I J Stratford

The University of Manchester, Manchester, England, United Kingdom

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Publications (231)831.78 Total impact

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    E J Searle, T M Illidge, I J Stratford
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    ABSTRACT: Recent drug discovery developments in the field of small molecule targeted agents have led to much interest in combining these with radiotherapy. There are good preclinical data to suggest this approach worthy of investigation and in this review we discuss how this has translated into recent clinical trials. The outcome of clinical trials investigating radiotherapy/targeted drug combinations published in the last 5 years is discussed, as are trials in progress. The perceived future opportunities and challenges in the development of this exciting area are considered.
    Clinical Oncology 03/2014; · 2.86 Impact Factor
  • E.J. Searle, T.M. Illidge, I.J. Stratford
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    ABSTRACT: Recent drug discovery developments in the field of small molecule targeted agents have led to much interest in combining these with radiotherapy. There are good preclinical data to suggest this approach worthy of investigation and in this review we discuss how this has translated into recent clinical trials. The outcome of clinical trials investigating radiotherapy/targeted drug combinations published in the last 5 years is discussed, as are trials in progress. The perceived future opportunities and challenges in the development of this exciting area are considered.
    Clinical Oncology. 01/2014;
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    ABSTRACT: Normal cells produce energy either through OXPHOS in the presence of oxygen or glycolysis in its absence. Cancer cells produce energy preferably through glycolysis even in the presence of oxygen, thereby, acquiring survival and proliferative advantages. Oncogenes and tumour suppressors control these metabolic pathways by regulating the expression of their target genes involved in these processes. During hypoxia, HIF-1 favours high glycolytic flux by upregulating glycolytic enzymes. Conversely, p53 inhibits glycolysis and increases OXPHOS expression through TIGAR and SCO2 gene expression, respectively. We hypothesise that the p300/CBP-associated factor (PCAF) as a common co-factor shared between p53 and HIF-1 plays an important role in the regulation of energy production by modulating SCO2 and TIGAR gene expression mediated by these two transcription factors. The possible involvement of HIF-1 in the regulation of SCO2 and TIGAR gene expression was investigated in cells with different p53 status in normoxia- and hypoxia-mimicking conditions. Putative hypoxia response elements (HREs) were identified in the regulatory region of SCO2 and TIGAR gene promoters. Chromatin immunoprecipitation experiments suggested that HIF-1 was recruited to the putative HREs present in the SCO2 and TIGAR promoters in a cell type-dependent manner. Transcriptional assays endorsed the notion that PCAF may be involved in the determination of the SCO2 and TIGAR cellular levels, thereby, regulating cellular energy metabolism, a view supported by assays measuring lactic acid production and oxygen consumption in cells ectopically expressing PCAF. The present study identified HIF-1 as a potential regulator of SCO2 and TIGAR gene expression. Furthermore, evidence to suggest that PCAF is involved in the regulation of cellular energy production pathways in hypoxia-mimicking conditions is presented. This effect of PCAF is exerted by orchestrating differential recruitment of HIF-1α and p53 to the promoter of TIGAR and/or SCO2 genes, thereby, tailoring physiological needs and environmental conditions to SCO2 and TIGAR gene expression.
    International Journal of Oncology 04/2013; · 2.66 Impact Factor
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    ABSTRACT: Passive immunotherapy with monoclonal antibodies has improved outcome for patients with B cell malignancies although many still relapse and little progress has been made with T cell malignancies. Novel treatment approaches are clearly required in this disease setting. There has been much recent interest in developing therapeutic approaches to enhance anti-tumor immune responses by using novel immunomodulatory agents in combination with "standard" of care treatments. Here, we report that intravenous administration of the TOLL-like receptor (TLR)-7 agonist, R848 in combination with radiation therapy (RT) leads to the long standing clearance of tumor in T and B cell lymphoma bearing mice. In combination, TLR7 / RT therapy leads to the expansion of tumor antigen-specific CD8(+) T cells and improved survival. Furthermore those mice that achieve long-term clearance of tumor following TLR7 / RT therapy are protected from subsequent tumor rechallenge by the generation of a tumor-specific memory immune response. Our findings demonstrate the potential for enhancing the efficacy of conventional cytotoxic anti-cancer therapy through combination with a systemically administered TLR7 agonist to improve anti-tumor immune responses and provide durable remissions.
    Blood 10/2012; · 9.78 Impact Factor
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    ABSTRACT: Radiosensitization efficiencies for seven different 2-nitroimidazoles including Ro-07-0582 and its urinary metabolite, Ro-05-9963, and two 5-nitroimidazoles including metronidazole, have been determined in hypoxic Chinese Hamster cells, line V79-379A, X-irradiated in vitro. All the compounds were active hypoxic cell sensitizers with the enhancement ratios increasing with drug concentration. The 2-nitroimidazoles were all more efficient than the 5-nitroimidazoles. Overall, the efficiencies, defined as the concentration required to give a particular enhancement ratio, varied by a factor of about 200. Electron-affinities of the sensitizers were determined by pulse radiolysis as the one-electron reduction potentials and these correlate well with the sensitization efficiencies of the compounds. The correlation extends beyond the nitroimidazole series as is shown by data for p-nitroacetophenone, nifuroxime (a nitrofuran) and oxygen itself. The nitroimidazoles varied by a factor of 70 in their octanol/water partition coefficients, but the effect of this parameter on sensitizing efficiency is small compared with the influence of electron affinity.
    Radiation Research 08/2012; 178(2):AV183-9. · 2.70 Impact Factor
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    British Journal of Cancer 07/2011; 105(5):628-639. · 5.08 Impact Factor
  • The Journal of Rheumatology 09/2010; 37(9):1968-9. · 3.26 Impact Factor
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    ABSTRACT: Metastases cause most cancer-related deaths. We investigated the use of hypoxia-selective cytotoxins as adjuvants to radiotherapy in the control of metastatic tumour growth. The NLCQ-1, RB6145 and tirapazamine were assessed against the spontaneously metastasising KHT model. Subcutaneous KHT tumours (250 mm(3)) were irradiated with 25 Gy (single fraction) to control primary growth. Equitoxic drug treatments (NLCQ-1 (10 mg kg(-1)) once daily; RB6145 (75 mg kg(-1)) and tirapazamine (13 mg kg(-1)) twice daily) were administered 3-6 days post-radiotherapy when hypoxic cells were evident in lung micrometastases. Mice were culled when 50% of controls exhibited detrimental signs of lung metastases. In total, 95% of control mice presented with lung disease. This was significantly reduced by NLCQ-1 (33%; P=0.0002) and RB6145 (60%; P=0.02). Semi-quantitative grading of lung disease revealed a significant improvement with all treatments, with NLCQ-1 proving most efficacious (median grades: control, 4; NLCQ, 0 (P<0.0001); RB6145, 1 (P<0.001), tirapazamine, 3 (P=0.007)). Positron emission tomography (PET) was evaluated as a non-invasive means of assessing metastatic development. Primary and metastatic KHT tumours showed robust uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG). Metastatic burden discernable by [(18)F]FDG PET correlated well with macroscopic and histological lung analysis. The hypoxia-selective cytotoxin NLCQ-1 controls metastatic disease and may be a successful adjuvant to radiotherapy in the clinical setting.
    British Journal of Cancer 07/2010; 103(2):201-8. · 5.08 Impact Factor
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    ABSTRACT: Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.Keywords: animal welfare; cancer research; fundamental and translational research; replacement, reduction and refinement (3Rs); pilot studies; tumour models; genetically engineered mouse models; human tumour xenografts; orthotopic models; metastatic models; therapy; imaging; pharmocokinetic, pharmacodynamic and efficacy studies; drugs; radiation therapy; imaging techniques; anaesthesia; restraint; humane endpoints; tumour burden; clinical signs; publication; best practice
    British Journal of Cancer 05/2010; 102(11):1555-1577. · 5.08 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 05/2010; 30(19).
  • Clinical Oncology 04/2010; 22(8):707-9. · 2.86 Impact Factor
  • K A Nolan, M P Humphries, R A Bryce, I J Stratford
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    ABSTRACT: The purpose of the work was to identify novel inhibitors of the enzyme NQO2. Using computational molecular modelling, a QSAR (R(2)=0.88) was established, relating inhibitory potency with calculated binding affinity. From this, the imidazoacridin-6-one, NSC660841, was identified as the most potent inhibitor of NQO2 yet reported (IC(50)=6 nM).
    Bioorganic & medicinal chemistry letters 03/2010; 20(9):2832-6. · 2.65 Impact Factor
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    ABSTRACT: The gastrointestinal tract microbiota (GTM) of mammals is a complex microbial consortium, the composition and activities of which influences mucosal development, immunity, nutrition and drug metabolism. It remains unclear whether the composition of the dominant GTM is conserved within animals of the same strain and whether stable GTMs are selected for by host-specific factors or dictated by environmental variables. The GTM composition of six highly inbred, genetically distinct strains of mouse (C3H, C57, GFEC, CD1, CBA nu/nu and SCID) was profiled using eubacterial -specific PCR-DGGE and quantitative PCR of feces. Animals exhibited strain-specific fecal eubacterial profiles that were highly stable (c. >95% concordance over 26 months for C57). Analyses of mice that had been relocated before and after maturity indicated marked, reproducible changes in fecal consortia and that occurred only in young animals. Implantation of a female BDF1 mouse with genetically distinct (C57 and Agoutie) embryos produced highly similar GTM profiles (c. 95% concordance) between mother and offspring, regardless of offspring strain, which was also reflected in urinary metabolite profiles. Marked institution-specific GTM profiles were apparent in C3H mice raised in two different research institutions. Strain-specific data were suggestive of genetic determination of the composition and activities of intestinal symbiotic consortia. However, relocation studies and uterine implantation demonstrated the dominance of environmental influences on the GTM. This was manifested in large variations between isogenic adult mice reared in different research institutions.
    PLoS ONE 01/2010; 5(1):e8584. · 3.53 Impact Factor
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    Breast Cancer Research 01/2010; · 5.33 Impact Factor
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    ABSTRACT: Small cell lung cancer (SCLC) is an aggressive tumor, associated with ectopic ACTH syndrome. We have shown that SCLC cells are glucocorticoid receptor (GR) deficient, and that restoration of GR expression confers glucocorticoid sensitivity and induces apoptosis in vitro. To determine the effects of GR expression in vivo, we characterized a mouse SCLC xenograft model that secretes ACTH precursor peptides, and so drives high circulating corticosterone concentrations (analogous to the ectopic ACTH syndrome). Infection of SCLC xenografts with GR-expressing adenovirus significantly slowed tumor growth compared with control virus infection. Time to fourfold initial tumor volume increased from a median of 9 days to 16 days (P=0.05; n=7 per group). Post-mortem analysis of GR-expressing tumors revealed a threefold increase in apoptotic (TUNEL positive) cells (P<0.01). Infection with the GR-expressing adenovirus caused a significant reduction in Bcl-2 and Bcl-xL transcripts. Furthermore, in both the GR-expressing adenovirus-infected cells and tumors, a significant number of uninfected cells underwent apoptosis, supporting a bystander cell killing effect. Therefore, GR expression is pro-apoptotic for human SCLCs in vivo, as well as in vitro, suggesting that loss of GR confers a survival advantage to SCLCs.
    Endocrine Related Cancer 12/2009; 17(1):203-13. · 5.26 Impact Factor
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    ABSTRACT: Hypoxia is as an indicator of poor treatment outcome. Consistently, hypoxic HCT116 colorectal cancer cells are resistant to oxaliplatin, although the mechanistic basis is unclear. This study sought to investigate the relative contribution of HIF-1 (hypoxia-inducible factor-1)-mediated gene expression and drug penetrance to oxaliplatin resistance using three-dimensional spheroids. Hypoxia-inducible factor-1alpha function was suppressed by the stable expression of a dominant-negative form in HCT116 cells (DN). Cells were drug exposed as monolayer or multicellular spheroid cultures. Cells residing at differing oxygenation status were isolated from Hoechst 33342-treated spheroids using flow cytometry. Sub-populations were subjected to clonogenic survival assays and to Inductively-Coupled Plasma Mass Spectroscopy to determine oxaliplatin uptake. In spheroids, a sensitivity gradient (hypoxic<aerobic) was revealed by survival assays and this correlated with levels of platinum-bound DNA. The resistance of hypoxic sub-populations exceeded relative changes in adduct levels, implicating factors other than drug penetrance in cell response. Dominant-negative monolayer cells showed no resistance to oxaliplatin in hypoxia and spheroids; the relative resistance of hypoxic compared with aerobic sub-populations was reduced compared with those from controls. Overall, data show that drug penetration, DNA damage levels and HIF-1-dependent processes, all contribute to the resistance of hypoxic cells to oxaliplatin.
    British Journal of Cancer 09/2009; 101(8):1290-7. · 5.08 Impact Factor
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    ABSTRACT: A number of pre-clinical studies have suggested that blocking vascular endothelial growth factor (VEGF) signalling can be beneficial in combination with radiotherapy. This study investigated the effects of cediranib, a highly potent orally available inhibitor of VEGF receptor tyrosine kinase activity in combination with radiation in Calu-6 lung xenografts. In nude mice, Calu-6 tumours were established and treatments initiated at a volume of 250 mm(3). Tumour-localized radiotherapy was given as three or five daily fractions of 2 Gy. Cediranib (3 mg kg(-1)) was administered 2 h prior to each fraction and continued post radiotherapy (concomitant regimen) or was initiated immediately after the completion of radiotherapy (sequential regimen). The endpoint was the time taken for tumour volume to quadruple (RTV4). Combined treatments resulted in a significantly enhanced growth delay compared with either modality alone. The therapeutic benefit was the same irrespective of the scheduling regimen. Tumour regression was observed post radiotherapy, which was associated with high levels of apoptosis and necrosis, and pronounced antivascular effects in histological samples. The amplified antivascular effect of cediranib when given after radiation suggests that pre-irradiated endothelium is sensitized to cediranib. Concomitant 5-day treatment with both cediranib and radiation reduced vessel density, perfusion and increased in tumour hypoxia. This was not associated with an acquired radioresistance suggesting that the maintenance of cediranib treatment post radiotherapy prevents the contribution of hypoxic cells to tumour regrowth. Collectively, these data support the contention that VEGFR inhibition can enhance radiation response in pre-clinical models and provide a rationale to develop cediranib in combination with radiotherapy in the clinical setting.
    The British journal of radiology 10/2008; 81 Spec No 1:S21-7. · 2.11 Impact Factor
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    ABSTRACT: Hypoxia inducible factor 1 (HIF-1) represses the transcription of pro-apoptotic bid in colorectal cancer cells in vitro. To assess the clinical relevance of this observation, HIF-1alpha and Bid were assessed in serial sections of 39 human colorectal adenocarcinomas by immunohistochemistry. In high HIF-1alpha nuclear-positive cell subpopulations, there was a significant reduction in Bid expression (ANOVA, P=0.04). Given the role of Bid in drug-induced apoptosis, these data add impetus to strategies targeting HIF-1 for therapeutic gain.
    British Journal of Cancer 08/2008; 99(3):459-63. · 5.08 Impact Factor
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    ABSTRACT: Glucocorticoid (GC) receptors (GRs) have profound anti-survival effects on human small cell lung cancer (SCLC). To explore the basis of these effects, protein partners for GRs were sought using a yeast two-hybrid screen. We discovered a novel gene, FAM33A, subsequently identified as a SKA1 partner and involved in mitosis, and so renamed Ska2. We produced an anti-peptide antibody that specifically recognized full-length human SKA2 to measure expression in human cell lines and tissues. There was a wide variation in expression across multiple cell lines, but none was detected in the liver cell line HepG2. A xenograft model of human SCLC had intense staining and archival tissue revealed SKA2 in several human lung and breast tumours. SKA2 was found in the cytoplasm, where it co-localized with GR, but nuclear expression of SKA2 was seen in breast tumours. SKA2 overexpression increased GC transactivation in HepG2 cells while SKA2 knockdown in A549 human lung epithelial cells decreased transactivation and prevented dexamethasone inhibition of proliferation. GC treatment decreased SKA2 protein levels in A549 cells, as did Staurosporine, phorbol ester and trichostatin A; all agents that inhibit cell proliferation. Overexpression of SKA2 potentiated the proliferative response to IGF-I exposure, and knockdown with shRNA caused cells to arrest in mitosis. SKA2 has recently been identified in HeLa S3 cells as part of a complex, which is critical for spindle checkpoint silencing and exit from mitosis. Our new data show involvement in cell proliferation and GC signalling, with implications for understanding how GCs impact on cell fate.
    Journal of Endocrinology 07/2008; 198(3):499-509. · 4.06 Impact Factor
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    ABSTRACT: The p53 tumour suppressor is involved in several crucial cellular functions including cell-cycle arrest and apoptosis. p53 stabilization occurs under hypoxic and DNA damage conditions. However, only in the latter scenario is stabilized p53 capable of inducing the expression of its pro-apoptotic targets. Here we present evidence that under hypoxia-mimicking conditions p53 acetylation is reduced to a greater extent at K320 site targeted by P300/CBP-associated factor (PCAF) than at K382 site targeted by p300/CBP. The limited amounts of acetylated p53 at K320 are preferentially recruited to the promoter of the p21(WAF-1/CIP-1) gene, which appears to be unaffected by hypoxia, but are not recruited to the BID promoter and hence p53 is incapable of upregulating pro-apoptotic BID in hypoxic conditions. As the K320 p53 acetylation is the site predominantly affected in hypoxia, the PCAF histone acetyltransferase activity is the key regulator of the cellular fate modulated by p53 under these conditions. In addition, we provide evidence that PCAF acetylates hypoxia-inducible factor-1alpha (HIF-1alpha) in hypoxic conditions and that the acetylated HIF-1alpha is recruited to a particular subset of its targets. In conclusion, PCAF regulates the balance between cell-cycle arrest and apoptosis in hypoxia by modulating the activity and protein stability of both p53 and HIF-1alpha.
    Oncogene 07/2008; 27(44):5785-96. · 8.56 Impact Factor

Publication Stats

5k Citations
831.78 Total Impact Points

Institutions

  • 1997–2014
    • The University of Manchester
      • School of Pharmacy and Pharmaceutical Sciences
      Manchester, England, United Kingdom
  • 1976–2012
    • The Hillingdon Hospitals NHS Foundation Trust
      अक्सब्रिज, England, United Kingdom
  • 2005
    • Liverpool John Moores University
      Liverpool, England, United Kingdom
  • 1993–2005
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 2000
    • De Montfort University
      Leiscester, England, United Kingdom
  • 1994–1997
    • Loughborough University
      • Department of Chemistry
      Loughborough, ENG, United Kingdom
  • 1986–1997
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 1996
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 1983–1989
    • Institute of Cancer Research
      Londinium, England, United Kingdom