Abstract:
:A novel sterically hindered platinum complex, AMD473 [cis-aminedichloro(2-methylpyridine) platinum (II)], has been selected for phase I clinical trials due to commence in 1997. AMD473 was rationally designed to react preferentially with nucleic acids over sulphur ligands such as glutathione. This report documents the in vitro circumvention of acquired cisplatin resistance mechanisms in human ovarian carcinoma (HOC) cell lines by AMD473. In a panel of 11 HOC cell lines, AMD473 showed intermediate growth inhibition potency (mean IC50 of 8.1 microM) in comparison to cisplatin (mean IC50 of 2.6 microM) and carboplatin (mean IC50 of 20.3 microM). AMD473 showed only a 30.7-fold increase in IC50 value from the most sensitive to the most resistant HOC cell line, whereas for cisplatin it was 117.9-fold and for carboplatin 119.7-fold. AMD473 also showed significantly (P < 0.05) reduced cross-resistance to cisplatin in a panel of three cell lines with known acquired platinum drug resistance mechanisms (mean RF for AMD473 was 1.9, for cisplatin 9.1). Cellular accumulation of AMD473 was not reduced in two HOC cell lines (A2780cisR and 41McisR), in which reduced cisplatin accumulation is a major mechanism of acquired cisplatin resistance. AMD473 naked-DNA binding was significantly less affected (P < 0.05) than that of cisplatin by the presence of 5 mM glutathione. Also, AMD473 almost completely circumvented acquired cisplatin resistance in a cell line (A2780cisR) with fivefold elevated intracellular glutathione levels compared with the parent A2780 cell line when measured by clonogenic assay (RF 4.5 for AMD473 vs RF 18 for cisplatin). AMD473 also showed a lower increase in IC50 than cisplatin in an A2780 cell line model with artificially elevated glutathione levels. AMD473 DNA binding was slower than that of cisplatin on both naked and cellular DNA. AMD473 also formed DNA interstrand cross-links (ICLs) at a slower rate than cisplatin (peak ICL formation was at 5 h for cisplatin vs > or = 14 h for AMD473) after equitoxic doses were exposed to HOC cells for 2 h. AMD473 ICLs in the CH1 HOC cell line were slowly formed and showed no visible signs of being repaired 24 h after removal of drug. This was paralleled by a slower, longer lasting induction of p53 protein by equitoxic doses of AMD473 in HOC cell lines with wild-type p53. This new class of sterically hindered platinum compound, selected for clinical trial in 1997, may therefore elicit improved clinical response in intrinsically and acquired cisplatin-resistant tumours in the clinic.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Holford J,Sharp SY,Murrer BA,Abrams M,Kelland LRdoi
10.1038/bjc.1998.59subject
Has Abstractpub_date
1998-01-01 00:00:00pages
366-73issue
3eissn
0007-0920issn
1532-1827journal_volume
77pub_type
杂志文章abstract::NAD(P)H:quinone oxidoreductase (NQO1, EC 1.6.99.2) is an obligate two-electron reductase that can either bioactivate or detoxify quinones and has been proposed to play an important role in chemoprevention. We have previously characterized a homozygous point mutation in the BE human colon carcinoma cell line that leads...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1997.11
更新日期:1997-01-01 00:00:00
abstract::A study is presented of all cases of primary sarcoma of bone registered during the period 1946 to 1974 for a specified population resident in south-western England. Ninety-six per cent of the 365 cases were histologically and radiologically verified and are separated into 8 categories of sarcoma. The number of tumours...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1977.221
更新日期:1977-10-01 00:00:00
abstract::The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College (London, UK) on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion ...
journal_title:British journal of cancer
pub_type: 杂志文章,评审
doi:10.1038/bjc.1998.300
更新日期:1998-06-01 00:00:00
abstract:BACKGROUND:Hypoxia can activate autophagy, a self-digest adaptive process that maintains cell turnover. Mammalian target of rapamycin (mTOR) inhibitors are used to treat cancer but also stimulate autophagy. METHODS:Human mammary cancer cells and derived xenografts were used to examine whether hypoxia could exacerbate ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.644
更新日期:2013-11-12 00:00:00
abstract::The aim of this study was to investigate the expression of the protein tyrosine phosphatases (PTP) PRL-1, PRL-2, and PRL-3 in human breast cancer and to evaluate its clinical and prognostic significance. PRL-PTP mRNA expression was examined in malignant (n = 7) and nonmalignant (n = 7) cryoconserved breast tissue samp...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603261
更新日期:2006-08-07 00:00:00
abstract::Eleven patients with measurable subcutaneous or pulmonary metastases were selected for a study of the effectiveness of the radiosensitizer misonidazole (MIS). Evaluable data were obtained in 6 patients and radiosensitization demonstrated in 5. Patients were irradiated either before or after MIS, and each patient acted...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1979.281
更新日期:1979-12-01 00:00:00
abstract::The effects of local tumour radiation over the dose range 7.5-30 Gy on the growth and cell kinetics of rat hepatoma H-4-II-E have been investigated. A plot of growth delays against log surviving fraction was linear below a fraction of 0.03, but failed to extrapolate to the origin. Following a single dose of 15 Gy to t...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1980.283
更新日期:1980-10-01 00:00:00
abstract::DT-diaphorase (DTD) is an important enzyme for the bioreductive activation of the new alkylating indoloquinone EO9. In preclinical studies, EO9 has shown selective anti-tumour activity against solid tumours and under hypoxic conditions. The levels of three reductive enzymes have been determined in three types of human...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1995.433
更新日期:1995-10-01 00:00:00
abstract::Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min i.v. infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1-5) at one of nine dose levels: 24, 48, ...
journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
doi:10.1038/sj.bjc.6690232
更新日期:1999-03-01 00:00:00
abstract::The survival and clonogenic growth (measured in terms of colony forming efficiency (CFE) of intravenously injected (i.v.) Walker (W256) tumour cells in the lungs of rats was greatly enhanced by states of topical and systemic stress induced by the intraperitoneal (i.p.) injection of rats with a single dose of 10(-5)-10...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1976.7
更新日期:1976-01-01 00:00:00
abstract:BACKGROUND:The role of processed meat in the aetiology of several cancers was explored in detail. METHODS:In the time period 1996-2004, a multisite case-control study was conducted in Montevideo, Uruguay. The study included 6 060 participants (3 528 cases and 2 532 controls) corresponding to cancers of the oral cavity...
journal_title:British journal of cancer
pub_type: 杂志文章,多中心研究
doi:10.1038/bjc.2012.433
更新日期:2012-10-23 00:00:00
abstract:BACKGROUND:Activating mutations of Fms-like tyrosine kinase 3 (FLT3) constitute a major driver in the pathogenesis of acute myeloid leukaemia (AML). Hence, pharmacological inhibitors of FLT3 are of therapeutic interest for AML. METHODS:The effects of inhibition of FLT3 activity by a novel potent FLT3 inhibitor, BPR1J-...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2011.564
更新日期:2012-01-31 00:00:00
abstract:BACKGROUND:The Mediterranean diet has been shown to have a beneficial role on various neoplasms, but data are scanty on pancreatic cancer. METHODS:We analysed data from two case-control studies conducted in Italy between 1983 and 2008, including 362 and 326 pancreatic cancer cases and 1552 and 652 hospital-controls, r...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.345
更新日期:2013-09-03 00:00:00
abstract:BACKGROUND:Twenty to 40% localised RCC patients may experience recurrence after curative surgery. Limited miRNA predictors have been identified for ccRCC recurrence. METHODS:Through a multi-phase study design, we analysed miRNAs in tissues obtained from 203 ccRCC patients. Paired t-test was used for tumour-normal comp...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2016.392
更新日期:2017-01-03 00:00:00
abstract::ERBB2 is frequently amplified in breast tumours as part of a wide region of amplification on chromosome 17q21. This amplicon contains many candidate genes for breast cancer susceptibility. We used a genetic association study design to determine if common genetic variation (frequency>or=5%) in a 400-kb region surroundi...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603473
更新日期:2006-12-18 00:00:00
abstract::In a case-control study using a large UK primary care database, we found that non-steroidal anti-inflammatory drugs had no protective effect against biliary carcinomas (cholangiocarcinoma and gall bladder cancer). Increased risks were observed for cigarette smoking, diabetes, gallstone disease and obesity. ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6604765
更新日期:2009-01-13 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::Hepatic arterial floxuridine (HAI) in 35 patients with systemic fluorouracil/folinic acid-resistant colorectal liver metastases achieved a 14% partial response and 26% disease stabilization rate, with a median response duration of 7 months from onset of HAI. ...
journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
doi:10.1038/bjc.1998.627
更新日期:1998-10-01 00:00:00
abstract::5-fluorouracil (5FU) is activated intracellularly to cytotoxic 5-fluoronucleotides (FNuct). These were detected non-invasively in rats bearing the Walker carcinosarcoma by 19F-magnetic resonance spectroscopy (MRS) following an i.v. bolus dose of 5FU (50 mg kg-1). Pre-treatment of the rats (3 to 24 h earlier) by methot...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1992.75
更新日期:1992-03-01 00:00:00
abstract::The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G(2) assay was used to measure chromosomal radiosensitivity. The results d...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6604345
更新日期:2008-05-20 00:00:00
abstract::The aim of this study was to find a procedure allowing estimation of individual pharmacokinetic parameters for adriamycin with minimal cost and disturbance for the patient. Twenty-five patients with breast cancer were treated by short infusion of adriamycin at a dose of 12 mg m-2 week-1 (41 courses). Population charac...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1989.226
更新日期:1989-07-01 00:00:00
abstract::Altered expression and activity of proteases is a key event in cancer, particularly in relation to invasion, modification of the extracellular matrix and metastasis. The transmembrane protease, serine 4 (TMPRSS4) is closely related to other cancer-associated proteases, such as hepsin, TMPRSS2 and matriptase. We review...
journal_title:British journal of cancer
pub_type: 杂志文章,评审
doi:10.1038/bjc.2014.403
更新日期:2015-01-06 00:00:00
abstract::Extramammary Paget's disease is a particular form of skin cancer of unknown histogenesis. To look for the genetic defects underlying the pathogenesis of this tumour, we have examined loss of heterozygosity (LOH), p53 and human papillomavirus (HPV) status, and the expression of c-erbB-2 and bcl-2 proteins in 14 cases. ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1997.482
更新日期:1997-01-01 00:00:00
abstract::To evaluate the toxicity, pharmacological and biological properties of ATN-161, a five -amino-acid peptide derived from the synergy region of fibronectin, adult patients with advanced solid tumours were enrolled in eight sequential dose cohorts (0.1-16 mg kg(-1)), receiving ATN-161 administered as a 10-min infusion th...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6603171
更新日期:2006-06-05 00:00:00
abstract::The association between body height and the incidence rate of breast cancer has been examined in 236 cases of breast cancer that occurred among 23,831 Norwegian women during 11-14 years of follow-up. At the time of height measurement they were 35-51 years of age. The age-adjusted incidence rate ratio (IRR) of breast c...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1990.197
更新日期:1990-06-01 00:00:00
abstract::Thirty-eight patients with previously treated Hodgkin's disease were given high dose combination chemotherapy using melphalan and BCNU and autologous bone marrow transplantation. In 25 patients etoposide was added in conventional dosage. During the course of the study the dose of melphalan was increased from 80 to 140...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1989.128
更新日期:1989-04-01 00:00:00
abstract::The S-phase fraction (SPF) in flow cytometric DNA histograms in soft tissue sarcoma (STS) can be calculated in various ways. The traditional planimetric method of Baisch has been shown to be prognostic, but is hampered by a failure rate of around 40%. We therefore tested other models to see if this rate could be decre...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6690193
更新日期:1999-03-01 00:00:00
abstract::Loss of the short arm of chromosome 1 is a hallmark of oligodendroglial tumours (OTs). Deletion mapping studies in OTs have revealed multiple commonly deleted regions on chromosome 1p, suggesting that there are more than one tumour suppressor gene. To map critical deletion regions on 1p, a series of 25 OTs were examin...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6602093
更新日期:2004-09-13 00:00:00
abstract::The purpose of the study is to test the hypothesis that expression of cell cycle regulatory proteins p16(INK4a) and pRb is significantly associated with prognosis in ovarian carcinomas. We performed immunohistochemical analysis of p16(INK4a) and pRb expression and correlated with survival in a series of 300 patients w...
journal_title:British journal of cancer
pub_type: 杂志文章,随机对照试验
doi:10.1038/sj.bjc.6603531
更新日期:2007-01-29 00:00:00
abstract:BACKGROUND:First Spanish trial of Ewing sarcoma (ES) including adults and children with the aim to test the efficacy of Gemcitabine and Docetaxel (G/D) in newly diagnosed high-risk (HR) patients. METHODS:This was a prospective, multicentric, non-randomised, open study for patients ⩽40 years with newly diagnosed ES. HR...
journal_title:British journal of cancer
pub_type: 杂志文章,多中心研究
doi:10.1038/bjc.2017.252
更新日期:2017-09-05 00:00:00