Publications
177 results found
Paul J, Marsh S, McLeod HL, et al., 2008, No evidence for taxane/platinum pharmacogenetic markers: Just lack of power? Reply, JOURNAL OF CLINICAL ONCOLOGY, Vol: 26, Pages: 1904-1905, ISSN: 0732-183X
Marsh S, Paul J, McLeod HL, et al., 2008, Ethnic considerations in pharmacogenetic studies - In reply, JOURNAL OF CLINICAL ONCOLOGY, Vol: 26, Pages: 1767-1768, ISSN: 0732-183X
Steele NL, Plumb JA, Vidal L, et al., 2008, A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors, CLINICAL CANCER RESEARCH, Vol: 14, Pages: 804-810, ISSN: 1078-0432
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- Citations: 219
Steele NL, Plumb JA, Vidal L, et al., 2008, A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors, Pages: 804-810, ISSN: 1078-0432
Purpose: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors. Experimental Design: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels. Results: Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m2/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m2; one patient at 1,200 mg/m2), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m2), grade 3 atrial fibrillation (one patient at 1,200 mg/m 2; one patient at 1,000 mg/m2), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m2). The maximum tolerated dose was 1,000 mg/m2/d. I.v. belinostat displayed linear pharmacokinetics with respect to Cmax and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for ≥4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m2/d), 50% achieved stable disease. Conclusions: I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity. © 2008 Ameri
Teodoridis JM, Hardie C, Brown R, 2008, CpG island methylator phenotype (CIMP) in cancer: Causes and implications., Cancer Lett, Vol: 268, Pages: 177-186
Dai W, Teodoridis JM, Graham J, et al., 2008, Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands, BMC Bioinformatics, Vol: 9
Ordway JM, Budiman MA, Korshunova Y, et al., 2007, Identification of Novel High-Frequency DNA Methylation Changes in Breast Cancer, PLOS ONE, Vol: 2, ISSN: 1932-6203
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- Citations: 84
Strathdee GR, Holyoake TL, Sim A, et al., 2007, <i>HOX</i> genes -: Candidate tumor suppressor genes in adult, and childhood leukemia., 49th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, Pages: 777A-777A, ISSN: 0006-4971
Appleton K, Mackay HJ, Judson I, et al., 2007, Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors, Pages: 4603-4609, ISSN: 0732-183X
Purpose: The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (decitabine) induces DNA demethylation and re-expression of epigenetically silenced genes, and increases carboplatin sensitivity of tumor xenograft models. We designed a clinical study to determine the feasibility of delivering a dose of decitabine, combined with carboplatin, that would be capable of producing equivalent biologic effects in patients with solid tumors. Patients and Methods: In a two-stage design, 33 patients received escalating doses of decitabine administered as a 6-hour infusion on day 1 followed by carboplatin, area under the concentration-time curve (AUC) 5 (cohort 1) and AUC 6 (cohort 2), on day 8 of a 28-day cycle. Pharmacodynamic analyses included 5-methyl-2′- deoxycytidine levels, MAGE1A CpG island methylation, and fetal hemoglobin (HbF) expression. Results: The major toxicity was myelosuppression. Dose limiting toxicities, prolonged grade 4 neutropenia (one patient), and sepsis and grade 3 anorexia/fatigue (one patient), were seen in two of four patients treated with decitabine 135 mg/m2 and carboplatin AUC 5. Dose limiting toxicity comprising neutropenic sepsis (one patient) and grade 3 fatigue (one patient) was seen in two of 10 patients treated at decitabine 90 mg/m2 and carboplatin AUC 6. Decitabine induced dosedependent, reversible demethylation in peripheral-blood cells (PBCs) maximally at day 10. Furthermore, decitabine 90 mg/m2 induced demethylation of the MAGE1A CpG island in PBCs, buccal cells, and tumor biopsies, as well as elevation of HbF expression. Conclusion: Decitabine can be combined safely with carboplatin at a dose and schedule that causes epigenetic changes equivalent to or greater than that observed in mice with carboplatin-sensitized xenografts. The recommended dose/schedule for phase II trials is decitabine 90 mg/m2 (day 1) followed by carboplatin AUC 6 (day 8) every 28 days. © 2007 by American Society of Clinical Oncology.
Marsh S, Paul J, King CR, et al., 2007, Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: The Scottish randomised trial in ovarian cancer, JOURNAL OF CLINICAL ONCOLOGY, Vol: 25, Pages: 4528-4535, ISSN: 0732-183X
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- Citations: 197
Brown R, Glasspool R, 2007, Epigenetic modulation of resistance to chemotherapy?, ANNALS OF ONCOLOGY, Vol: 18, Pages: 1429-1430, ISSN: 0923-7534
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- Citations: 8
Robinson HMR, Bratlie-Thoresen S, Brown R, et al., 2007, Chk1 is required for G2/M checkpoint response induced by the catalytic topoisomerase II inhibitor ICRF-193, CELL CYCLE, Vol: 6, Pages: 1265-1267, ISSN: 1538-4101
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- Citations: 23
Robinson HMR, Black EJ, Brown R, et al., 2007, DNA mismatch repair and Chk1-dependent centrosome amplification in response to DNA alkylation damage, CELL CYCLE, Vol: 6, Pages: 982-992, ISSN: 1538-4101
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- Citations: 20
Strathdee G, Sim A, Soutar R, et al., 2007, <i>HOXA5</i> is targeted by cell-type-specific CpG island methylation in normal cells and during the development of acute myeloid leukaemia, CARCINOGENESIS, Vol: 28, Pages: 299-309, ISSN: 0143-3334
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- Citations: 37
Hall JA, Brown R, Paul J, 2007, An exploration into study design for biomarker identification: issues and recommendations., Cancer Genomics Proteomics, Vol: 4, Pages: 111-119, ISSN: 1109-6535
Genomic profiling produces large amounts of data and a challenge remains in identifying relevant biological processes associated with clinical outcome. Many candidate biomarkers have been identified but few have been successfully validated and make an impact clinically. This review focuses on some of the study design issues encountered in data mining for biomarker identification with illustrations of how study design may influence the final results. This includes issues of clinical endpoint use and selection, power, statistical, biological and clinical significance. We give particular attention to study design for the application of supervised clustering methods for identification of gene networks associated with clinical outcome and provide recommendations for future work to increase the success of identification of clinically relevant biomarkers.
Giotopoulos G, McCormick C, Cole C, et al., 2006, DNA methylation during mouse hemopoietic differentiation and radiation-induced leukemia, EXPERIMENTAL HEMATOLOGY, Vol: 34, Pages: 1462-1470, ISSN: 0301-472X
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- Citations: 33
de Graeff P, Hall J, Crijns APG, et al., 2006, Factors influencing p53 expression in ovarian cancer as a biomarker of clinical outcome in multicentre studies, BRITISH JOURNAL OF CANCER, Vol: 95, Pages: 627-633, ISSN: 0007-0920
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- Citations: 31
Robinson HMR, Jones R, Walker M, et al., 2006, Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil, ONCOGENE, Vol: 25, Pages: 5359-5369, ISSN: 0950-9232
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- Citations: 41
Strathdee G, Sim A, Parker A, et al., 2006, Promoter hypermethylation silences expression of the <i>HoxA4</i> gene and correlates with IgVh mutational status in CLL, LEUKEMIA, Vol: 20, Pages: 1326-1329, ISSN: 0887-6924
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- Citations: 33
Hardie C, Teodoridis JM, Hall J, et al., 2006, Analysis of methylation of CpG islands in ovarian cancer, Publisher: BLACKWELL PUBLISHING, Pages: 865-865, ISSN: 1470-0328
Wei SH, Balch C, Paik HH, et al., 2006, Prognostic DNA methylation biomarkers in ovarian cancer, CLINICAL CANCER RESEARCH, Vol: 12, Pages: 2788-2794, ISSN: 1078-0432
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- Citations: 118
White DJ, Meyer S, Will AM, et al., 2006, No evidence of significant <i>FANCF</i>, <i>FANCB</i> or <i>NBS1</i> methylation in sporadic acute childhood leukaemia, 46th Annual Scientific Meetign of the British-Society-for-Haematology, Publisher: BLACKWELL PUBLISHING, Pages: 22-22, ISSN: 0007-1048
O'Brien V, Brown R, 2006, Signalling cell cycle arrest and cell death through the MMR System, CARCINOGENESIS, Vol: 27, Pages: 682-692, ISSN: 0143-3334
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- Citations: 163
Hardie C, Teodoridis JM, Hall J, et al., 2006, Analysis of methylation of CpG islands during ovarian cancer progression, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Lindsey JC, Lusher ME, Strathdee G, et al., 2006, Epigenetic inactivation of <i>MCJ</i> (<i>DNAJD1</i>) in malignant paediatric brain tumours, INTERNATIONAL JOURNAL OF CANCER, Vol: 118, Pages: 346-352, ISSN: 0020-7136
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- Citations: 48
Glasspool RM, Teodoridis JM, Brown R, 2006, Epigenetics as a mechanism driving polygenic clinical drug resistance, Br J Cancer, Vol: 94, Pages: 1087-1092
Brown R, Appleton K, Plumb JA, et al., 2005, Pharmacodynamic effects in patients treated with 6 hour infusion of the demethylating agent 5-aza-2′deoxycytidine (decitabine)., AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 9071S-9072S, ISSN: 1078-0432
Gallagher WM, Bergin OE, Rafferty M, et al., 2005, Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies, CARCINOGENESIS, Vol: 26, Pages: 1856-1867, ISSN: 0143-3334
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- Citations: 96
Lyko F, Brown R, 2005, DNA methyltransferase inhibitors and the development of epigenetic cancer therapies, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol: 97, Pages: 1498-1506, ISSN: 0027-8874
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- Citations: 393
Chan MWY, Wei SH, Wen P, et al., 2005, Hypermethylation of 18S and 28S ribosomal DNAs predicts progression-free survival in patients with ovarian cancer, CLINICAL CANCER RESEARCH, Vol: 11, Pages: 7376-7383, ISSN: 1078-0432
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- Citations: 55
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