Abstract:
:During the development of indazolylpyrimidines as novel and potent inhibitors of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) tyrosine kinase, we observed that some human tumour xenografts are more sensitive to VEGFR2 kinase inhibitors than others. A better understanding of the basis for this differential response may help to identify a predictive marker that would greatly aid in the identification of a suitable patient population for treatment. One representative compound from the indazolylpyrimidine series is GW654652 that inhibited all three VEGFRs with similar potency. The inhibition of VEGFR2 kinase by GW654652 was about 150 to >8800 more potent than the inhibition of eight other kinases tested. GW654652 inhibited VEGF- and bFGF-induced proliferation in endothelial cells with an IC(50) of 110 and 1980 nM, respectively, and has good pharmacokinetic profile in mouse and dog. We investigated the association between VEGF and VEGFR2 expression and the antitumour efficacy of GW654652, in various xenograft models. Statistically significant associations were observed between the antitumour efficacy of GW654652 in xenografts and VEGF protein (P=0.005) and VEGFR2 expression (P=0.041). The oral dose of GW654652 producing 50% inhibition of tumour growth (ED(50)) decreased with increasing levels of VEGF (r=-0.94); and, in contrast, the ED(50) increased with the increased expression of VEGFR2 (r=0.82). These results are consistent with the observed inverse correlation between VEGF and VEGFR2 expression in tumours. These findings support the hypothesis that VEGF and VEGFR2 expression by tumours may predict the therapeutic outcome of VEGFR kinase inhibitors.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Dev IK,Dornsife RE,Hopper TM,Onori JA,Miller CG,Harrington LE,Dold KM,Mullin RJ,Johnson JH,Crosby RM,Truesdale AT,Epperly AH,Hinkle KW,Cheung M,Stafford JA,Luttrell DK,Kumar Rdoi
10.1038/sj.bjc.6602109subject
Has Abstractpub_date
2004-10-04 00:00:00pages
1391-8issue
7eissn
0007-0920issn
1532-1827pii
6602109journal_volume
91pub_type
杂志文章abstract::Flunarizine is a class IV calcium channel blocker which increases oxygen delivery to hypoxic regions in solid tumours, exerting a radiosensitising effect in vivo in animal tumour models. Precisely how the drug improves oxygenation is not well understood. We hypothesised that metabolic conditions present within solid t...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1993.134
更新日期:1993-04-01 00:00:00
abstract::A comparative study has been made of fibroblasts obtained from patients with differing susceptibilities to malignant disease, both with respect to their chromosome complements and their transformation with SV40 virus. Fibroblasts from 2 Bloom's syndrome patients were found not to have raised SV40 transformation rates ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1977.235
更新日期:1977-11-01 00:00:00
abstract::Somatostatin receptor (sstr)-mediated radiation therapy is a new therapeutic modality for neuroendocrine (NE) tumours. High expression of sstr in NE tumours leads to tumour-specific uptake of radiolabelled somatostatin analogues and high absorbed doses. In this study, we present the first optimised radiation therapy v...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6602845
更新日期:2005-11-14 00:00:00
abstract::A population-based, case-control study was conducted in Los Angeles County, California, to investigate the inter-relationships of obesity, hypertension and medications in relation to renal cell carcinoma (RCC) risk. A total of 1204 RCC patients and an equal number of neighbourhood controls were included. Obesity was a...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1998.248
更新日期:1998-05-01 00:00:00
abstract:BACKGROUND:Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2017.433
更新日期:2018-02-20 00:00:00
abstract::Telomerase, an enzyme related with cellular immortality, has been extensively studied in many kinds of malignant tumours for clinical diagnostic or prognostic utilities. Telomerase activity is mainly regulated by the expression of hTERT (human telomerase reverse transcriptase), which is a catalytic component of human ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6602054
更新日期:2004-08-31 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:BACKGROUND:Extracellular matrix (ECM) plays a crucial role in tumour behaviour. Prolyl-4-hydroxlase-A2 (P4HA2) is a key enzyme in ECM remodelling. This study aims to evaluate the prognostic significance of P4HA2 in breast ductal carcinoma in situ (DCIS). METHODS:P4HA2 expression was assessed immunohistochemically in m...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/s41416-018-0337-x
更新日期:2018-12-01 00:00:00
abstract:BACKGROUND:Tissue micro-arrays (TMAs) are increasingly used to generate data of the molecular phenotype of tumours in clinical epidemiology studies, such as studies of disease prognosis. However, TMA data are particularly prone to missingness. A variety of methods to deal with missing data are available. However, the v...
journal_title:British journal of cancer
pub_type: 杂志文章,meta分析
doi:10.1038/sj.bjc.6606078
更新日期:2011-02-15 00:00:00
abstract::The cytocidal properties of metronidazole against hypoxic mammalian cells are described. This chemotherapeutic action has been shown to be dependent on drug concentration and duration of exposure. The x-ray TCD50 for a murine anaplastic carcinoma was reduced from 6081 rad to 4643 rad when animals were given metronidaz...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1976.78
更新日期:1976-05-01 00:00:00
abstract::Cellular senescence is an established tumour-suppressive mechanism that prevents the proliferation of premalignant cells. However, several lines of evidence show that senescent cells, which often persist in vivo, can also promote tumour progression in addition to other age-related pathologies via the senescence-associ...
journal_title:British journal of cancer
pub_type: 杂志文章,评审
doi:10.1038/bjc.2016.115
更新日期:2016-05-24 00:00:00
abstract:BACKGROUND:Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with re...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.826
更新日期:2014-03-04 00:00:00
abstract::Epidemiologic evidence has recently identified an association between an endemic outbreak of pleural and peritoneal mesothelioma in the Urgup region of Turkey and exposure to zeolite fibres. This malignancy is usually associated with exposure to asbestos dusts whose mineralogical characteristics differ from those of z...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1986.158
更新日期:1986-07-01 00:00:00
abstract::The incidence of colorectal carcinoma is rising at an alarming pace in Asian urban societies such as Hong Kong. Detailed examination of the epidemiological pattern and genetic mutation of colorectal cancer in the Hong Kong Chinese population is overdue. We compared the reported age incidence of colorectal carcinoma in...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1997.605
更新日期:1997-01-01 00:00:00
abstract::Immunohistochemical localization of chondroitin sulphate and dermatan sulphate proteoglycans (PGs) was observed in 70 tumour tissues, using monoclonal antibodies 9A-2 and 3B-3 raised against core molecules obtained from chondroitin sulphate PG by chondroitinase ABC-treatment. They recognize a stub of delta Di-4S and d...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1988.12
更新日期:1988-01-01 00:00:00
abstract::Hyper-activation of mitogen-activated protein kinase (MAPK) has recently been reported in several human cancers and activation of MAPK in those cancers may be associated with carcinogenesis through aberrant cell proliferation. To understand the roles of the MAPK pathway in colorectal tumorigenesis, we examined the sta...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6690817
更新日期:1999-12-01 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::The evolution and structure of adenomatous polyps and adenocarcinomata of the colon in NMRI mice induced by dimethylhydrazine are described. Severe toxic reactions in the liver and other organs are produced by dimethylhydrazine (DMH), but tumours are induced only in the colon and around the anus. The 100% incidence an...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1973.183
更新日期:1973-12-01 00:00:00
abstract::Comparative genomic hybridization (CGH) was used to detect copy number changes of DNA sequences in the Ewing family of tumours (ET). We analysed 20 samples from 17 patients. Fifteen tumours (75%) showed copy number changes. Gains of DNA sequences were much more frequent than losses, the majority of the gains affecting...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1997.242
更新日期:1997-01-01 00:00:00
abstract::SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is an anti-tumour agent that has a highly selective toxicity to hypoxic cells. In this study we delineate the role of several different bioreductive enzymes in the metabolism of SR 4233 by two tumour cell lines HT 1080 (human fibrosarcoma) and SCCVII (mouse carcinoma)....
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1993.59
更新日期:1993-02-01 00:00:00
abstract:BACKGROUND:The risk and prognosis of ovarian cancer have not been well established in women with endometriosis. Thus, we investigated the impact of endometriosis on the risk and prognosis for ovarian cancer, and evaluated clinicopathologic characteristics of endometriosis-associated ovarian cancer (EAOC) in comparison ...
journal_title:British journal of cancer
pub_type: 杂志文章,meta分析
doi:10.1038/bjc.2014.29
更新日期:2014-04-02 00:00:00
abstract:BACKGROUND:Though p53 mutations are rare in ES, there is a strong indication that p53 mutant tumours form a particularly bad prognostic group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients. METHODS:PRIMA-1...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.635
更新日期:2013-11-12 00:00:00
abstract:BACKGROUND:Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer the...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.692
更新日期:2014-01-07 00:00:00
abstract::Resistance to cytotoxics precludes the successful treatment of many solid tumours. Inhibition of DNA synthesis in normal tissues with antimetabolites such as hydroxyurea (HU) may be a useful means of improving the selective uptake of toxic thymidine analogues by the relatively resistant tumour cells. HU also inhibits ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1993.120
更新日期:1993-04-01 00:00:00
abstract::Computed tomographic scanning of the chest in 100 patients with newly diagnosed malignant lymphoma detected mediastinal lymphadenopathy (39%) and parenchymal deposits (15%) with a significantly greater sensitivity and specificity than conventional radiological techniques. This principally affected the staging and trea...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1984.97
更新日期:1984-05-01 00:00:00
abstract::Genomic alterations in the p53 tumour-suppressor gene and overexpression of p53 protein, resulting from gene mutations, are frequently found in pancreatic cancer. In this study we analysed the sera of 160 patients with malignant and benign pancreatic diseases for the presence of circulating antibodies to the p53 prote...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1994.443
更新日期:1994-11-01 00:00:00
abstract::The duration of the DNA synthesis period in normal and malignant human tissues from the larynx, trachea bronchus and esophagus of 13 patient has been estimated by a tritiated thymidine, carbon-14 thymidine double-labeling method in vitro. The DNA synthesis times range from approximately 10 to 25 hours, are shortest in...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1970.15
更新日期:1970-03-01 00:00:00
abstract::The evidence base for head and neck cancers is low with relatively few randomized controlled trials of the two main treatments, surgery and radiotherapy. The aim of the study was to investigate the patterns of surgery and radiotherapy treatment for head and neck cancers in three large areas of England and to investiga...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6690695
更新日期:1999-09-01 00:00:00
abstract::The tissue-specific translation elongation factor eEF1A2 is a potential oncogene that is overexpressed in human ovarian cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-alpha) making analysis with commercial antibodies difficult. We wanted to establish the express...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603748
更新日期:2007-05-21 00:00:00
abstract::The in vitro metabolisms of [14C]7,12-dimethylbenz(a)anthracene (DMBA) by post-mitochondrial supernates and microsomes from intact and regenerating rat livers were compared. Both cell fractions from regenerating livers at 48, 72, and 96 h after partial hepatectomy metabolized less [14C]DMBA than similar fractions from...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1977.112
更新日期:1977-06-01 00:00:00