1999-05-01 00:00:00
abstract：:The National Registry of Childhood Tumours contains over 51000 records of children born in Great Britain who developed cancer under the age of 15 years. Patterns of childhood cancer among families containing more than one child with cancer have been studied. A total of 225 "sib pair' families have been ascertained fro...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.331
更新日期：1996-07-01 00:00:00
abstract：:The growth inhibitory effects of interferons, IFN-alpha and IFN-gamma on human lung cancer cell lines were studied using both a tetrazolium (MTT) colorimetric assay and direct cell counting. Significant discrepancies between the two assays were observed, the MTT assay consistently underestimating the growth inhibitory...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1989.306
更新日期：1989-10-01 00:00:00
abstract：BACKGROUND:While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning V...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/s41416-018-0128-4
更新日期：2018-06-01 00:00:00
abstract：:Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness. Angiotensin II (ANGII) was initially described as a vasoconstrictor; recent studies have shown its participation in cellular proliferation, vascularisation, and apoptosis. We conducted a prospective study to evaluate the...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6604431
更新日期：2008-07-08 00:00:00
abstract：BACKGROUND:To prospectively examine the association between diabetes and risk of prostate cancer defined by clinical and molecular features. METHODS:A total of 49,392 men from the Health Professionals Follow-up Study (HPFS) were followed from 1986 to 2014. Data on self-reported diabetes were collected at baseline and ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/s41416-020-0910-y
更新日期：2020-08-01 00:00:00
abstract：:The acute toxicity, pharmacokinetics and hypoxic cytotoxicity of RSU-1069 were investigated using the subcutaneous (sc) rat 9L tumour model. The pharmacokinetics were studied after i.p. injection of RSU-1069 (20 mg kg-1 or 100 mg kg-1). For both doses, the elimination of RSU-1069 followed first-order kinetics in both ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1991.116
更新日期：1991-04-01 00:00:00
abstract：:Perforin (PFP) is a cytotoxic protein released from killer cells. PFP immunoreactivity in human peripheral blood lymphocytes (PBL) and tumour infiltrating lymphocytes (TIL) was investigated immunocytochemically with the aid of an anti-PFP monoclonal antibody. PFP was detected in the cytoplasm of 10% of PBL. We perform...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1991.283
更新日期：1991-08-01 00:00:00
abstract：:Previous studies have characterized the enzymatic properties and inhibition of a trypsin-like neutral protease on the surface of Ehrlich ascites cells by means of kinetic analysis. The present study links these kinetic studies with the recently reported role of a tumour-cell membrane-bound serine protease in tumour-in...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1982.304
更新日期：1982-12-01 00:00:00
abstract：:We compared the long-term impact of 1- and 2-year screening mammography intervals using prognostic, screening, and outcome information for women aged 50-74 years obtained from the Screening Mammography Program of British Columbia in two time periods, prior to 1997 (policy of annual mammography) and after 1997 (biennia...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6602393
更新日期：2005-03-14 00:00:00
abstract：:Lung cancer is the primary cause of cancer mortality in developed countries. First diagnosis only when disease has already reached the metastatic phase is the main reason for failure in treatment. To this regard, although low-dose spiral computed tomography (CT) has proven to be effective in the early detection of lun...
journal_title：British journal of cancer
pub_type： 杂志文章,评审
doi：10.1038/sj.bjc.6605660
更新日期：2010-06-08 00:00:00
abstract：:A cell-free plasmid reactivation assay was used to determine the fidelity of DNA double-strand break (DSB) repair in a panel of eight DSB repair-proficient human tumour cell lines. Nuclear protein extracts derived from radiosensitive tumour cells were less capable of correctly rejoining EcoRI-induced DSBs than were si...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1997.576
更新日期：1997-01-01 00:00:00
abstract：BACKGROUND:Activins and inhibins belong to the TGFβ-superfamily, which controls cell proliferation and differentiation in many organs. Activin A, the dimer of inhibin βA subunit, acts strongly anti-proliferative in hepatocytes. Little is known on the other activin/inhibin subunits in human liver and hepatocellular carc...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2011.53
更新日期：2011-04-12 00:00:00
abstract：:Stathmin is an intracellular phosphoprotein that is overexpressed in a number of human malignancies. Our previous study using proteomic profiling showed that significant upregulation of stathmin occurs in oral squamous-cell carcinoma (OSCC)-derived cell lines. In the current study, to determine the potential involveme...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6602991
更新日期：2006-03-13 00:00:00
abstract：:We analysed antibodies specific for human p53 in sera from primary breast cancer patients using three different immunoassays and we related these results to the p53 level in tumour tissue detected by immunohistochemistry. Only 44% (11/25) of apparently enzyme-linked immunosorbent assay (ELISA)-positive sera were from ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1995.242
更新日期：1995-06-01 00:00:00
abstract：BACKGROUND:Stage at diagnosis is a strong predictor of cancer survival. Differences in stage distributions and stage-specific management help explain geographic differences in cancer outcomes. Stage information is thus essential to improve policies for cancer control. Despite recent progress, stage information is often...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2016.177
更新日期：2016-07-26 00:00:00
abstract：:When assessing the value of a particular treatment, it is important to consider the impact it may have on the quality of life of those being treated. This is particularly so for cancer patients, whose life expectancy may be short. Patients with advanced colorectal cancer who participated in two international comparati...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
doi：10.1038/bjc.1998.420
更新日期：1998-01-01 00:00:00
abstract：:The results of treating two series of patients with Burkitt's lymphoma are presented in the form of survival curves. The second series shows an improved survival rate which seems to be due to a potentiating effect by potassium iodide on oral cyclophosphamide. So far no reason for this effect has been found. ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1971.6
更新日期：1971-03-01 00:00:00
abstract：:The co-injection of extracellular matrix components, such as Matrigel, with human tumour cells into nude mice has been reported to facilitate tumour formation and growth, but it is unknown whether such components exert similar effects on tumour progression and metastasis. Metastatic behaviour is known to be enhanced w...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1994.284
更新日期：1994-08-01 00:00:00
abstract：:Matrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may c...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/sj.bjc.6690291
更新日期：1999-04-01 00:00:00
abstract：:Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by incre...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.673
更新日期：1996-12-01 00:00:00
abstract：BACKGROUND:Body mass index (BMI) has been associated with the risk of oesophageal cancer. But the influence of BMI on postoperative complication and prognosis has always been controversial. METHODS:In total, 2031 consecutive patients who underwent oesophagectomy between 1998 and 2008 were classified according to Asian...
journal_title：British journal of cancer
pub_type： 杂志文章,meta分析
doi：10.1038/bjc.2013.666
更新日期：2013-11-26 00:00:00
abstract：:Wistar rats were sensitized to rat embryonic tissue by immunization with irradiated (5000 rad) rat embryo cells (2 X 10(6) s.c. + 1 X 10(6) i.p.) derived from embryos aged 14-15 days, or by implantation of irradiated (5000 rad) tissue grafts from these embryos. Three to five immunizations were given at weekly interval...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1976.94
更新日期：1976-06-01 00:00:00
abstract：BACKGROUND:Malignancy alters cellular complex lipid metabolism and membrane lipid composition and turnover. Here, we investigated whether tumorigenesis in cancer-derived prostate epithelial cell lines influences protein kinase C-linked turnover of ethanolamine phosphoglycerides (EtnPGs) and alters the pattern of ethano...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2014.457
更新日期：2014-10-14 00:00:00
abstract：:The influence of cyclooxygenase-2 (COX-2) overexpression on the development of tumours has been well documented. The underlying mechanism however has still not been completely elucidated. An escape of proliferating cells from the regulatory influence of TGF-beta for example in the intestine has been discussed as well ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6604048
更新日期：2007-11-19 00:00:00
abstract：:Anti-Her-2/neu antibody is known to induce apoptosis in HER-2/neu overexpressing breast cancer cells. However, exact regulatory mechanisms mediating and controlling this phenomenon are still unknown. In the present study, we have investigated the effect of anti-Her-2/neu antibody on apoptosis of HER-2/neu overexpressi...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1054/bjoc.2001.2197
更新日期：2001-11-30 00:00:00
abstract：:Currently, there are no effective biomarkers for ovarian cancer prognosis or prediction of therapeutic response. The objective of this study was to examine a panel of 10 serum biochemical parameters for their ability to predict response to chemotherapy, progression and survival of ovarian cancer patients. Sera from ov...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6604630
更新日期：2008-10-07 00:00:00
abstract：BACKGROUND:Determining the rate of breast cancer (BC) growth in vivo, which can predict prognosis, has remained elusive despite its relevance for treatment, screening recommendations and medicolegal practice. We developed a model that predicts the rate of in vivo tumour growth using a unique study cohort of BC patients...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/s41416-019-0539-x
更新日期：2019-09-01 00:00:00
abstract：:Between 1980 and 1985, 914 patients with head and neck squamous cell carcinoma underwent lymph node dissection in our institution. The prognostic value of clinical factors has already been reported (Mamelle et al, 1994, Am J Surg 168: 494-498). We present here a comparison of biological characteristics of pharyngeal t...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1998.320
更新日期：1998-06-01 00:00:00
abstract：:Regional lymph node metastasis is a very important prognostic indicator. In the metastatic process, reduction in cell to cell adhesion including E-cadherin-catenin cell adhesion complex is an essential step. We investigated immunohistochemical expression of E-cadherin, alpha-catenin and beta-catenin in 159 tissue samp...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6601124
更新日期：2003-08-04 00:00:00
