Abstract：
BACKGROUND:Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. METHODS:Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. RESULTS:Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208. CONCLUSIONS:Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Cortes J,Tamura K,DeAngelo DJ,de Bono J,Lorente D,Minden M,Uy GL,Kantarjian H,Chen LS,Gandhi V,Godin R,Keating K,McEachern K,Vishwanathan K,Pease JE,Dean Edoi
10.1038/s41416-018-0082-1subject
Has Abstractpub_date
2018-05-01 00:00:00pages
1425-1433issue
11eissn
0007-0920issn
1532-1827pii
10.1038/s41416-018-0082-1journal_volume
118pub_type
杂志文章,多中心研究abstract：:Seventy-one patients suffering from acute myeloid leukaemia (AML) who were already in complete remission and had already received one further course of cytotoxic drugs as consolidation therapy were randomised to receive maintenance chemotherapy alone or the same maintenance chemotherapy plus immunotherapy with BCG and...
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/bjc.1978.1
更新日期：1978-01-01 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：:Nuclear polyploidization in the livers of CF-1 mice, exposed to dieldrin (0, 1, 5 and 10 ppm in the diet), was studied up to the median time of liver tumour development (ranging from 15 to 27 months) in the respective treatment groups. In untreated controls nuclear polyploidization is characterized by a linear increas...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1988.160
更新日期：1988-07-01 00:00:00
abstract：:Despite expressing both Fas and Fas ligand, DU145 and LNCaP prostate cancer cells were resistant to anti-Fas-induced cell death. Resistance to Fas-mediated cytotoxicity could be overcome in DU145, but not in LNCaP, cells by pretreating cells with sublethal doses of cytotoxic drugs, such as camptothecin. Activated casp...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6690365
更新日期：1999-05-01 00:00:00
abstract：:Chromosome 9p21 gene copy number in Ewing's sarcoma family of tumour (ESFT) cell lines and primary ESFT has been evaluated using Multiplex Ligation-dependent probe amplification, and the clinical significance of CDKN2A loss and p16/p14(ARF) expression investigated. Homozygous deletion of CDKN2A was identified in 4/9 (...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6603819
更新日期：2007-06-18 00:00:00
abstract：:Virus-directed enzyme prodrug therapy (VDEPT) utilising the bacterial enzyme nitroreductase delivered by a replication-defective adenovirus vector to activate the prodrug CB1954 is a promising strategy currently undergoing clinical trials in patients with a range of cancers. An understanding of the mechanism of tumour...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6601211
更新日期：2003-09-01 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：:Women referred to a familial breast cancer clinic completed questionnaires before and after counselling and at annual follow-up to assess their risk estimate and psychological characteristics. The aims were to determine whether those who attended the clinic overestimated their risk or were highly anxious and whether c...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6690078
更新日期：1999-02-01 00:00:00
abstract：:Covalent modifications of histones, such as acetylation, methylation, and phosphorylation, and other epigenetic modulations of the chromatin, such as methylation of DNA and ATP-dependent chromatin reorganisation, can play a major part in the multistep process of carcinogenesis, with far-reaching implications for human...
journal_title：British journal of cancer
pub_type： 杂志文章,评审
doi：10.1038/sj.bjc.6601575
更新日期：2004-02-23 00:00:00
abstract：:We carried out a comparison of three commonly used mucin markers, CA549, CA15.3 and MCA. Serum samples from 184 healthy women and 237 patients with primary breast cancer were evaluated. The markers were measured using commercially available immunometric assays. Like CA15.3 and MCA, CA549 was significantly associated w...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1994.136
更新日期：1994-04-01 00:00:00
abstract：:Over the period 1966-1995, based on 11,662 patients, the incidence of squamous cell carcinoma of the skin increased three to four times in Norway mainly as a result of an increased number of localized tumours. In men, cancer of the auricle was the second most common site; in women the incidence was low. ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6690725
更新日期：1999-10-01 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：:Capecitabine and docetaxel have considerable single-agent activity in gastric cancer with distinct mechanisms of action and no overlap of key toxicities. A synergistic interaction between these two drugs is mediated by taxane-induced upregulation of thymidine phosphorylase. We investigated the activity and the feasibi...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/sj.bjc.6601724
更新日期：2004-04-05 00:00:00
abstract：:Recent evidence has demonstrated that endothelial-to-mesenchymal transition (EndMT) may have a significant role in a number of diseases. Although EndMT has been previously studied as a critical process in heart development, it is now clear that EndMT can also occur postnatally in various pathologic settings, including...
journal_title：British journal of cancer
pub_type： 杂志文章,评审
doi：10.1038/sj.bjc.6604662
更新日期：2008-11-04 00:00:00
abstract：BACKGROUND:Appreciating variation in the length of pre- or post-presentation diagnostic intervals can help prioritise early diagnosis interventions with either a community or a primary care focus. METHODS:We analysed data from the first English National Audit of Cancer Diagnosis in Primary Care on 10 953 patients with...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2015.40
更新日期：2015-03-31 00:00:00
abstract：:Histochemical studies on the cell surface and intercellular matrix of normal cervical epithelium, and squamous cell carcinomata have shown the mucosubstances present may be symbolized by the descriptive formula:C(G) mucosubstance; B 3.5; A 2.5 (0.6m MgCl(2)); T; S.This indicates that sulphate groups are absent and tha...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1970.88
更新日期：1970-12-01 00:00:00
abstract：:Alternative splicing of survivin mRNA gives rise to multiple isoforms, that is, survivin and 3 splice variants, survivin-2B, survivin-3B and survivin-DeltaEx3. The aim of this study was to compare the expression of survivin, survivin-2B and survivin-DeltaEx3 in normal breast tissue, fibroadenomas, primary breast cance...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6602314
更新日期：2005-01-17 00:00:00
abstract：:On the basis of preclinical data suggesting the possibility of maximising the efficacy of 5-fluorouracil and cisplatin by interferon, a pilot clinical trial was initiated in recurrent and/or metastatic head and neck cancer. Thirty-four patients were treated with cisplatin at 100 mg m-2, followed by 5-fluorouracil at 1...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/bjc.1994.72
更新日期：1994-02-01 00:00:00
abstract：:To evaluate whether green tea consumption provides protection against stomach cancer death, relative risks were calculated using Cox proportional hazards regression analysis in the Japan Collaborative Study for Evaluation of Cancer Risk, sponsored by the Ministry of Health and Welfare (JACC Study). The study was based...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6600487
更新日期：2002-07-29 00:00:00
abstract：:The GER human pancreatic carcinoma cell line possesses receptors for 1,25-dihydroxyvitamin D3. We report that the vitamin D analogue EB 1089 inhibits the growth of these cells in vitro and when grown as tumour xenografts in immunodeficient mice. Tumour-bearing mice were given EB 1089 at a dose of 5 microg kg(-1) body ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1997.501
更新日期：1997-01-01 00:00:00
abstract：:This study evaluates the overall survival and disease free survival of melanoma patients that were treated with an autologous melanoma cell vaccine, administered as a post-operative adjuvant. Included are 43 patients with totally resected metastatic melanoma (28-AJCC stage III, 15-AJCC stage IV), with a median follow ...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/sj.bjc.6600251
更新日期：2002-05-20 00:00:00
abstract：:Thirty-four patients with progressive low grade non-Hodgkin's lymphoma were treated with 1 microgram oral alfacalcidol daily. Complete response was seen in four patients and a partial response in four patients with an overall response rate of 24%. Median duration of response was 14 months. Disease stabilised in ten ot...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1991.108
更新日期：1991-03-01 00:00:00
abstract：:Microsatellite instability is present in over 80% of the hereditary non-polyposis colorectal carcinoma and about 15-20% of the sporadic cancer. Microsatellite instability is caused by the inactivation of the mismatch repair genes, such as primarily hMLH1, hMSH2. To study the mechanisms of the inactivation of mismatch ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6600148
更新日期：2002-02-12 00:00:00
abstract：BACKGROUND:Chemerin, a known chemoattractant, participates in multiple biological events. However, its role in cancer remains largely unknown. METHODS:Chemerin expression was evaluated by real-time PCR, western blot and immunohistochemistry. Forced expression, RNAi, immunoprecipitation, etc. were used in function and ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/s41416-018-0077-y
更新日期：2018-05-01 00:00:00
abstract：BACKGROUND:The human epidermal growth factor receptor (EGFR) is an important therapeutic target in oncology, and three different types of EGFR inhibitors have been approved for the treatment of cancer patients. However, there has been no clear association between the expression levels of EGFR protein in the tumours det...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2012.27
更新日期：2012-02-28 00:00:00
abstract：:The haemodynamics of the uterine arteries and myometrium were assessed using Doppler ultrasound in forty consecutive patients requiring treatment for invasive mole and choriocarcinoma. The investigations were performed prior to the commencement of chemotherapy and the subjects followed prospectively. The Doppler wavef...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1992.379
更新日期：1992-11-01 00:00:00
abstract：:In the early period following radical hepatectomy for hepatoma, recurrences in the remaining liver are frequently found. In regenerating liver, implantation and growth of tumour cells released into the portal system during surgical treatment might be promoted. We examined the relationship between liver regeneration an...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1992.170
更新日期：1992-06-01 00:00:00
abstract：:Associations between work in the electrical and electronic industry and cancer incidence were assessed using data for 371 890 cancers registered in England between 1981 and 1987, of which 7981 were in electrical workers. Proportional registration ratios (PRRs) were calculated, both with and without the commonest cance...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.167
更新日期：1996-04-01 00:00:00
abstract：:We identified 2384 patients in the Danish Cancer Register in whom cancer had been diagnosed in 1960-1996 before they reached the age of 20 and compared them with 53 143 sex- and age-matched controls identified from the Register of Population Statistics. Complete education records and demographic and socioeconomic info...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6602085
更新日期：2004-08-31 00:00:00
abstract：:The carcinogenicity of the vegetative tissues of bracken fern (Pteridium) has long been established. More recently, the carcinogenic effects of the spores of bracken have also been recognized. Both vegetative tissues and spores of bracken can induce adducts in DNA in animal tissues, but the possible genotoxic or carci...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1054/bjoc.2000.1204
更新日期：2000-07-01 00:00:00
