Abstract:
BACKGROUND:We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. METHODS:We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). RESULTS:We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. CONCLUSIONS:In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Khanim F,Davies N,Veliça P,Hayden R,Ride J,Pararasa C,Chong MG,Gunther U,Veerapen N,Winn P,Farmer R,Trivier E,Rigoreau L,Drayson M,Bunce Cdoi
10.1038/bjc.2014.83subject
Has Abstractpub_date
2014-03-18 00:00:00pages
1506-16issue
6eissn
0007-0920issn
1532-1827pii
bjc201483journal_volume
110pub_type
杂志文章abstract:BACKGROUND:It is known that cancer stage is affected by comorbidity, but the evidence regarding the magnitude and even direction of this effect is highly inconsistent and poorly understood. The aims of this study were to establish the impact of comorbidity on cancer stage at diagnosis, using both specific individual co...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2015.355
更新日期:2015-11-03 00:00:00
abstract:BACKGROUND:Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated nuclear AR expression in...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2015.63
更新日期:2015-03-31 00:00:00
abstract:BACKGROUND:Cross-talk between receptor tyrosine kinases and the oestrogen receptor (ER) is implicated in resistance to endocrine therapy. We investigated whether AEE788 (a combined inhibitor of EGFR, HER2 and VEGFR) plus tamoxifen or letrozole enhanced the individual anti-tumour effects of these agents. METHODS:Breast...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6605641
更新日期:2010-04-13 00:00:00
abstract::Fine needle aspiration (FNA) biopsy is the least invasive method of sampling breast cancer in vivo and provides material for breast cancer diagnosis. FNA has also been used to examine cellular markers to predict and monitor the effects of therapy. The aim of this study was to assess the accuracy of using FNA material ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1054/bjoc.2001.2064
更新日期:2001-10-19 00:00:00
abstract::The objective of the study was to investigate the predictive value of various clinical, biochemical, and histopathological parameters, with special emphasis on the expression of the retinoblastoma protein (pRB), on the radiation response in bladder cancer. In order to obtain a truly objective response measure, patient...
journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
doi:10.1038/sj.bjc.6601063
更新日期:2003-07-21 00:00:00
abstract::The aim of this study was to ascertain whether assessing the growth fraction of cervical carcinoma of 28 patients, using antibody Ki-67, would be of value in clinical practice. The results showed no relationship between growth fraction and age, clinical stage, lymph node involvement or short term (3-5 years) survival....
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1992.167
更新日期:1992-05-01 00:00:00
abstract::Markers of the inflammatory response, interleukin 6, C-reactive protein, albumin and full blood count, were measured in non-small-cell lung cancer (NSCLC) patients (n = 21) with and without weight loss ( > 5%). There were significant increases in circulating C-reactive protein (P < 0.001), interleukin 6 (P < 0.01) and...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1996.294
更新日期:1996-06-01 00:00:00
abstract:BACKGROUND:Limited literature on the role of intraarterial chemotherapy as first-line therapy for penile squamous cell carcinoma is available. METHODS:From 2005 to 2013, a total of 12 patients with various stages of penile squamous cell carcinoma received intraarterial chemotherapy. The chemotherapeutic agents used we...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2014.394
更新日期:2014-09-09 00:00:00
abstract::Although the presence of axillary node metastases in breast cancer is a key prognostic indicator and may influence treatment decisions, a significant proportion of patients diagnosed as axillary node negative (ANN) using standard histopathological techniques may have occult nodal metastases (OMs). A combination of lim...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1996.16
更新日期:1996-01-01 00:00:00
abstract::Vascular endothelial growth factor is an important angiogenic factor for tumour progression because it increases endothelial-cell proliferation and remodels extracellular matrix in blood vessels. We demonstrated that hyperthermia at 42 degrees C, termed heat shock, suppressed the gene expression and production of vasc...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6600268
更新日期:2002-05-20 00:00:00
abstract::We have treated 40 patients was relapsed or resistant lymphoma with the combination of Etoposide, Prednisolone, Ifosfamide and Cisplatin (EPIC). Complete response was obtained in 11 patients (28%) with an overall response of 58%. The presence of bulky disease (P < 0.005), elevated LDH serum levels (P < 0.005), respons...
journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
doi:10.1038/bjc.1993.393
更新日期:1993-09-01 00:00:00
abstract::Staging and surgical as well as post-operative treatment of primary Fallopian tube carcinoma (FTC) followed the lines established for primary ovarian cancer (OC). In a nationwide retrospective analysis we were able to find a distinct difference between these two tumours. A total of 262 patients, 68 with FTC and 194 wi...
journal_title:British journal of cancer
pub_type: 杂志文章,多中心研究
doi:10.1038/bjc.1994.105
更新日期:1994-03-01 00:00:00
abstract:BACKGROUND:Non-invasive biomarkers of disease progression in mice with cancer are lacking making it challenging to implement appropriate humane end points. We investigated whether body temperature, food and water consumption could be used to predict tumour burden. METHODS:Thirty-six male, wild-type C57Bl/6 mice were i...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.818
更新日期:2014-02-18 00:00:00
abstract::The registered incidence rate of childhood central nervous system (CNS) tumours has increased in several countries. It is uncertain whether these increases are biologically real or owing to improved diagnostic methods. We explored the medical records of 626 CNS tumours diagnosed in Danish children between 1980 and 199...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603278
更新日期:2006-08-07 00:00:00
abstract::In the past decade, an increasing number of frequently positive randomised clinical trials have been completed, allowing new consideration of the present therapeutic armamentarium for advanced renal cell carcinoma. These studies were predominantly designed to compare the experimental drugs with 1 of 2 active control a...
journal_title:British journal of cancer
pub_type: 杂志文章,评审
doi:10.1038/bjc.2014.240
更新日期:2015-01-06 00:00:00
abstract::This corrects the article DOI: 10.1038/bjc.2017.85. ...
journal_title:British journal of cancer
pub_type: 杂志文章,已发布勘误
doi:10.1038/bjc.2018.3
更新日期:2018-03-20 00:00:00
abstract::Apoptosis is a physiological form of cell death important in normal processes such as morphogenesis and the functioning of the immune system. In addition, defects in the apoptotic process play a major role in a number of important areas of disease, such as autoimmune diseases and cancer. DNA-damage-induced apoptosis p...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603257
更新日期:2006-08-21 00:00:00
abstract::Interferon-alpha (IFN-alpha) is a clinically useful cytokine for treatment of a variety of cancers, including chronic myelocytic leukaemia (CML). Most CML cells are sensitive to IFN-alpha; however, its biological effects on leukaemic cells are incompletely characterized. Here, we provide evidence that IFN-alpha induce...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6690163
更新日期:1999-03-01 00:00:00
abstract::Clonogenic survival of HeLa, Chinese hamster and HaK cells after treatment with a range of cisplatin concentrations and exposure times was determined and cellular platinum concentrations were measured by PIXE. It was demonstrated that cisplatin cytotoxicity of the three cell lines varied considerably as a function of ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1986.168
更新日期:1986-08-01 00:00:00
abstract::The characteristics of 7 human melanoma cell lines were compared with those of the xenografts from which they were established. The ultrastructure, melanin content, isozyme pattern and chromosome numbers of the cell lines were closely similar to those of the corresponding xenografts. The different cell lines gave rise...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1981.276
更新日期:1981-12-01 00:00:00
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 t...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/s41416-020-0824-8
更新日期:2020-06-01 00:00:00
abstract::An apparently unique circulating common oncofoetal protein has been identified in rat small-bowel, colonic and pancreatic adenocarcinomas. The tumours were induced by ionizing radiation (small bowel), an alkyl hydrocarbon, 1,2-dimethylhydrazine (colon) and a polyaromatic hydrocarbon, 7,12-dimethylbenz[a]anthracene (pa...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1981.120
更新日期:1981-06-01 00:00:00
abstract:BACKGROUND:There are currently two million cancer survivors in the United Kingdom, and in recent years this number has grown by 3% per annum. The aim of this paper is to provide long-term projections of cancer prevalence in the United Kingdom. METHODS:National cancer registry data for England were used to estimate can...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2012.366
更新日期:2012-09-25 00:00:00
abstract::Our recent genome-wide allelotyping analysis of gallbladder carcinoma identified 3p, 8p, 9q and 22q as chromosomal regions with frequent loss of heterozygosity. The present study was undertaken to more precisely identify the presence and location of regions of frequent allele loss involving those chromosomes in gallbl...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6600490
更新日期:2002-08-12 00:00:00
abstract::Endogamous groups in Western India have been known to have a wide degree of genetic diversity. Analysis of the data available on some of the endogamous groups belonging to two main communities attending the Tata Memorial Hospital, Bombay, viz. Hindus from Maharashtra, and Hindus from Gujarat show that one of the endog...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1971.77
更新日期:1971-12-01 00:00:00
abstract::Although osteosclerotic bone metastases are characteristic of prostate cancer, mixed metastases with a lytic component are not uncommon. Type I collagen is synthesised by osteoblasts and accounts for about 90% of the organic matrix of bone. We have used new specific immunoassays for PICP (carboxy-terminal propeptide o...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1995.204
更新日期:1995-05-01 00:00:00
abstract::The role of secreted frizzled-related protein (SFRP) genes in gastric cancer remains largely unknown. We determined the frequency and functional significance of SFRPs hypermethylation in human gastric cancer. The expression and methylation status of four SFRP members (SFRP1, 2, 4, and 5) in primary gastric cancer samp...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603968
更新日期:2007-10-08 00:00:00
abstract:BACKGROUND:To compare the imaging and clinical features of temporal lobe necrosis (TLN) in nasopharyngeal carcinoma (NPC) patients treated with two-dimensional radiotherapy (2D-RT) or those with intensity-modulated radiotherapy (IMRT). METHODS:We retrospectively analysed NPC patients who underwent 2D-RT (72 patients, ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2014.243
更新日期:2014-05-27 00:00:00
abstract::In a population-based cohort study of all women aged over 50 years with breast cancer in the Swedish Cancer Register in 1961-2003, those diagnosed before 31 December 1987 were regarded as unexposed to tamoxifen, whereas those diagnosed after that date were considered potentially exposed. Crosslinkages within the Cance...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603214
更新日期:2006-07-03 00:00:00
abstract:BACKGROUND:This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. METHODS:Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosuti...
journal_title:British journal of cancer
pub_type: 杂志文章,多中心研究
doi:10.1038/bjc.2014.508
更新日期:2014-11-25 00:00:00