Abstract:
:An increase in the number of identified therapeutic cancer targets achieved through recent biomedical research has resulted in the generation of a large number of molecules that need to be tested further. Current development of (anticancer) drugs is a rather inefficient process that for an average new molecule takes around 10-15 years. It is also a challenging process as it is associated with high costs and a low rate of approval. It is known that less than 10% of new molecular entities entering clinical Phase I testing progress beyond the investigational programme and reach the market; this probability is even lower for anticancer agents. In 2003, the US Food and Drug Administration (US FDA) declared the urgent need for new toolkits to improve the critical development path that leads from scientific discovery to the patient. In this scenario, Phase 0 (zero) trials should allow an early evaluation in humans of pharmacokinetic and pharmacodynamic profiles of test compounds through administration of sub-pharmacological doses and for a short time period to a low number of humans. Typically, Phase 0 studies have no therapeutic or diagnostic intent. Owing to the low doses administered and the low risk of toxicity, shorter preclinical packages to support these studies are required. Phase 0 trials have been proposed to help in making an early selection of promising candidates for further evaluation in Phase I-III trials, providing a potentially useful instrument for drug discovery, particularly in the field of oncology. Phase 0 studies are expected to reduce costs of drug development, and to limit the preclinical in vitro and in vivo testing and the time period of drug development. However, there are also concerns about the utility and feasibility of Phase 0 studies. In January 2006, guidelines on exploratory investigational new drug studies in humans have been published by the US FDA, and currently a Phase 0 programme is ongoing at the National Cancer Institute to evaluate the impact (feasibility and utility) of Phase 0 studies on drug development. In Europe, a Position Paper produced by the Evaluation of Medicinal Products (EMEA) in 2004 raised the possibility of a reduced preclinical safety package to support early microdose clinical studies, and, as announced by a recent Concept Paper on medicinal products published by the committee for medicinal products for human use of the EMEA, EMEA's guidelines on Phase 0 studies are expected shortly. The true impact of Phase 0 studies on the drug development process as well as on the safety needs to be carefully explored.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Marchetti S,Schellens JHdoi
10.1038/sj.bjc.6603925subject
Has Abstractpub_date
2007-09-03 00:00:00pages
577-81issue
5eissn
0007-0920issn
1532-1827pii
6603925journal_volume
97pub_type
杂志文章,评审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. ME...
journal_title:British journal of cancer
pub_type: 杂志文章,多中心研究
doi:10.1038/s41416-018-0082-1
更新日期:2018-05-01 00:00:00
abstract::Hypomethylation has been reported to be responsible for the activation of several oncogenes. The possibility that hypomethylation is involved in the regulation of MET transcription was investigated through the analysis of the methylation status of one CpG island containing 43 CpGs in six cases of papillary carcinoma, ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6601988
更新日期:2004-08-16 00:00:00
abstract:BACKGROUND:The purpose of this study was to identify prostate cancer (PC) oncogenic microRNAs (miRs) based on miR microarray and to investigate whether these oncogenic miRs may be useful as PC biomarkers. METHODS:Initially, we carried out miR microarray and real-time PCR using RWPE-1, PC-3, DU-145 and LNCaP cells. To ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.125
更新日期:2013-04-30 00:00:00
abstract::The lability of cell surface histocompatibility antigens of 2 murine lymphomata was examined. These 2 tumours differ greatly in their capacity to metastasize in syngeneic hosts. Cells of the metastatic lymphoma released histocompatibility antigens in vivo and in vitro at a greater rate than cells of the non-metastasiz...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1976.2
更新日期:1976-01-01 00:00:00
abstract::A brief review is presented of the evidence linking the development of certain types of neoplasms, and of the malignant lymphomas in particular, to chronic immunosuppression in animals and man and to the naturally occurring human immunologic deficiency states. The discussion then focuses on Hodgkin's disease and consi...
journal_title:British journal of cancer
pub_type: 杂志文章,评审
doi:10.1038/bjc.1971.78
更新日期:1971-12-01 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::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::We assessed incidence and mortality of colorectal cancer (CRC) at various ages among women and men in 38 European countries. The ages at which defined levels of incidence and mortality were reached varied between 9 and 17 years between countries. This variation requires consideration in the definition of screening gui...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6604488
更新日期:2008-08-05 00:00:00
abstract::A regional cancer network has been set up in the Rhône-Alpes region in France. The aim of the project is to improve the quality of care and to rationalize prescriptions in the network. In this network, we assessed the impact of the implementation of a clinical practice guidelines project by assessing the conformity of...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6600057
更新日期:2002-02-01 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::Identification of a biomarker of prognosis and response to therapy that can be assessed preoperatively would significantly improve overall outcomes for patients with pancreatic cancer. In this study, patients whose tumours exhibited high LMO4 expression had a significant survival advantage following operative resectio...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6604177
更新日期:2008-02-12 00:00:00
abstract::Experimental studies indicated that long-chain polyunsaturated fatty acids may increase sensitivity of mammary tumours to several cytotoxic drugs. To evaluate this hypothesis in breast cancer, we have prospectively studied the association between levels of fatty acids stored in breast adipose tissue and the response o...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6690281
更新日期:1999-04-01 00:00:00
abstract::Teratomas have been induced in Japanese quail (Coturnix coturnix Japonica) by intra-testicular injections of 3% zinc chloride solution during a period of testicular growth artificially stimulated by increased photoperiod. These tumours resemble those previously induced by similar methods in domestic fow1 and have hist...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1971.40
更新日期:1971-06-01 00:00:00
abstract::Collagen breakdown, and thus bone resorption, can now be assessed by measuring the urinary excretion of the collagen crosslinks, pyridinoline (Pyd) and deoxypyridinoline (Dpd). In a pilot study we measured Pyd and Dpd in 20 patients with breast cancer, ten with known bone metastases and ten with no recognised metastas...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1991.419
更新日期:1991-11-01 00:00:00
abstract::The reactivation of U.V.-irradiated adenovirus 2 in HeLa cells is enhanced 8-9 fold if the cells are given a brief hyperthermic shock before infection. Maximum reactivation is achieved by heating for 10 min at 45.5 degrees C and with a delay of 36 h between heating and infection. The induction process requires protein...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1984.32
更新日期:1984-02-01 00:00:00
abstract::Fifty-two previously untreated patients with advanced non-small-cell lung cancer (NSCLC) were treated on a 14 day cycle with cisplatin (60 mg m-2 i.v.) and vindesine (3 mg m-2 i.v.) on day 1, followed by a 3 day continuous infusion of 5-fluorouracil (800 mg m-2 day-1) starting on day 8. An overall response rate of 40....
journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
doi:10.1038/bjc.1996.211
更新日期:1996-05-01 00:00:00
abstract::In a previous study we found that aromatic amines, particularly 4-aminobiphenyl, formed haemoglobin adducts at higher concentrations in the blood of smokers compared to non-smokers. We re-analyse here data on haemoglobin adducts of 14 aromatic amines in order to ascertain if the inter-individual variability left unexp...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1990.120
更新日期:1990-04-01 00:00:00
abstract::Administration of 5-aminolaevulinic acid (ALA) leads to porphyrin accumulation in malignant and premalignant tissues, and ALA is used as a prodrug in photodynamic therapy (PDT). To understand the mechanism of porphyrin accumulation after the administration of ALA and to investigate whether ALA-induced protoporphyrin I...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1998.559
更新日期:1998-09-01 00:00:00
abstract::The genetic basis for the majority of early onset or non-syndromic "familial" colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regi...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1054/bjoc.2001.1959
更新日期:2001-08-17 00:00:00
abstract::The survival of 64 consecutive patients with disseminated midgut carcinoid tumours was compared in a retrospective study with that of 25 consecutive patients with sporadic malignant endocrine pancreatic tumours treated according to similar surgical principles. The presence of hepatic metastases implied a worse prognos...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6690494
更新日期:1999-06-01 00:00:00
abstract::The largest single underlying cause of hepatocellular carcinoma (HCC) worldwide is hepatitis B virus (HBV) infection. Hepatitis B virus increases cellular oxidative stress and the development of HCC occurs after a long latency period. The study was carried out to determine whether mitochondrial DNA abnormalities were ...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6602496
更新日期:2005-04-11 00:00:00
abstract::The murine dose of i.v. C. parvum (466 microgram) was compared with a single, low, human-equivalent dose of 70 microgram and with repeated weekly low doses. All treatments increased the antibody titre against C. parvum (CP). However, repeated doses stimulated a much higher titre than single doses. In all treated anima...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1980.64
更新日期:1980-03-01 00:00:00
abstract::The micronucleus (MN) test has been carefully characterized in four human tumour cell lines of widely differing radiosensitivity. Two radioresistant bladder carcinoma cell lines (MGH-U1 and RT112), one sensitive medulloblastoma cell line (D283MED) and a sensitive neuroblastoma cell line (HX142) were used. The number o...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1993.17
更新日期:1993-01-01 00:00:00
abstract:BACKGROUND:The distinct expression pattern of tumour-associated antigens (TAAs) might be a critical reason for the inefficacy of immunity-based treatments and heterogeneous postsurgical recovery in patients with solid tumours, including hepatocellular carcinoma (HCC). However, little is known about the clinical value o...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.2013.390
更新日期:2013-08-20 00:00:00
abstract:BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) has poor survival and treatment options. PDAC cells shift their metabolism towards glycolysis, which fuels the plasma membrane calcium pump (PMCA), thereby preventing Ca2+-dependent cell death. The ATP-generating pyruvate kinase-M2 (PKM2) is oncogenic and overexpressed...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/s41416-019-0675-3
更新日期:2020-01-01 00:00:00
abstract::Meningiomas are common, mostly benign, tumours arising from leptomeningeal cells of the meninges, which frequently contain mutations in the neurofibromatosis type 2 (NF2) gene. In this study, we analysed a protein product of the neurofibromatosis type 1 (NF1) gene, neurofibromin, in human established leptomeningeal ce...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1997.456
更新日期:1997-01-01 00:00:00
abstract::Since hyperinsulinaemia may promote obesity-linked cancers, we compared type 2 diabetes prevalence among oesophageal adenocarcinoma (OAC) patients and population controls. Diabetes increased the risk of OAC (adjusted odds ratio 1.59, 95% confidence interval (CI) 1.04-2.43), although the risk was attenuated after furth...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6604908
更新日期:2009-03-10 00:00:00
abstract::Two subtypes of thrombospondin (TSP-1 and TSP-2) have inhibitory roles in angiogenesis in vitro, although the biological significance of these TSP isoforms has not been determined in vivo. We examined TSP-1 and TSP-2 gene expression by reverse transcription polymerase chain reaction (RT-PCR) analysis in 61 colon cance...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6690056
更新日期:1999-01-01 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::Some 1220 male and 2102 female cases of malignant neoplasms diagnosed histologically at the Department of Pathology of the Gadjah Mada University in Yogyakarta during the period 1970-73 were analysed. The most frequent tumour sites were among men: nasopharyngeal cancer, 21-8% and skin cancer, 17-6%. Among women the ge...
journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1977.164
更新日期:1977-07-01 00:00:00