84 results on '"John F. Smyth"'
Search Results
2. Association of galectin-3 expression with melanoma progression and prognosis
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Tamasin Doig, John F. Smyth, John M. S. Bartlett, Yan Xu, David W. Melton, Thomas Brenn, V. R. Doherty, Ewan Brown, and Niall Anderson
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Adult ,Male ,Proto-Oncogene Proteins B-raf ,Cancer Research ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Angiogenesis ,Galectin 3 ,DNA Mutational Analysis ,Metastasis ,Risk Factors ,Humans ,Medicine ,Melanoma ,Survival analysis ,Aged ,Proportional Hazards Models ,Analysis of Variance ,Tissue microarray ,business.industry ,Microarray analysis techniques ,Middle Aged ,Microarray Analysis ,Prognosis ,medicine.disease ,Immunohistochemistry ,Survival Analysis ,Neoplasm Proteins ,Scotland ,Oncology ,Galectin-3 ,Mutation ,Disease Progression ,Cancer research ,Female ,business - Abstract
Galectin-3 plays an important role in adhesion, proliferation, differentiation, angiogenesis and metastasis in multiple tumours. To investigate the role of galectin-3 in melanoma pathogenesis we examined the expression of galectin-3 in melanocytic lesions and analysed the correlation between galectin-3 expression and clinicopathologic factors including patient survival and BRAF mutation status.We evaluated the expression of galectin-3 in 53 cases of benign naevi, 31 cases of dysplastic naevi, 59 in-situ melanomas, 314 cases of primary melanoma and 69 metastatic melanomas using tissue microarray and immunohistochemistry.Marked differences in expression of galectin-3 were seen between different categories of melanocytic lesions (ANOVA p0.0001). An increase in expression of galectin-3 between benign naevi and thin primary melanomas and a progressive decrease in expression between thin primary melanomas and thicker melanomas or metastatic melanomas was seen. Strong galectin-3 expression was associated with improved overall survival (p=0.002 and p=0.0002 for cytoplasmic and nuclear expression, respectively) and melanoma-specific survival (p=0.017 and p=0.003 for cytoplasmic and nuclear expression, respectively). A multifactorial Cox regression analysis suggested that galectin-3 expression was an independent prognostic marker for overall survival in melanoma (risk ratio 0.73, 95% CI 0.547-0.970, p=0.031 for cytoplasmic expression and risk ratio 0.76, 95% CI 0.587-0.985, p=0.036 for nuclear expression). No association between galectin-3 expression and BRAF mutation status was observed.This study suggests that galectin-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanoma.
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- 2012
3. A clinical study assessing the tolerability and biological effects of infliximab, a TNF-α inhibitor, in patients with advanced cancer
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U. Prabhakar, R. Vora, M. Nakada, M. DeWitte, R. E. Corringham, C. Sturgeon, Duncan I. Jodrell, S. A. Hoare, Ewan Brown, John F. Smyth, David Propper, Frances R. Balkwill, Rhona Aird, Kellie A. Charles, and R. L. Rye
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Adult ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Sensitivity and Specificity ,Gastroenterology ,Drug Administration Schedule ,Drug Hypersensitivity ,Neoplasms ,Internal medicine ,medicine ,Humans ,Hypersensitivity, Delayed ,Infusions, Intravenous ,skin and connective tissue diseases ,education ,Chemokine CCL2 ,Aged ,Stomatitis ,education.field_of_study ,Dose-Response Relationship, Drug ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Antibodies, Monoclonal ,Cancer ,Hematology ,Middle Aged ,medicine.disease ,Infliximab ,Clinical trial ,stomatognathic diseases ,C-Reactive Protein ,Treatment Outcome ,Cytokine ,Oncology ,Tolerability ,Toxicity ,Immunology ,Linear Models ,Female ,Tumor necrosis factor alpha ,business ,medicine.drug - Abstract
Background Tumour necrosis factor-α (TNF-α) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-α monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. Patients and methods Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-α, CCL2, IL-6 and C-reactive protein (CRP). Results Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-α was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10–50+ weeks). There was no evidence of disease acceleration in any patient. Conclusions Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-α and CCL2 being correlated with infliximab response.
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- 2008
4. Role of TGFα stimulation of the ERK, PI3 kinase and PLCγ pathways in ovarian cancer growth and migration
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Jane M Sewell, John F. Smyth, and Simon P. Langdon
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MAPK/ERK pathway ,TGF alpha ,Receptor, ErbB-2 ,Neuregulin-1 ,medicine.medical_treatment ,Protein Serine-Threonine Kinases ,Phosphatidylinositol 3-Kinases ,Cell Movement ,ErbB ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Humans ,Epidermal growth factor receptor ,Extracellular Signal-Regulated MAP Kinases ,Ovarian Neoplasms ,Mitogen-Activated Protein Kinase 3 ,biology ,Phospholipase C gamma ,Cell growth ,Growth factor ,Cell Biology ,Transforming Growth Factor alpha ,Cell biology ,ErbB Receptors ,Type C Phospholipases ,Cancer research ,biology.protein ,Female ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Transforming growth factor - Abstract
The Epidermal Growth Factor Receptor (EGFR) and its structural relative erbB2 are frequently over-expressed in ovarian cancers and both are strongly associated with poor patient survival. To investigate the relative roles of these receptors in the regulation of cell growth and migration, a panel of ovarian carcinoma cell lines were stimulated with TGF alpha and NRG1beta. TGF alpha had a much greater influence on cell migration than NRG1beta where growth effects were equivalent. The extent of TGF alpha-stimulated migration on collagen in these assays could be associated with erbB2 expression levels. In addition, TGF alpha was found to stimulate activation of the ERK, PI3 kinase and PLC gamma pathways. Direct blockade of the TGF alpha-interacting receptor EGFR inhibited both cell growth and migration, as well as downstream signaling induced by the growth factor. Specific blockade of the downstream proteins MEK and PI3 kinase significantly affected TGF alpha-induced mitogenesis in the cell lines tested but had less impact upon migration. Conversely, inhibition of the PLC gamma pathway had little effect on cell growth but significantly decreased TGF alpha-driven migration. These results corroborate the likely importance of migration as well as growth in erbB receptor over-expressing ovarian cancers and directly implicate the roles of ERK and PI3 kinase in growth control, and PLC gamma in the regulation of migration in this disease.
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- 2005
5. Current research and treatment for epithelial ovarian cancer A Position Paper from the Helene Harris Memorial Trust
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Martin Gore, G. Chenevix-Trench, T. Hamilton, Ian Jacobs, Robert C. Bast, N. Urban, R. Souhami, Jonathan S. Berek, Frances R. Balkwill, Gordon B. Mills, John F. Smyth, and S. Ursulic
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Gynecology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Receptor expression ,education ,Psychological intervention ,Early detection ,Disease ,medicine.disease ,Oncology ,Family medicine ,medicine ,Position paper ,Epithelial ovarian cancer ,Ovarian cancer ,business ,health care economics and organizations - Abstract
In March 2003, an international mulltidisciplinary group of scientists and clinicians with a specific interest in ovarian cancer met for 4 days to discuss research into and treatment of this challenging disease. Under the headings of molecular genetics, molecular biology, the biology of ovarian cancer, old therapies, new targets and the early detection of the disease, this Position Paper summarises the presentations and discussion from the 9th Biennial Helene Harris Memorial Trust Forum on Ovarian Cancer. In particular, we highlight the potential of international collaborations in translating laboratory science into useful clinical interventions. (C) 2003 Elsevier Ltd. All rights reserved.
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- 2003
6. Malignant mixed mesodermal tumours
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Awatif Al-Nafussi, M. Abdulkader, John F. Smyth, Charlie Gourley, and Hani Gabra
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Cancer Research ,Mixed tumor ,Pathology ,medicine.medical_specialty ,business.industry ,Mesenchymal stem cell ,Cancer ,Mesenchyma ,Malignancy ,medicine.disease ,Oncology ,Carcinosarcoma ,medicine ,Genital neoplasm ,business ,Sarcomatoid carcinoma - Abstract
Mixed mesodermal tumours (MMTs) are relatively rare gynaecological tumours that have been poorly studied in clinical and molecular terms. They are chemosensitive (at least initially), although ultimately they have a poor prognosis. The biology of the tumour is fascinating in view of its composition of both epithelial and mesenchymal entities. We review herein the literature on the clinical and biological aspects of this malignancy.
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- 2002
7. Enhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation
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Janet S. Macpherson, John F. Smyth, Brian Burchell, Jeffrey Cummings, Duncan I. Jodrell, Brian T. Ethell, and Gary Boyd
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Magnetic Resonance Spectroscopy ,Metabolic Clearance Rate ,Metabolite ,Glucuronidation ,Anthraquinones ,Glucuronates ,SN-38 ,Pharmacology ,Irinotecan ,Biochemistry ,Mass Spectrometry ,chemistry.chemical_compound ,Glucuronides ,Tumor Cells, Cultured ,medicine ,Humans ,Enzyme Inhibitors ,neoplasms ,Active metabolite ,biology ,Chemistry ,Topoisomerase ,digestive system diseases ,Cell culture ,Colonic Neoplasms ,biology.protein ,Tyrosine ,Camptothecin ,Topoisomerase I Inhibitors ,Glucuronide ,HT29 Cells ,medicine.drug - Abstract
As part of a program to identify novel mechanisms of resistance to topoisomerase I (topo I) inhibitors, the cellular pharmacology of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of clinically used irinotecan (CPT-11) and NU/ICRF 505, an anthraquinone-tyrosine conjugate, has been investigated in two human colorectal cancer (CRC) cell lines. Two novel metabolites of NU/ICRF 505 (M1 and M2) and a single metabolite of SN-38 (M1) were detected by high performance liquid chromatography in the culture medium of HT29 cells but were absent in HCT116 cells. Identities of all three metabolites were established by a combination of biochemical and physicochemical techniques. M1 of SN-38 was the C10-(beta)-glucuronide of the parent lactone while M1 of NU/ICRF 505 was the C4-O-glucuronide and M2 the tyrosine-O-glucuronide, both of the parent compound. Drug transport studies revealed that by 24hr HT29 cells had effectively cleared 82.5% of NU/ICRF 505 (10 microM) into the culture medium as the two glucuronides. In contrast, intracellular concentrations of NU/ICRF 505 were maintained in HCT116 cells in the absence of glucuronidation at a level 550 times greater than in HT29 cells. HT29 cells cleared 40.9% of SN-38 (1 microM) as the glucuronide to the culture medium, while the parent drug was maintained at a level 2-fold greater in HCT116 cells. Enhanced drug clearance due to glucuronidation may contribute to intrinsic drug resistance of human CRC.
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- 2002
8. Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report
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J.P Droz, M.J. de Vries, M Roelvink, A. Anthoney, Pierre Fumoleau, Véronique Diéras, W Fiedler, John F. Smyth, Bruno Coudert, Markus Borner, and R. Morant
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Nausea ,medicine.medical_treatment ,Antineoplastic Agents ,Small-cell carcinoma ,Drug Administration Schedule ,Oligodeoxyribonucleotides, Antisense ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Carcinoma, Small Cell ,Enzyme Inhibitors ,Lung cancer ,neoplasms ,Aged ,Chemotherapy ,business.industry ,Respiratory disease ,Cancer ,Middle Aged ,Thionucleotides ,medicine.disease ,Hematologic Diseases ,humanities ,respiratory tract diseases ,Surgery ,Proto-Oncogene Proteins c-raf ,Treatment Outcome ,Disease Progression ,Vomiting ,Female ,medicine.symptom ,business ,Progressive disease - Abstract
Two multicentre phase II trials were designed to determine if tumour responses can be achieved in progressive small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) patients treated with ISIS 5132, an inhibitor of C-raf kinase mRNA expression (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA), and to further characterise the safety of the compound. Between August 1998 and November 1999, 26 patients (18 NSCLC, 8 SCLC) were entered. Out of these, 23 were eligible, 22 (18 NSCLC, 4 SCLC) were treated with ISIS 5132 (2 mg/kg/day, 21 days continuous intravenous (i.v.) infusion every 4 weeks) and were evaluable for toxicity and 18 (15 NSCLC, 3 SCLC) were evaluable for efficacy. For the whole group haematological toxicity did not exceed grade 2. One patient experienced a grade 4 increased prothrombin time. Non-haematological toxicity was mild to moderate, with the observation of asthenia and nausea and vomiting. Progressive disease (PD) was diagnosed in 10 patients (8 NSCLC and 2 SCLC). 8 more patients (7 NSCLC, 1 SCLC) were considered as treatment failures. In conclusion, this study using ISIS 5132 with this dose and schedule of administration excludes a 20% response rate with 95% confidence intervals for NSCLC and cannot draw any conclusions for SCLC patients as only a few were involved in the study.
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- 2001
9. A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly
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G. Camboni, Duncan I. Jodrell, L.K. Dawson, A. Bowman, B. Byrne, R Rye, John F. Smyth, and A. Bernareggi
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Adult ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Antineoplastic Agents ,Urine ,Pharmacology ,Neutropenia ,Gastroenterology ,Lethargy ,chemistry.chemical_compound ,Pharmacokinetics ,Neoplasms ,Internal medicine ,medicine ,Humans ,Infusions, Intravenous ,Aged ,Cardiotoxicity ,Pixantrone ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,Isoquinolines ,medicine.disease ,Hematologic Diseases ,Oncology ,chemistry ,Toxicity ,Vomiting ,medicine.symptom ,Tomography, X-Ray Computed ,business - Abstract
The anthracenedione analogue, BBR 2778 is an active antitumour agent preclinically and has reduced potential for cardiotoxicity compared with other similar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapidly from 20 to 240 mg/m2. The dose-limiting toxicity (DLT) was neutropenia, common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Other toxicities > or = CTC grade 3 were: vomiting, lymphopenia, thrombocytopenia and lethargy. Blue discoloration of veins and urine was also noted. In 1 patient (120 mg/m2, four cycles) left ventricular ejection reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2) at 180 mg/m2 = 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a patient with previously treated small cell lung carcinoma (SCLC), a 49% reduction in measurable disease was noted with resolution of pericardial and pleural effusions (120 mg/m2 x eight cycles). From the results of this phase I study a dose of 180 mg/m2 as a 1 h infusion every 3 weeks would be recommended for phase II trials.
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- 2000
10. Discussion
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V.J. Spanswick, Maria Tomasz, John F. Smyth, and Jeffrey Cummings
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Pharmacology ,chemistry.chemical_classification ,Mitomycin C ,Cytochrome P450 reductase ,Cytochrome P450 ,Biology ,Biochemistry ,Enzyme ,chemistry ,Mechanism of action ,In vivo ,Cancer cell ,medicine ,biology.protein ,Enzyme kinetics ,medicine.symptom - Abstract
Mitomycin C (MMC) is the prototype bioreductive DNA alkylating agent. To exploit its unique properties and maximize patient responses, different therapeutic approaches have been investigated. Recently, the focus has concentrated on monitoring the levels of the proteins metabolizing the drug and relating these to activity in a regimen referred to as enzyme-directed bioreductive drug development. To be successful, it is important to understand the enzymology of metabolic activation not only in cell lines but also in solid tumour models. A general mechanism of action for MMC has now emerged that is activated regardless of the source of reducing equivalents, comprising three competing pathways that give rise to unique reactive intermediates and different DNA adducts. Partitioning into the pathways is dictated by chemical considerations such as pH and drug concentration. DT-diaphorase stands out in this mechanism, since it is much less effective at metabolizing MMC at neutral pH. At least five different enzymes can catalyse MMC bioreduction in vitro, and as many activities may be present in solid tumours, including a series of novel mitochondrial reductases such as a cytochrome P450 reductase. Competition between reductases for MMC appears to be based solely on protein levels rather than enzyme kinetics. Consequentially, DT-diaphorase can occupy a central role in MMC metabolic activation since it is often highly overexpressed in cancer cells. Although a good correlation has been observed in cell lines between DT-diaphorase expression and aerobic cytotoxicity, this does not hold consistently in vivo for any single bioreductive enzyme, suggesting revision of the enzyme-directed hypothesis as originally formulated.
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- 1998
11. Estrogen regulation of transforming growth factor-α in ovarian cancer
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Kenneth G. MacLeod, John F. Smyth, G. J. Rabiasz, P.P Macineira-Perez, R. A. Hawkins, A. J. Crew, Gillian L. Hirst, B. J. B. Simpson, John M. S. Bartlett, Simon P. Langdon, and William R. Miller
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medicine.medical_specialty ,TGF alpha ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Receptor expression ,Clinical Biochemistry ,Down-Regulation ,Estrogen receptor ,Biology ,Biochemistry ,Endocrinology ,Epidermal growth factor ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Humans ,RNA, Messenger ,Autocrine signalling ,Receptor ,Molecular Biology ,Ovarian Neoplasms ,Binding Sites ,Estradiol ,Tumor Necrosis Factor-alpha ,Antibodies, Monoclonal ,Estrogens ,Cell Biology ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Receptors, Estrogen ,Estrogen ,Culture Media, Conditioned ,Cancer research ,Molecular Medicine ,Female ,Cell Division ,Transforming growth factor - Abstract
Transforming growth factor alpha (TGF α ) may be induced by estrogen in estrogen responsive systems and can contribute to the growth-modulatory effects of this hormone. To test whether TGF α contributes to estrogen-regulated growth in ovarian cancers, we have compared the effects of 17 β -estradiol (E 2 ) and TGF α in a range of ovarian carcinoma cell lines. Addition of E 2 to the estrogen receptor (ER)-positive cell lines (PE01, PE04 and PE01 CDDP ) produced a 2–4 fold increase in TGF α protein concentrations in media conditioned by the cells. Both E 2 and TGF α stimulated the growth of the PE01 and PE04 lines and inhibited the growth of the PE01 CDDP line. Furthermore, the E 2 -mediated growth effects could be reversed by an epidermal growth factor (EGF) receptor-targeted antibody. E 2 also down-regulated EGF receptor expression in ER-positive cell lines. In a series of primary ovarian tumors, higher concentrations of ER were associated with an increased percentage of tumors expressing TGF α mRNA and a decreased percentage expressing EGF receptor protein. All these data are consistent with E 2 increasing production of TGF α in ER-positive ovarian cancer and this in turn acting through the EGF receptor to modulate growth in an autocrine manner.
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- 1998
12. Pharmacological and Biochemical Determinants of the Antitumour Activity of the Indoloquinone EO9
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John F. Smyth, V.J. Spanswick, A.A. Ritchie, Jill Gardiner, and Jeffrey Cummings
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Indoles ,Cytochrome ,Metabolite ,Aziridines ,Mice, Nude ,Antineoplastic Agents ,Adenocarcinoma ,Reductase ,Biochemistry ,Mice ,chemistry.chemical_compound ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Indolequinones ,Cytochrome b5 reductase ,Pharmacology ,biology ,Cytochrome c ,Biological activity ,chemistry ,Mechanism of action ,Colonic Neoplasms ,biology.protein ,medicine.symptom ,Drug metabolism - Abstract
ABSTRACT. EO9 is a novel bioreductive drug which has recently undergone extensive clinical evaluation. Its mechanism of action remains to be clearly defined. Antitumour activity of EO9 has been determined in 2 human colon cancer xenografts (HT-29 and BE) and 2 murine colon adenocarcinomas (MAC 16 and 26) after intratumoural injection of 250 μg of drug. Levels of the major bioreductive enzymes (DT-diaphorase, cytochrome P-450 reductase and cytochrome b5 reductase) were measured in tumours using cytochrome c reduction and menadione as the intermediate electron acceptor. There was no correlation between chemosensitivity (T/C: HT-29, 15%; BE, 27%; MAC 16, 33% and MAC 26, 60%) and enzyme activity (r2 = 0.47 for DT-diaphorase, r2 = 0.1 for cytochrome P-450 reductase and r2 = 0.52 for cytochrome b5 reductase). Drug metabolism was followed in vitro using tumour homogenates incubated under aerobic and anaerobic conditions. Four metabolites were identified by HPLC and characterised by UV-visible spectroscopy. With the exception of the hydrolysis product EO5A, all other metabolites appeared to be drug adducts. No correlation was observed between the kinetics of metabolite formation and antitumour activity. A good correlation (r2 = 0.86) was found with the rate of disappearance of parent drug and antitumour activity. These data show that the overall capacity of a tumour to metabolise EO9 is the most important determinant of antitumour activity rather than the expression of the major bioreductive enzymes and that the parent drug rather than a metabolite leads to the active form of the drug.
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- 1998
13. 'The Art of Successful Publication' ECCO 13 Workshop Report
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Maurizio D'Incalci, Jaap Verweij, Lekshmy Balakrishnan, and John F. Smyth
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Publishing ,Cancer Research ,business.industry ,Writing ,Library science ,Congresses as Topic ,Europe ,Competition (economics) ,Oncology ,Medicine ,Relevance (law) ,Cancer development ,Periodicals as Topic ,Element (criminal law) ,business ,Editorial Policies ,Scientific communication - Abstract
Having your work published in a good journal is the life-blood of research. Publications are the key element in scientific communication and influence future funding and cancer development for the authors. Every year more and more manuscripts are submitted and competition for acceptance is fierce. The editors of EJC recently held a workshop to discuss ways to improve manuscript writing, and this paper summarises their recommendations. Choose a title carefully, keep the introduction short, avoid confusing methods with results, and use figures wherever possible. Discuss only the relevance of new findings to published literature. Above all read the specific "instructions to authors" -- it is surprising how often this is ignored -- at peril!
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- 2006
14. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: Results of a double-blind, randomised trial
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Timothy J. Perren, A Bowman, K. J. Quinn, M Tedeschi, Robin J Prescott, John F. Smyth, and Peter M Wilkinson
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Adult ,medicine.medical_specialty ,Randomization ,medicine.medical_treatment ,Antidotes ,Renal function ,Antineoplastic Agents ,Gastroenterology ,Drug Administration Schedule ,law.invention ,chemistry.chemical_compound ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Drug Interactions ,Aged ,Ovarian Neoplasms ,Cisplatin ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Hematology ,Glutathione ,Middle Aged ,Clinical trial ,Endocrinology ,Oncology ,chemistry ,Toxicity ,Quality of Life ,Female ,business ,medicine.drug - Abstract
6Boehnnger Mannheim, Italv Summary Background: Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. Patients and methods: One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) ± glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. Results: When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control - 58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control - 74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). Conclusions: The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.
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- 1997
15. Preclinical studies on the broad-spectrum neuropeptide growth factor antagonist G
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Jeffrey Cummings, D.A. Jones, Simon P. Langdon, and John F. Smyth
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Pharmacology ,medicine.medical_specialty ,Lung Neoplasms ,Growth factor ,medicine.medical_treatment ,Antagonist ,Mice, Nude ,Neuropeptide ,Antineoplastic Agents ,Biological activity ,Vascular permeability ,Biology ,In vitro ,Mice ,Endocrinology ,Interleukin 1 receptor antagonist ,In vivo ,Internal medicine ,medicine ,Animals ,Carcinoma, Small Cell ,Drug Screening Assays, Antitumor ,Oligopeptides - Abstract
1. Antagonist G is a broad-spectrum neuropeptide growth factor antagonist that inhibits the growth of small cell lung cancer (SCLC) cells both in vitro and in vivo. 2. Antagonist G is metabolized in peripheral tissues by a chymotrypsin-like serine carboxypeptidase causing C-terminal deamidation and removal of the methionine residue. 3. The metabolites of Antagonist G retain neuropeptide antagonist properties and are thought to contribute to the parent peptide's antitumor activity. 4. Pharmacokinetic studies following systemic (IP) administration to nude mice revealed that the tissue distribution of Antagonist G is likely to be determined by vascular permeability. 5. Preclinical toxicology studies have been completed, and we have now started a phase I clinical trial.
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- 1997
16. Processing of [d-Arg1,d-Phe5,d-Trp7,9,Leu11]Substance P in Xenograft Bearing Nu/Nu Mice
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John F. Smyth, Simon P. Langdon, Jeffrey Cummings, A.A. Ritchie, Alexander MacLellan, and D.A. Jones
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Lung Neoplasms ,Physiology ,medicine.medical_treatment ,Transplantation, Heterologous ,Mice, Nude ,Neuropeptide ,Antineoplastic Agents ,Substance P ,Peptide ,Pharmacology ,Biochemistry ,Mice ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,Pharmacokinetics ,In vivo ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Tissue Distribution ,Carcinoma, Small Cell ,chemistry.chemical_classification ,Growth factor ,Antagonist ,Molecular biology ,In vitro ,chemistry ,Female ,Neoplasm Transplantation ,Half-Life - Abstract
JONES, D. A., A. J. MacLELLAN, J. CUMMINGS, A. A. RITCHIE, S. P. LANGDON AND J. F. SMYTH. Processing of [ d-arg1,d -Phe5, d -Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice. PEPTIDES 18(7) 1073–1077, 1997.—[ d -Arg1, d -Phe5, d -Trp7,9,Leu11]Substance P is a broad-spectrum neuropeptide growth factor antagonist that has exhibited in vitro activity against a range of human cancer cell lines. The fate of this compound in vivo following IP administration at 12 μg/g to nu/nu mice bearing the H69 small-cell lung cancer xenograft has been studied. Metabolism was confined to the C-terminus producing [ d -Arg1, d -Phe5, d -Trp7,9,Leu11]substance P acid and [ d -Arg1, d -Phe5, d -Trp7,9]substance P(1–10). The peptide had a long half-life in plasma (45.9 min) and became widely distributed among the tissues studied with the highest accumulation observed in the liver (AUC 1102 μg/g × min) and the lowest in the brain (5 μg/g × min). Uptake into the tumor xenograft was poor (AUC 189 μg/g × min); however, uptake into the lungs was much greater (AUC 507 μg/g × min), offering encouragement that therapeutic concentrations may be targeted to primary lung tumors.
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- 1997
17. Determination of the novel topoisomerase I inhibitor NU/ICRF 505 and its major metabolite in plasma, tissue and tumour by high-performance liquid chromatography
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Jeffrey Cummings, Ian Meikle, Janet S. Macpherson, and John F. Smyth
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Metabolite ,Mice, Nude ,Anthraquinones ,Antineoplastic Agents ,High-performance liquid chromatography ,Mice ,chemistry.chemical_compound ,Tumor Cells, Cultured ,Trifluoroacetic acid ,Animals ,Humans ,Sample preparation ,Enzyme Inhibitors ,Chromatography, High Pressure Liquid ,Detection limit ,Chromatography ,General Chemistry ,Reference Standards ,chemistry ,Colonic Neoplasms ,Tyrosine ,Topoisomerase I Inhibitors ,Quantitative analysis (chemistry) ,Ammonium acetate ,Neoplasm Transplantation ,Conjugate - Abstract
A high-performance liquid chromatographic technique is presented for the determination of the novel topoisomerase I inhibitor NU/ICRF 505 (a tyrosine conjugate of anthraquinone), its major metabolite (NU/ICRF 505/M) and an internal standard (NU/ICRF 513, dihydroxyphenylalanine conjugate). The method uses a reversed-phase (Apex ODS-2) stationary phase and a mobile phase consisting of 0.25 M ammonium acetate adjusted to pH 3 with 25% (v/v) trifluoroacetic acid and methanol with gradient elution. Between-day variation in retention times were less than 1% for NU/ICRF 505 and 513 and 2.4% for the metabolite. Selective detection was achieved at a wavelength of 545 nm giving a limit of detection of 2 ng on column and 50 ng/ml after sample preparation for all three components. Chromatograms were free from interfering peaks even at very high detector sensitivity. Sample preparation was based on incubation of biological specimens (0.5 ml plasma or homogenate) with dimethylsulphoxide and acetonitrile at 4°C for 30 min followed by centrifugation. Liver and tumour were homogenised in phosphate buffered saline. Recoveries were consistently high (81.7–106.7% for NU/ICRF 505; 88.7–103.3% for NU/ICRF 513 and 83.7–98.7% for NU/ICRF 505/M) with between day coefficients of variation of normally less than 10%. The method will contribute significantly to the preclinical evaluation of NU/ICRF 505.
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- 1996
18. Enzymology of mitomycin C metabolic activation in tumour tissue
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John F. Smyth, Jeffrey Cummings, and V.J. Spanswick
- Subjects
Pharmacology ,chemistry.chemical_classification ,biology ,Cytochrome ,Cytochrome c ,Dicoumarol ,Reductase ,NAD(P)H Dehydrogenase (Quinone) ,Biochemistry ,Enzyme assay ,Enzyme ,chemistry ,biology.protein ,medicine ,Drug metabolism ,medicine.drug - Abstract
In this study, the enzymology of mitomycin C (MMC) bioactivation in two murine colon adenocarcinomas, MAC 16 and MAC 26, was examined. Subcellular quinone reductase assessment via cytochrome c reduction confirmed a number of active enzymes. MAC 16 exhibited 22-fold greater levels of cytosolic DT-diaphorase than MAC 26, while microsomal NADPH:cytochrome P-450 reductase levels were similar in both tumour types. Metabolism of MMC by subcellular fractions isolated from both MAC 16 and MAC 26 was quantitated by monitoring the formation of the principle metabolite 2,7-diaminomitosene (2,7-DM) via high-performance liquid chromatography (HPLC). In MAC 16 only, activity displaying the properties of cytosolic DT-diaphorase and microsomal NADPH:cytochrome P-450 reductase was detected and confirmed, using the enzyme inhibitors dicoumarol and cytochrome P-450 reductase antiserum, respectively. The highest level of MMC metabolism was associated with the mitochondrial fraction from both tumours and was the sole enzyme activity detected in MAC 26. The greatest mitochondrial drug metabolism was achieved in the presence of NADPH as cofactor and hypoxia (MAC 16-specific activity, 3.67 +/- 0.58 nmol/30 min/mg; MAC 26 specific-activity, 3.87 +/- 0.71 nmol/30 min/mg) and was unaffected by the addition of the inhibitors dicoumarol and cytochrome P-450 reductase antiserum. NADH-dependent mitochondrial activity was only observed in MAC 16 at approximately 4-fold less than that seen with NADPH. MAC 26 homogenate incubations displayed enhanced metabolism under hypoxia, presumably due to the presence of the identified mitochondrial enzyme. MAC 16 homogenates showed no increase in metabolism under hypoxia, suggesting that other enzyme(s) may be predominant. These data indicate the presence of a novel mitochondrial one-electron reductase capable of metabolising MMC in MAC 16 and MAC 26.
- Published
- 1996
19. Cancer Genetics and Cell and Molecular Biology
- Author
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John F. Smyth
- Subjects
Pulmonary and Respiratory Medicine ,Molecular epidemiology ,business.industry ,Cancer ,Disease ,Critical Care and Intensive Care Medicine ,medicine.disease ,Malignancy ,Bioinformatics ,Metastasis ,Pharmacotherapy ,Immunology ,medicine ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Lung cancer ,business - Abstract
Lung cancer, the most prevalent cancer in the western world, is predominantly caused by smoking and thus perceived as a "self-inflicted" disease. Nevertheless, only 20% of smokers develop lung cancer. This review examines the concept of high-risk populations and screening. It looks at developments in the molecular epidemiology of the disease that shed new light on genetic changes that may predispose individuals to malignancy. Improvements in existing drug therapy are discussed as well as important new therapeutic developments, including antigrowth factors (antagonists G and D), antimetastatic agents (matrix metalloproteinase inhibitors), and natural products, arising from a greater understanding of signal transduction pathways and the process of cell metastasis.
- Published
- 1996
20. Optimum anti-emetic therapy for cisplatin induced emesis over repeat courses: Ondansetron plus dexamethasone compared with metoclopramide, dexamethasone plus lorazepam
- Author
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David Cunningham, B. McQuade, D Van Straelen, P.H.M. de Mulder, A. du Bois, R Crombez, R Parideans, John F. Smyth, Alan L Stewart, J. McRae, Peter Selby, Jaap Verweij, and Mario Dicato
- Subjects
Adult ,Male ,Metoclopramide ,medicine.drug_class ,Nausea ,medicine.medical_treatment ,Lorazepam ,Dexamethasone ,Drug Administration Schedule ,Ondansetron ,Double-Blind Method ,medicine ,Humans ,Antiemetic ,Aged ,Chemotherapy ,business.industry ,Incidence ,Hematology ,Middle Aged ,Europe ,Oncology ,Tolerability ,Anesthesia ,Antiemetics ,Corticosteroid ,Drug Therapy, Combination ,Female ,Cisplatin ,medicine.symptom ,business ,medicine.drug - Abstract
nGlaxo Research and Development Limited, Greenford, Middlesex, U.K. Summary Background: This study was undertaken to compare the efficacy and tolerability of ondansetron plus dexamethasone (O+D) with metoclopramide plus dexamethasone plus lorazepam (M+D+L) over three consecutive courses of cisplatin chemotherapy. Patients and methods: This was an international, multicentre, double-blind, double-dummy, parallel group study. O+D patients were randomised to receive ondansetron 8 mg intravenously (i.v.) plus dexamethasone 20 mg i.v. prior to cisplatin (50-100 mg/m2) chemotherapy. On the following 4 days they were treated with ondansetron 8 mg bd orally and dexamethasone 4mg bd orally. M + D+L patients were randomised to receive metoclopramide 3 mg/kg i.v., dexamethasone 20 mg i.v. and lorazepam 1.5 mg/m2 i.v. (max 3 mg) prior to cisplatin chemotherapy and a further dose of metoclopramide 3 mg/kg i.v. approximately 2 hours following the first dose of metoclopramide. Treatment for the following 4 days was metoclopramide 40 mg tds and dexamethasone 4 mg bd orally. Two hundred and thirty-seven patients were recruited into the study (117 patients received O + D and 120 received M+D+L). Results: On the first course of chemotherapy, O + D was significantly superior to the M+D+L regimen for complete control of emesis (days 1-5, 54% versus 37%, respectively, P" 0.014). This was maintained over the three treatment cycles; 38% of O+D and 20% of M+D+L patients remained free of emesis (P — 0.003). Maintenance of control of nausea grade as none or mild on days 1-5 over the three courses was significantly better in the O+D group (48%) than in the M+D+L (26%, P - 0.003). The most commonly occurring adverse events in the O+D group were constipation (25%) and headache (19%). In the M+D+L group drowsiness (38% of patients), malaise/fatigue (16% of patients), constipation (13% of patients), anxiety (11% of patients) and dizziness (10% of patients) were the most commonly reported adverse events. Extrapyramidal symptoms were reported by 20% of patients in the M+D+L group. Despite the inclusion of lorazepam, 14% of patients in the M+D+L group were withdrawn from the study due to extrapyramida l symptoms, which in the opinion of the investigators, were probably or almost certainly related to study medication. Conclusion: This study shows that O+D is significantly more effective and better tolerated than M+D+L for the control of emesis and nausea over a series of three courses of cisplatin chemotherapy.
- Published
- 1996
21. 40 Years on – dreams, realities and appropriate optimism
- Author
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John F. Smyth
- Subjects
Cancer Research ,Optimism ,Oncology ,media_common.quotation_subject ,Psychology ,Social psychology ,media_common - Published
- 2004
22. Pharmacokinetics, metabolism, tissue and tumour distribution of the neuropeptide growth factor antagonist [Arg6, D-Trp7,9, NmePhe8]-substance P (6—11) in nude mice bearing the H69 small-cell lung cancer xenograft
- Author
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D.A. Jones, Simon P. Langdon, Alexander MacLellan, Jeffrey Cummings, A.A. Ritchie, Enrique Rozengurt, and John F. Smyth
- Subjects
Male ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Cmax ,Mice, Nude ,Neuropeptide ,Antineoplastic Agents ,Biology ,Mice ,Pharmacokinetics ,Internal medicine ,Blood plasma ,medicine ,Animals ,Humans ,Tissue Distribution ,Carcinoma, Small Cell ,Volume of distribution ,Growth factor ,Antagonist ,Half-life ,Hematology ,Endocrinology ,Oncology ,Oligopeptides ,Neoplasm Transplantation - Abstract
Summary Background [Arg6, D-Trp7-9, NmePhe8)-Substance P (6–11) (codenamed antagonist G) represents the first broad spectrum antagonist of a number of neuropeptides shown to act as growth factors in small-cell lung cancer (SCLC) and is shortly to enter clinical trials. Design Pharmacokinetics, metabolism, tissue and tumour disposition have been studied in mice (nu/nu) bearing the NCI-H69 human SCLC xenograft after systemic drug administration at an active dose (45 mg/kg i.p.). Results The peptide exhibited a relatively long half life (28.9 min; clearance 45.6 ml/min/kg) and distributed widely (volume of distribution 1490 ml/kg). Marked accumulation of antagonist G (and its metabolites) was noted in the liver (AUC 5278 μg/g × min) and to a lesser extent the spleen (AUC 930 μg/g × min) but only low levels appeared to cross the blood brain barrier (AUC in brain, 20 μg/g × min) or be taken up into the heart (AUC 101 ng/g × min). Tumour uptake was intermediate in value out of the 7 tissues studied (AUC 195 (μg/g × min). Metabolism was restricted almost exclusively to the C terminal of the peptide producing 4 major products: M1, deamidated antagonist G; M2, H-Arg-DTrp-NmePhe-DTrp-Leu-OH, both of which retain growth factor antagonist activity; M3, a combination of oxidised antagonist G [Met11(O)] and oxidised deamidated antagonist G; and M4, a combination of H-Arg-DTrp-NmePhe-DTrp-OH and H-DTrp-NmePhe-DTrp-Leu-OH. Extensive bio-transformation to predominately Ml and M2 occurred in most tissues including the tumour where the parent peptide accounted for only 48.5% of the total. Conclusions Levels of antagonist G required to produce a small but significant effect on the growth of SCLC cell lines in vitro are in the region of 4–7 μM. Taking into account metabolites, a peak concentration of 4.1 μg/g (4.3 uM) was achieved in the H69 xenograft. These studies reveal a favourable preclinical pharmacology profile for antagonist G and offer hope that anticancer activity may be achievable in man.
- Published
- 1995
23. Biochemistry of topoisomerase I and II inhibition by anthracenyl-amino acid conjugates
- Author
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John A. Hadfield, Ian Meikle, Jeffrey Cummings, Janet S. Macpherson, and John F. Smyth
- Subjects
Cell Survival ,Stereochemistry ,Molecular Sequence Data ,Biochemistry ,Catalysis ,Structure-Activity Relationship ,chemistry.chemical_compound ,medicine ,Humans ,Topoisomerase II Inhibitors ,Amino Acids ,Tyrosine ,Amsacrine ,Ternary complex ,Anthracenes ,Pharmacology ,chemistry.chemical_classification ,Base Sequence ,Molecular Structure ,biology ,Hydrolysis ,Topoisomerase ,DNA ,Amino acid ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Topoisomerase I Inhibitors ,HeLa Cells ,medicine.drug - Abstract
Mono-conjugation of an anthraquinone nucleus with a range of naturally occurring amino acids chemically modified at their C-terminus has been adopted as a synthetic approach in the rational design of novel topoisomerase (topo) inhibitors. The biochemistry of topo I and II inhibition has been investigated for a series of 16 new compounds (NU/ICRF 500–515) from which structure-activity relationships have been investigated. Only three compounds could be demonstrated to bind to DNA: two serine derivatives (NU/ICRFs 500 and 506) and an arginine derivative (NU/ICRF 510). In decatenation and relaxation assays with purified enzyme, several compounds were shown to be potent catalytic inhibitors of topo II (100% inhibition at 5 μg/mL (10–15 μM) or less) without stabilizing cleavable complex formation. These included the three DNA binding species (of which NU/ICRF 506 was the most active) and a dihydroxyphenylalanine analogue (NU/ICRF 513). Both NU/ICRFs 500 and 506 were further shown to antagonize DNA cleavage induced by amsacrine. Only NU/ICRF 506 unequivocally inhibited the catalytic activity of topo I without induction of DNA cleavage, and was the only combined topo I and II catalytic inhibitor. One compound, NU/ICRF 505 (tyrosine conjugate), stabilized topo I cleavable complexes without inhibiting the catalytic activity of topo I and II. Modifications to the structure of NU/ICRF 505 revealed that the presence of an unhindered hydroxyl on the tyrosine ring and a more hydrophobic ethyl ester at the amino acid C-terminal were both essential, suggesting a highly specific interaction between drug, enzyme and DNA in the ternary complex. Molecular modelling studies suggested that the observed differences in topo inhibition are a consequence of major conformational alterations brought about by small changes in the amino acid substituent, and confirmed a rigid structural requirement for the induction of topo I cleavage, in addition to a less rigid structural requirement for topo II inhibition. A strong correlation was observed between topo inhibition and in vitro cytotoxicity against the human ovarian cancer cell line A2780 ( ic 50 range 3.4–11.6 μM), suggesting a mechanism of cell kill, at least in part, involving topo inhibition.
- Published
- 1995
24. Processing of the neuropeptide growth factor antagonist [Arg6, D-Trp7,9, NmePhe8]-substance P (6–11) by a small cell lung cancer cell line (H69)
- Author
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Alexander MacLellan, John F. Smyth, D.A. Jones, Simon P. Langdon, Jeffrey Cummings, and Enrique Rozengurt
- Subjects
medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,medicine.medical_treatment ,Cell ,Antineoplastic Agents ,Substance P ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Internal medicine ,Gastrin-releasing peptide ,medicine ,Humans ,Carcinoma, Small Cell ,IC50 ,Chromatography, High Pressure Liquid ,Pharmacology ,Growth factor ,Antagonist ,Biological activity ,Molecular biology ,Peptide Fragments ,Culture Media ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Cell culture ,Growth inhibition - Abstract
[Arg6, D-Trp7.9, NmePhe8]-substance P (6-11) (antagonist G) is a broad spectrum neuropeptide growth factor antagonist about to enter clinical trials as an anticancer drug. Its fate has been studied after incubation with two densities (5 x 10(4) cells/mL and 1 x 10(6) cells/mL) of the H69 small cell lung cancer cell line for up to 7 days at a concentration of 20 microM, corresponding to the IC50 for growth inhibition. HPLC analyses were conducted on cell pellets and media and in controls consisting of cell free media and water. Over 7 days in media containing cells a 70.4% reduction in parent peptide concentration occurred at the high density and a 44.1% reduction at low density. Despite this, there was a steady elevation in peptide associated with cells reaching a 189% increase by day 7. Oxidation of G at the C-terminal methionine residue occurred in all media studied indicative of a chemical process. The two major active metabolites of antagonist G (deamidated G and G minus Met11) were detected only in media in the presence of cells. These accumulated with time in media and cells together with oxidized products. These results reveal complex cellular pharmacology for antagonist G where H69 cells are increasingly exposed to 4 different peptide products rather than 1.
- Published
- 1995
25. Metabolism of the anticancer peptide: H-Arg-d-Trp-NmePhe-d-Trp-Leu-Met-NH2
- Author
-
Simon P. Langdon, Jeffrey Cummings, T. Higgins, Alexander MacLellan, Enrique Rozengurt, D.A. Jones, and John F. Smyth
- Subjects
Lung Neoplasms ,Physiology ,Molecular Sequence Data ,Transplantation, Heterologous ,Mice, Nude ,Neuropeptide ,Antineoplastic Agents ,Spectrometry, Mass, Fast Atom Bombardment ,Biology ,Pharmacology ,Biochemistry ,Cell Line ,Mice ,Cellular and Molecular Neuroscience ,Endocrinology ,Tumor Cells, Cultured ,Animals ,Humans ,Protease Inhibitors ,Amino Acid Sequence ,Amino Acids ,Carcinoma, Small Cell ,Peptide sequence ,Chromatography, High Pressure Liquid ,chemistry.chemical_classification ,Oligopeptide ,Clinical Trials, Phase I as Topic ,Antagonist ,3T3 Cells ,Metabolism ,In vitro ,Amino acid ,Kinetics ,Liver ,chemistry ,Cell culture ,Female ,Oligopeptides - Abstract
H-Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH2 (Antagonist G) will be the first broad-spectrum neuropeptide antagonist to enter a phase I clinical trial. Its in vitro and in vivo metabolism has been extensively characterized. The major metabolites were identified and their structures elucidated by mass spectroscopy and amino acid analysis. Metabolism occurred almost exclusively at the C-terminus and was arrested by phenylmethylsulfonylfluoride, a known serine-protease inhibitor. Biological characterization of the metabolites demonstrated that the degradation of Antagonist G produces metabolites that retain neuropeptide antagonist properties.
- Published
- 1995
26. The Anti-proliferative Activity of Interferon-γ on Ovarian Cancer: In Vitro and in Vivo
- Author
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F. Burke, Frances R. Balkwill, Lucy Wall, and John F. Smyth
- Subjects
medicine.medical_treatment ,Antineoplastic Agents ,Ovary ,Interferon-gamma ,In vivo ,Tumor Cells, Cultured ,medicine ,Carcinoma ,Animals ,Humans ,Interferon gamma ,Ovarian Neoplasms ,Clinical Trials as Topic ,Cell growth ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,medicine.anatomical_structure ,Cytokine ,Oncology ,Immunology ,Cancer research ,Female ,Ovarian cancer ,business ,Cell Division ,medicine.drug - Published
- 2003
27. Treatment of advanced breast cancer with the aromatase inhibitor 4-hydroxyandrostenedione: a phase II trial
- Author
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John F. Smyth, Mitchell Dowsett, M. Stewart, A. Rodger, Robert C. F. Leonard, A. Bowman, and A. P. M. Forrest
- Subjects
medicine.medical_specialty ,Chemotherapy ,Aromatase inhibitor ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Cancer ,General Medicine ,medicine.disease ,Gastroenterology ,Surgery ,Stable Disease ,Internal medicine ,Toxicity ,medicine ,Hormone therapy ,business ,Intramuscular injection ,Progressive disease - Abstract
50 postmenopausal women with advanced breast cancer were treated with 4-hydroxy-androstenedione (4-OHA) by intramuscular injection of 500 mg given every 2 weeks for 24 weeks unless progression of disease or intolerable side-effects precluded further treatment. All patients had received prior chemotherapy or hormone therapy and 16 patients had responded to their most recent treatment. 46 patients were evaluable for efficacy; 1 died of progressive disease within 3 weeks and 3 were withdrawn for unrelated medical conditions and were ineligible for assessment. All 50 patients were evaluated for toxicity; systemic symptoms were uncommon but 10 patients reported buttock discomfort. Of the 46 patients assessable for response, 7 (15%) had a partial response and 12 (26%) stable disease with 27 (59%) showing disease progression. The median duration of response was 85 weeks (range 32–219 weeks) and the median time to progression was 12 weeks (range 2–219 weeks).
- Published
- 1994
28. Growth inhibition of oestrogen receptor-positive human ovarian carcinoma by anti-oestrogens in vitro and in a xenograft model
- Author
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A.A. Ritchie, A. J. Crew, John F. Smyth, Simon P. Langdon, M. Muir, A. E. Wakeling, and William R. Miller
- Subjects
Cancer Research ,medicine.medical_specialty ,Polyunsaturated Alkamides ,Transplantation, Heterologous ,Mice, Nude ,Adenocarcinoma ,Biology ,Mice ,chemistry.chemical_compound ,In vivo ,Internal medicine ,Ovarian carcinoma ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,skin and connective tissue diseases ,Fulvestrant ,Ovarian Neoplasms ,Dose-Response Relationship, Drug ,Estradiol ,Estrogen Antagonists ,Antiestrogen ,In vitro ,Transplantation ,Tamoxifen ,Endocrinology ,Receptors, Estrogen ,Oncology ,chemistry ,Cell culture ,Cancer research ,Female ,Growth inhibition ,Cell Division ,Neoplasm Transplantation ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
This paper presents results of the in vitro and in vivo effects of anti-oestrogens on the growth of human ovarian cancer cells. Tamoxifen and the "pure" anti-oestrogens, ICI 164,384 and ICI 182,780, inhibited the oestrogen-stimulated growth of the oestrogen receptor (ER)-positive PE04 and PE01 cell lines grown in culture, the latter two compounds being more potent than tamoxifen. In the absence of 17 beta-oestradiol (E2), tamoxifen, but not the pure anti-oestrogens, produced a small degree of growth stimulation in the PE01 and PE04 lines at concentrations between 10((7) and 10(-9) M. In contrast, growth of the ER-negative PE014 line was unaffected by E2 and all three anti-oestrogens. The effects of tamoxifen and ICI 182,780 on PE04 cells grown as xenografts in nude mice were also studied. Both anti-oestrogens produce significant growth inhibitory effects. These results indicate that ovarian carcinoma cells may be sensitive to anti-oestrogens in vitro and in vivo, and support the view that anti-oestrogens merit further clinical studies in patients with ER-positive tumours.
- Published
- 1994
29. Editorial comment on ‘A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy' by Schmitt et al
- Author
-
R.L Hayward and John F. Smyth
- Subjects
Cancer Research ,Lymphoma, B-Cell ,Transgene ,Apoptosis ,Mice, Transgenic ,Transfection ,Viral vector ,Mice ,In vivo ,Animals ,Medicine ,Clonogenic assay ,Mitotic catastrophe ,Cyclin-Dependent Kinase Inhibitor p16 ,business.industry ,Genes, p53 ,medicine.disease ,Lymphoma ,Treatment Outcome ,Oncology ,Drug Resistance, Neoplasm ,Cancer research ,Stem cell ,business ,Neoplasm Transplantation ,Ex vivo ,DNA Damage - Abstract
‘What are the mechanisms of intrinsic drug resistance in solid tumours, and how might they be circumvented?’ These are key questions for molecular oncologists, for clinicians and patients. For many years, it was assumed that the interaction of a DNA damaging drug with its target would yield a lethal lesion, and that determinants of intrinsic drug resistance should therefore be sought upstream of this interaction, in drug metabolism or drug transport mechanisms. It is now apparent that cellular responses in vitro to a given DNA lesion can include necrosis, mitotic catastrophe, apoptosis, prolonged cell cycle arrest or even unrestrained growth. The response depends on the cellular genotype and, specifically, on the integrity of response pathways downstream of the drug–target interaction. Despite this progress in the laboratory, the proof that downstream events determine therapeutic responses in the clinic remains elusive. A seminal series of papers from Scott Lowe’s laboratory represent a major step in this direction. Lowe and colleagues prove conclusively that downstream determinants of apoptosis profoundly influence the response to therapy in vivo. They also demonstrate, for the first time, that prolonged drug induced growth arrest can result in prolonged disease stability whilst providing a residual pool of viable malignant cells from which late relapsing clones may ultimately emerge. These papers have mapped out new challenges and new opportunities for the oncologist of the future. Utilising the Em-myc transgenic murine model of B-cell lymphoma (in which myc overexpression drives lymphomagenesis), Lowe and colleagues have developed a rapid technique for the introduction of defined compound genetic lesions, allowing study of resulting phenotypes in a well-controlled fashion in vivo [1]. Primary lymphoma or haematopoetic stem cells, isolated from mice of known genetic background (Em-myc crossed with P53-null, or ARF-null or ARF/INK4a-null), are retrovirally transduced ex vivo with a gene of interest and reintroduced into the tail veins of syngeneic recipients. The transduction process itself does not alter the subsequent behaviour of the resulting lymphoma, so that controls transduced with the green fluorescent protein (GFP) gene alone yield lymphomas histopathologically indistinguishable from the parent lymphoma. Introduction of a gene of interest along with GFP in a bicistronic retroviral vector allows study of the effect of that gene on tumour behaviour by the elegant non-invasive means of whole-animal fluorescence imaging. An early paper in the series demonstrates conclusively that overexpression of the anti-apoptotic protein bcl-2 produces a multi-drug resistance phenotype in primary lymphomas in vivo [2]. This effect is suppressed by prior serial passage of the lymphoma lines in vitro, because the cells acquire multi-drug resistance merely as a consequence of prolonged cell culture. Furthermore, the effect of bcl-2 is completely obscured in standard clonogenic assays of drug sensitivity, because bcl-2 suppresses drug-induced apoptosis, but not prolonged growth arrest, both equally efficient means of reducing clonogenicity. These observations shed some light on why assays of drug response in established cell lines or xenografts derived from solid tumours have failed in the past to consistently predict clinical response, and indeed have often provided contradictory results. In general, such models simply cannot recapitulate conditions pertaining in vivo.
- Published
- 2002
30. DNA topoisomerase I and II as targets for rational design of new anticancer drugs
- Author
-
Jeffrey Cummings and John F. Smyth
- Subjects
medicine.drug_class ,Drug Resistance ,Antineoplastic Agents ,Topoisomerase-I Inhibitor ,Cleavage (embryo) ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Topoisomerase II Inhibitors ,biology ,Topoisomerase ,Hematology ,Cell cycle ,DNA Topoisomerases, Type II ,DNA Topoisomerases, Type I ,Oncology ,chemistry ,Biochemistry ,Drug Design ,biology.protein ,Topoisomerase I Inhibitors ,Topoisomerase-II Inhibitor ,Camptothecin ,DNA ,Topoisomerase inhibitor ,medicine.drug - Abstract
Summary Background Topoisomerase I and II (topo I and II) are enzymes which alter the topological state of DNA through DNA strand cleavage, strand passage and religation. They participate in most aspects of DNA metabolism and are therefore vital to the cell undergoing division. Only one form of topo I has been identified whereas two isoenzymes of topo II have been described: the α form (170 kDa protein) and β form (180 kDa protein). Both topo II isoenzymes have distinct nuclear localisation, are regulated independently, differ in their responsiveness to inhibitors and are differentially expressed in drug resistant cell lines. Results Several clinically active anticancer drugs (e.g., doxorubicin, m-AMSA, VP-16 and camptothecins) poison these enzymes by stabilizing a putative reaction intermediate called the cleavable complex (cc) where the topoisomerase remains covalently attached to either one strand of DNA (topo I) or both strands of double helix (topo II) after strand cleavage. DNA cleavage sites appear unique for different classes of inhibitor, and are probably critical for defining cytotoxicity. Formation of the cc may cause cell death either by colliding with replication forks, by promoting illegitimate genomic-DNA recombination, by arresting cells in the G2-phase of the cell cycle or by inducing apoptosis. Conclusion New classes of inhibitor have recently been described with novel mechanisms of action including compounds which do not stabilize cleavable complexes or bind significantly to DNA. These may prove to be more selective and less toxic. They may also avoid the possible problem of therapy-related leukemias associated with topo inhibitors which induce DNA cleavage and chromosomal aberrations.
- Published
- 1993
31. Randomized phase II trial of iproplatin and carboplatin in advanced breast cancer
- Author
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J. Renard, John F. Smyth, Michel Clavel, Jan B. Vermorken, Pierre Dodion, Stan B. Kaye, and Stein Gundersen
- Subjects
Iproplatin ,Cisplatin ,medicine.medical_specialty ,Chemotherapy ,Palliative care ,endocrine system diseases ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Hematology ,medicine.disease ,Gastroenterology ,Metastatic breast cancer ,female genital diseases and pregnancy complications ,Carboplatin ,Surgery ,chemistry.chemical_compound ,Breast cancer ,Oncology ,chemistry ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Summary Background The observed activity of cisplatin in breast cancer and its unattractive toxicity profile in palliative treatment warranted further study of platinum analogues in this disease. Patients and methods Sixty-two patients with recurrent or metastatic breast cancer, 61 of whom had been previously treated with chemotherapy, were randomly assigned to therapy with either iproplatin (n = 32) or carboplatin (n = 30). Both platinum analogues were administered intravenously, iproplatin at a dose of 240 mg/m2 every 4 weeks and carboplatin at a dose of 450 mg/m2 every 5 weeks. Results Only two patients responded to iproplatin (7%) for durations of 21 and 61 weeks, and one patient responded to carboplatin (3%) for a duration of 64 weeks. All responses were complete. At the given dose schedules carboplatin was more myelosuppressive than iproplatin. Non-hematologic toxicities included nausea and vomiting (93% vs. 90%), diarrhea (20% vs. 10%) and hemorrhage (16% vs. 10%) for iproplatin and carboplatin, respectively. Two patients developed alopecia with carboplatin. No renal toxicity was observed. Conclusions Both iproplatin and carboplatin have limited activity in previously treated women with advanced breast cancer when given in conventional dosages.
- Published
- 1993
32. Determination of mitomycin C, 2,7-diaminomitosene, 1,2-cis- and 1,2-trans-1-hydroxy-2,7-diaminomitosene in tumour tissue by high-performance liquid chromatography
- Author
-
Linda Chirrey, John F. Smyth, Gavin Halbert, Jeffrey Cummings, and N. Willmott
- Subjects
Chromatography ,medicine.diagnostic_test ,Mitomycin ,Metabolite ,Sodium ,Mitomycin C ,Extraction (chemistry) ,Mammary Neoplasms, Experimental ,chemistry.chemical_element ,General Chemistry ,Hydrogen-Ion Concentration ,High-performance liquid chromatography ,Mitomycins ,Rats ,chemistry.chemical_compound ,Porfiromycin ,chemistry ,Ionic strength ,Spectrophotometry ,medicine ,Animals ,Female ,Spectrophotometry, Ultraviolet ,Chromatography, High Pressure Liquid - Abstract
A high-performance liquid chromatographic method is described for the determination of mitomycin C (MMC) and its metabolites 2,7-diaminomitosene (2,7-DM), 1,2-cis-1-hydroxy-2,7-diaminomitosene (cis-hydro) and 1,2-trans-1-hydroxy-2,7-diaminomitosene (trans-hydro) in tumour tissue. N-la-Methylmitomycin C (porfiromycin, PM) was used as an internal standard. Two factors were critical in resolving the metabolites: pH and buffer ionic strength, where the retention times of the four components were affected in the order 2,7-DM >> cis-hydro >> trans-hydro >> MMC. The optimal isocratic conditions (flow-rate 1 ml/min) were 18 mM sodium phosphate pH 5.8-methanol (74:26) and a column temperature of 40 degrees C on a Spherisorb ODS-2 column (25 cm x 4.6 mm I.D.). Liquid-liquid extraction [twice with chloroform-propan-2-ol-ethyl acetate (2:2:1)] is described for tumour tissue. Recoveries varied depending on the component: MMC, 71.9 +/- 12.4%; PM, 85.5 +/- 27%; 2,7-DM, 51.7 +/- 5.4%; cis-hydro, 52.0 +/- 16.8%; trans-hydro, 62 +/- 8%. When applied to the analysis of a rat mammary carcinoma treated intra-tumourally with 450 micrograms of MMC five drug-related "metabolite" peaks were detected. Three of these co-chromatographed with standards of 2,7-DM, cis- and trans-hydro, and had identical absorption maxima to their respective standards, with the possible exception of trans-hydro.
- Published
- 1993
33. The enzymology of doxorubicin quinone reduction in tumour tissue
- Author
-
John F. Smyth, N. Willmott, Jeffrey Cummings, Robert J. Riley, Lucy Allan, and Paul Workman
- Subjects
Naphthacenes ,Reductase ,Biology ,Biochemistry ,chemistry.chemical_compound ,Oxidoreductase ,medicine ,Animals ,Glycosides ,Quinone Reductases ,Biotransformation ,Hypoxanthine ,Pharmacology ,chemistry.chemical_classification ,Quinones ,Mammary Neoplasms, Experimental ,Cytochrome P450 reductase ,Rats, Inbred Strains ,Dicoumarol ,Rats ,Oxygen ,Enzyme ,chemistry ,Doxorubicin ,Microsomes, Liver ,Microsome ,Female ,NAD+ kinase ,Oxidation-Reduction ,Subcellular Fractions ,medicine.drug - Abstract
We have reported previously that enzymes present in the Sp 107 rat mammary carcinoma catalyse doxorubicin quinone reduction (QR) to 7-deoxyaglycone metabolites in vivo [Willmott and Cummings, Biochem Pharmacol 36: 521-526, 1987]. In order to provide insights into the role of QR in the antitumour mechanism of action of doxorubicin, we have attempted in this work to identify the enzyme(s) responsible. NAD(P)H: (quinone acceptor) oxidoreductase (DT-diaphorase) was the major quinone reductase in the tumour accounting for approximately 70% of all the activity measured in microsomes and cytosols (microsomal activity, 28.4 +/- 4.6 nmol/min/mg; cytosolic activity, 94.3 +/- 11.9 nmol/min/mg). Its presence was confirmed by western blot analysis. Low levels of NADH cytochrome b5 reductase (15.6 +/- 6.3 nmol/min/mg) and NADPH cytochrome P450 reductase (14.5 +/- 4.0 nmol/min/mg) were detectable in microsomes. The presence of the latter was confirmed by western blot analysis. Pretreatment of tumours with doxorubicin (48 hr) at a therapeutic dose decreased the level of activity of all the reductases studied by at least 2-fold (P0.01, Student's t-test). Doxorubicin was shown not to be a substrate for purified rat Walker 256 tumour DT-diaphorase with either NADH or NADPH as co-factor and utilizing up to 20,000 units of enzyme/incubation but was confirmed to be a substrate for purified rat liver cytochrome P450 reductase. 7-Deoxyaglycone metabolite formation by purified cytochrome P450 reductase had an absolute requirement for NADPH as co-factor, was inhibited by molecular oxygen and dicoumarol (IC50 approx. 50 microM), and modulated by specific reductase antiserum. Reductive deglycoslation of doxorubicin to 7-deoxyaglycones was localized to the microsomal fraction of the Sp 107 tumour, with negligible activity being found in cytosols (NADH, NADPH and hypoxanthine as co-factors) and mitochondria (NADH and NADPH). The tumour microsomal enzyme had an absolute co-factor requirement for NADPH, was inhibited by oxygen and dicoumarol, and modulated by cytochrome P450 reductase antiserum. These data indicate strongly that NADPH cytochrome P450 reductase is the principal enzyme responsible for catalysing doxorubicin QR in the Sp 107 tumour.
- Published
- 1992
34. Studies on the molecular pharmacology of GR63178A
- Author
-
John F. Smyth, Jeffrey Cummings, Ian D. Hickson, Gordon A. Leonard, Brigid M Hoey, Andrew M. Fry, Martin A. Graham, John Butler, and Raymond C. French
- Subjects
Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Oligonucleotide ,Chemistry ,DNA damage ,Stereochemistry ,Radical ,Topoisomerase ,Biochemistry ,Quinone ,Mechanism of action ,medicine ,biology.protein ,medicine.symptom ,Free Radical Formation - Abstract
GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.
- Published
- 1992
35. Cutaneous malignant melanoma, Scotland, 1979-89
- Author
-
M. A. Cornbleet, D Hole, A. W. Hutcheon, K. M. Mclaren, R. Rankin, John F. Smyth, Tom Aitchison, John A. A. Hunter, Rona M. Mackie, D.S. Soutar, Alan Evans, D.H Jones, A.C.H. Watson, and K Blessing
- Subjects
medicine.medical_specialty ,education.field_of_study ,business.industry ,Incidence (epidemiology) ,Melanoma ,Population ,General Medicine ,Male trunk ,medicine.disease ,Surgery ,Internal medicine ,Epidemiology ,medicine ,education ,business ,Public education ,Pathological ,Survival rate - Abstract
The Scottish Melanoma Group (SMG) was established in 1979 to assess mortality from and incidence, features, pathological data, and management of cutaneous malignant melanoma in Scotland. Incidence during the first five years and five-year survival have already been reported. We now have data about incidence and mortality over eleven years in relation to anatomical site and pathological types. From 1979 to 1989, 1354 male and 2459 female patients with primary cutaneous malignant melanomas were first diagnosed in Scottish residents. The incidence rate per 100,000 population per year has increased from 3.4 in 1979 to 7.1 in 1989 for men, and from 6.6 to 10.4 for women. The overall increase over eleven years is 82% (7.4% per year). The greatest rates of increase are seen in lesions of the superficial spreading histogenetic type, arising on the female leg and the male trunk. Following public education programmes started in 1985, the proportion of all melanomas less than 1.5 mm thick has shown a sustained and significant increase. Mortality data for 1661 patients for whom a minimum of five-year follow-up is available shows five-year survival of 71.6% overall (77.6% for women, 58.7% for men). The survival advantage for women persists when appropriate statistical adjustment is made for thickness, ulceration, and histogenetic type. These data are useful in designing public education programmes aimed at both primary and secondary prevention of melanoma and in auditing changes in trends that might result from such education.
- Published
- 1992
36. Phase II study of tauromustine in malignant glioma
- Author
-
Svante Wählby, John F. Smyth, James W. Ironside, Anna Gregor, Ian R. Whittle, Moira Stewart, Ron Rye, Per-Uno Malmström, R. Rampling, Matti S. Aapro, B. Demierre, and Robin Sellar
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Taurine ,medicine.medical_treatment ,Phases of clinical research ,Antineoplastic Agents ,Astrocytoma ,Gastroenterology ,Drug Administration Schedule ,Nitrosourea Compounds ,Internal medicine ,Glioma ,medicine ,Humans ,Prospective Studies ,Survival rate ,Chemotherapy ,Leukopenia ,Brain Neoplasms ,business.industry ,Nausea ,Middle Aged ,medicine.disease ,Thrombocytopenia ,Surgery ,Discontinuation ,Oncology ,Drug Evaluation ,Tauromustine ,Female ,medicine.symptom ,business ,Anaplastic astrocytoma - Abstract
46 eligible patients with either anaplastic astrocytoma (AA) or glioblastoma (GBM) and clinical and computed-tomography-confirmed relapse following primary surgery and radiotherapy received oral tauromustine 130 mg/m2 every 5 weeks. A prospective design allowed for concurrent assessment of both clinical and radiological responses and drug toxicity. 41% of patients improved clinically whilst 46% improved radiologically with 3 complete, 7 partial and 7 minimal responses (WHO criteria). Toxicity included grade III or IV gastrointestinal side-effects (15%), grade III or IV leukopenia (24%) and grade III and IV thrombocytopenia (44%). In 9 clinically responding patients, haematological toxicity led to discontinuation of treatment. All patients were followed-up until death and second-line chemotherapy was not used. Median post-treatment survival was 26 weeks for patients with GBM and 57 weeks for patients with AA. Overall 2-year survival rate was 69% for AA and 23% for GBM. Tauromustine given at the time of relapse has demonstrable antitumour activity in patients not previously treated with chemotherapy.
- Published
- 1992
37. The late results of consolidation treatment following induction chemotherapy for small cell lung cancer
- Author
-
Gabor Newaishy, Anna Gregor, Graham K. Crompton, M. A. Cornbleet, Robert C. F. Leonard, Robert E. Coleman, Andrew P. Greening, John F. Smyth, and M. Stewart
- Subjects
Pulmonary and Respiratory Medicine ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Lung ,M.2 ,business.industry ,medicine.medical_treatment ,Respiratory disease ,Induction chemotherapy ,medicine.disease ,Surgery ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,Conventional PCI ,medicine ,Prophylactic cranial irradiation ,business - Abstract
33 106 (32%) patients with limited disease (LD) small cell lung cancer (SCLC) achieved a bronchoscopically confirmed complete response (CR) following 4 courses of induction chemotherapy. These patients were offered ‘late intensification’ with high dose melphalan (HDM) (140 mg/m 2 ) and autologous bone marrow support. LDCR patients were advised also to receive radiotherapy to the primary site and prophylactic cranial irradiation (PCI). After a minimum follow-up of 3 years, the LDCR patients who received HDM ( n =13) have had a median disease-free survival (DFS) of 15 months and a median overall survival (OS) of 16 months, compared with a DFS of 9 months ( P =0.06) and OS of 11 months ( P =0.23) for patients who did not receive late intensification ( n =20). Chest radiotherapy and PCI reduced the frequency of recurrence at these sites. Only patients who had received both chest radiotherapy and PCI were disease-free at 18 months. In this non-randomised study it is not possible to state with certainty the contribution of consolidation treatment in SCLC. Nevertheless, in patients with chemosensitive limited disease, late intensification chemotherapy, chest radiotherapy and PCI all appear to have a positive effect on DFS.
- Published
- 1991
38. The role of protein kinase C and the phosphatidylinositol cycle in multidrug resistance in human ovarian cancer cells
- Author
-
Lorraine Anderson, Jeffrey Cummings, John F. Smyth, and Tracey D. Bradshaw
- Subjects
medicine.medical_specialty ,Inositol Phosphates ,Drug Resistance ,chemistry.chemical_element ,Calcium ,Biology ,Phosphatidylinositols ,Models, Biological ,Biochemistry ,Calcium in biology ,Cell Line ,chemistry.chemical_compound ,Internal medicine ,Phorbol Esters ,medicine ,Humans ,Phosphatidylinositol ,Inositol phosphate ,Calcimycin ,Protein Kinase C ,Protein kinase C ,Ovarian Neoplasms ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Cell growth ,Bombesin ,Molecular biology ,Endocrinology ,chemistry ,Doxorubicin ,Cell culture ,Female - Abstract
The present study aimed to investigate the role of protein kinase C (PKC), the phosphatidylinositol pathway (PI) and cytosolic calcium in multidrug resistance (MDR) in human ovarian carcinoma cells. Binding of the phorbol ester 13,14-dibutyrate (PDBu) was 3-fold higher in resistant A2780AD versus sensitive A2780 cells indicating increased PKC activity. However, when inositol phosphate production (IP) was measured in quiescent cells similar total IP release was seen in both lines suggesting no difference in the basal turnover of PI. Non-specific stimulation of the PI pathway was achieved with the calcium ionophore A23187 which increased IP production in a time- and dose-dependent fashion in both cell lines but was significantly less effective in A2780AD. The PI pathway was investigated further using the agonists aluminium fluoride, serum and bombesin but these agents failed to elicit a response. The effect of a wide range of Adriamycin concentrations on the PI cycle and cell growth was also studied. Intracellular calcium was measured with the fluorescent dye fura-2-pentaacetoxymethylester (Fura-2). A23187 produced a rise in cytosolic calcium in A2780 and A2780AD but from a level 3-fold lower in the unstimulated resistant cell line. The dose responsiveness of this effect was greater but irreversible in A2780AD cells. Collectively these results imply that alterations in PI turnover appear not to be responsible for the differences in PDBu binding and calcium handling observed between A2780 and A2780AD and suggests only a minor role for the PI cycle in the maintenance of MDR in human ovarian cancer cell lines.
- Published
- 1991
39. The molecular pharmacology of doxorubicin in vivo
- Author
-
John F. Smyth, N. Willmott, Lorraine Anderson, and Jeffrey Cummings
- Subjects
Binding Sites ,Free Radicals ,Chemistry ,Cell Membrane ,DNA, Neoplasm ,Molecular Pharmacology ,Pharmacology ,Enzymes ,DNA Topoisomerases, Type II ,Oncology ,Doxorubicin ,In vivo ,Neoplasms ,medicine ,Humans ,medicine.drug - Published
- 1991
40. Determination of covalent binding to intact DNA, RNA, and oligonucleotides by intercalating anticancer drugs using high-performance liquid chromatography. Studies with doxorubicin and NADPH cytochrome P-450 reductase
- Author
-
John F. Smyth, Jeffrey Cummings, and Agnieszka Bartoszek
- Subjects
Ion chromatography ,Oligonucleotides ,Biophysics ,DNA, Single-Stranded ,Antineoplastic Agents ,Breast Neoplasms ,Biochemistry ,chemistry.chemical_compound ,Affinity chromatography ,Tumor Cells, Cultured ,Animals ,Humans ,Carbon Radioisotopes ,Molecular Biology ,Chromatography, High Pressure Liquid ,NADPH-Ferrihemoprotein Reductase ,chemistry.chemical_classification ,Chromatography ,Chemistry ,Oligonucleotide ,RNA ,DNA ,DNA, Neoplasm ,Cell Biology ,Metabolism ,Enzyme ,Doxorubicin ,Nucleic acid - Abstract
An HPLC method is described which can determine covalent binding to intact nucleic acid by intercalating anticancer drugs and at the same time remove noncovalently bound intercalated drug. The method uses a column containing a nonporous 2-microns DEAE anion-exchange resin capable of chromatographing nucleic acids greater than 50,000 bases in size in under 1 h. After priming with 1 mg of DNA, the column behaves as an intercalator affinity column, strongly retaining the drug while allowing the nucleic acid to pass through normally. Retained drug is released with an injection of 0.1 M potassium hydroxide. Incubations were performed with the intercalator doxorubicin, which is also believed to bind covalently to DNA. When [14C]doxorubicin was mixed with DNA, at a concentration where all the drug would bind by intercalation, the column retained 82% of the total radioactivity, only 18% migrated with the nucleic acid. If the DNA was mildly denatured by treatment with 2 M sodium chloride at 50 degrees C for 45 min before chromatography, then 99.8% of total radioactivity was retained, only background counts migrated with the nucleic acid, as was the case with single-stranded DNA and RNA without any treatment. Purified NADPH cytochrome P-450 reductase was used to activate doxorubicin. DNA inhibited the metabolism of the drug by the enzyme, no covalent binding occurred with RNA, low levels occurred with single-stranded DNA (34 pmol/100 micrograms), and the highest levels were recorded with oligonucleotides (243 pmol/100 micrograms). The assay was sufficiently sensitive to measure covalent binding to DNA extracted from MCF-7 human breast cancer cells treated with 50 microM [14C]doxorubicin (18.6 pmol/100 micrograms). Thus, covalent binding to DNA, RNA, and oligonucleotides by intercalators can be measured quickly (20 min) without the need to either digest the nucleic acid or subject it to long sample preparation techniques.
- Published
- 1991
41. Original article: Potentiation of cisplatin by alpha-Interferon in advanced non-small cell lung cancer (NSCLC): A phase II study
- Author
-
Anna Gregor, S. G. Allan, A. Bowman, John F. Smyth, Andrew P. Greening, M. Stewart, Robert C. F. Leonard, Graham K. Crompton, M.A. Combleet, and R.J. Fergussion
- Subjects
Oncology ,Cisplatin ,medicine.medical_specialty ,Performance status ,business.industry ,Phases of clinical research ,Alpha interferon ,non-small cell lung cancer (NSCLC) ,Hematology ,medicine.disease ,Squamous carcinoma ,Internal medicine ,Toxicity ,medicine ,Lung cancer ,business ,medicine.drug - Abstract
Summary Studies in experimental human lung cancer models have suggested that interferon may enhance significantly the response to some cytotoxic drugs. We have performed a phase II study of cisplatin (100 mg/m2 q.21 or 28 days) and alpha-2 interferon (3 or 5 MU three times weekly) in 68 patients with advanced non-small cell lung cancer and good performance status. As toxicity was acceptable, the dose of interferon and schedule of cisplatin were increased at the midpoint of the study. 46% (11/24) of patients with squamous carcinoma responded and an overall partial response rate of 30% was attained in 60 evaluable patients. There was no potentiation of haematological, renal or neurological toxicity but nausea and vomiting were severe. These results suggest that the combination has activity in this usually refractory disease.
- Published
- 1990
42. Relationship between reductive drug metabolism in tumour tissue of anthracyclines in microspherical form and anti-tumour activity
- Author
-
John F. Smyth, N. Willmott, Elaine Marley, and Jeffrey Cummings
- Subjects
Pharmacology ,Drug ,Metabolic Clearance Rate ,media_common.quotation_subject ,Mammary Neoplasms, Experimental ,Rats, Inbred Strains ,Metabolism ,Biology ,Biochemistry ,Microspheres ,Rats ,Pharmacokinetics ,Targeted drug delivery ,Doxorubicin ,In vivo ,medicine ,Animals ,Drug Screening Assays, Antitumor ,Oxidation-Reduction ,Anaerobic exercise ,Drug metabolism ,medicine.drug ,media_common - Abstract
Increased activity against a rat solid tumour of doxorubicin incorporated into protein microspheres and administered intratumourally was associated with both increased duration of exposure of tumour tissue to native drug and anaerobic bioreduction of doxorubicin to 7-deoxyaglycones, indicating formation of reactive drug intermediates within tumour tissue. To investigate which of these aspects of drug disposition determined activity we have compared the in vivo fate (clearance from and metabolism by tumour tissue) of doxorubicin in microspherical form with the analogue 4'-deoxydoxorubicin and related this to the tumour growth delay recorded for these drugs. Within the dose range 42 to 55 micrograms, growth delay (14-18 days) of doxorubicin in microspherical form was markedly superior to drug in solution, whereas growth delay of 4'-deoxydoxorubicin in microspherical form (4.3-7.2 days) was not greater than drug in solution. Metabolism to 7-deoxyaglycones by tumour tissue was not a prominent feature of either drug when administered in solution. However, in microspherical form both drugs were extensively metabolized (peak concentrations: 3.6 micrograms/g doxorubicin 7-deoxyaglycone; 2.5 micrograms/g 4'-deoxydoxorubicin 7-deoxyaglycone). Native drug concentrations in tumour tissue were similar after administration in microspherical form at 48 hr (doxorubicin 3.8 micrograms/g; 4'-deoxydoxorubicin 3.7 micrograms/g) and 72 hr (doxorubicin 2.4 micrograms/g; 4'-deoxydoxorubicin 2.7 micrograms/g). At both time points, following administration in microspherical form, tumour tissue concentrations of doxorubicin were significantly greater than when drug was administered in solution, whereas no significant differences were observed for 4'-deoxydoxorubicin. The results are inconsistent with the process of anaerobic bioreduction of doxorubicin to 7-deoxyaglycones being an important component of its anti-tumour activity in microspherical form and point to the importance of increased duration of exposure to native drug.
- Published
- 1990
43. The Old Order Changeth – A valedictory from the Editor-in-Chief
- Author
-
John F. Smyth
- Subjects
Cancer Research ,Oncology ,Order (business) ,Philosophy ,Editor in chief ,Management - Published
- 2010
44. How to improve the cost effectiveness of oncology drug development
- Author
-
Christopher McCabe and John F. Smyth
- Subjects
Cancer Research ,Oncology ,business.industry ,Cost effectiveness ,Anti cancer drugs ,Oncology drug ,Medicine ,Computational biology ,Pharmacology ,Integrative genomics ,Non-coding RNA ,business - Published
- 2010
45. Short report: Phase II trials of fosquidone (GR63178A) in carcinoma of the breast, head and neck, ovary and melanoma
- Author
-
Jantien Wanders, John F. Smyth, D.J.T. Wagener, Ian Judson, Jaap Verweij, Stan B. Kaye, Michel Clavel, W.W. ten Bokkel Huinink, Franco Cavalli, and Martine Piccart
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,Melanoma ,medicine.medical_treatment ,Head and neck cancer ,Phases of clinical research ,Cancer ,Hematology ,medicine.disease ,Gastroenterology ,Chemotherapy regimen ,Surgery ,Oncology ,Internal medicine ,medicine ,Carcinoma ,Headaches ,medicine.symptom ,business - Abstract
A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.
- Published
- 1992
46. The strength of European oncology
- Author
-
John F. Smyth
- Subjects
Europe ,Cancer Research ,medicine.medical_specialty ,Text mining ,Oncology ,business.industry ,Research ,medicine ,Humans ,Medical physics ,Medical Oncology ,business - Published
- 2008
47. Food for thought – should we stop doing research?
- Author
-
John F. Smyth
- Subjects
Cancer Research ,Biomedical Research ,business.industry ,Status quo ,Emerging technologies ,Research ,media_common.quotation_subject ,Context (language use) ,Public relations ,Medical Oncology ,Social issues ,Product (business) ,Oncology ,Food ,Excellence ,Political agenda ,Political science ,Health care ,Humans ,business ,media_common - Abstract
Accepted 21 September 2006 Available online 14 November 2006 Probably the last thing anyone wants to think about in early The problem of ‘Affordability of Health Care’ is one of the January is food – but the title did catch your attention didn’t it? The question of abandoning research is not as stupid as it first might seem – ‘we have a problem’ as the astronauts famously said – there is a genuine crisis developing, analogous to a production line where no-one can clear the finished product from the end of the conveyer belt. The successful results of research over the past 20 years now present us with unparalleled opportunities to improve screening, diagnosis and treatment of patients with cancer – but we cannot afford to implement the new technologies. Examples are plentiful and of course not restricted to oncology, but the introduction of new drugs always catches headlines. The decision by the UK authority The National Institute for Clinical Excellence (NICE) not to recommend Avastin for patients with colorectal cancer last year was a landmark in deciding against the introduction of a drug approved for efficacy and safety for that indication by the UK’s own licensing board. I am not criticising that particular decision but using this as an example of modern science outstripping financial resource. It would be absurd to slow down or abandon research but we have to find new ways to facilitate the uptake of successful research or it becomes just an intellectual activity for academia with no commercial profitability (which feeds future research) and of course fails the principle goal of improving health. er Ltd. All rights reserved 20. major social problems facing every community worldwide – the affluent, the poor – everyone. This is all about assessing priorities. The problems in Europe are of particular concern since there is great variability in attitude towards priority setting as well as obvious variability in wealth. The particular problem of variable access to new medicines was addressed in the report from the Karolinska Institute, which is updated in a special issue of EJC soon to be published, but it is essential to embrace the problem in the context of cancer care in its totality and not just to focus on the introduction of new medicines. Within the oncology community we have to accept that the overall results of cancer treatment remain poor with the majority of patients dying from their disease and many within months or very few years from diagnosis. This contrasts with progress in other branches of medicine, but the high incidence of cancer and the devastation that it brings to families preserves its place on the political agenda. In countries such as the UK where governments attempt to provide healthcare free of charge (from taxation) it is already clear that the status quo is unsustainable – hence the NICE decision on drugs such as Avastin. Under these circumstances what do you do about totally new interventions such as national programmes for bowel cancer screening, or the vaccination of girls against herpes viruses to prevent
- Published
- 2007
48. The two-faced keeper of gates to heaven
- Author
-
John F. Smyth
- Subjects
Cancer Research ,History ,media_common.quotation_subject ,Media studies ,Oncology ,Hurricane katrina ,Western europe ,Sympathy ,Guardian ,Heaven ,Tragedy (event) ,Natural disaster ,media_common ,Front (military) - Abstract
There are several reasons why Janus the ancient roman god sive cancer conferences to ensure that quality reigns over might be adopted as a patron of oncology. Suitably the guardian of the Gate of Heaven, Janus was represented with two faces, one in front and one behind. January is the month dedicated to Janus who presided over the entrance to the New Year, and with his two faces could look back to the past year and forward to the year ahead – we welcome the latter. 2005 was truly an ‘‘annus horribilis’’. Of all professions, oncologists are particularly used to tragedy and the unfairness of life-threatening illnesses at an inappropriate age, but last year the whole world witnessed natural disasters on an unprecedented scale: the Asian Tsunami; appalling drought in Africa and Western Europe; and in the USA, the hurricane Katrina. The now famous conference centre in New Orleans hosted many oncology conferences, for example, the huge 2004 ASCO meeting and it is through such events that many cancer researchers came to know and love the uniqueness of the ‘‘old’’ New Orleans. The future of this city is uncertain – especially as a conference venue upon which so much of the city s economy depended. Our heartfelt sympathy has been extended to all those involved. The world is already short of venues capable of hosting the ever increasingly large conferences for which there seems to be an insatiable appetite. Year on year there are more and more conferences attended by more and more enthusiasts – will it ever cease? I have written in these pages before to express a personal hope that we will move to fewer more comprehen
- Published
- 2006
49. Early mortality rates: a tool for phase III trials or for changing standard practice?
- Author
-
John F. Smyth, Jaap Verweij, and Medical Oncology
- Subjects
Protocol (science) ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Mortality rate ,Organ dysfunction ,Population ,Novelty ,Phase (combat) ,Clinical trial ,Regimen ,Oncology ,medicine ,medicine.symptom ,Intensive care medicine ,education ,business - Abstract
Defining and describing (dose-related) side-effects of chemotherapy are among the aims of phase I and II oncology trials. Phase I studies are intended to assess the safety of a drug or regimen, phase II to confirm the feasibility and assess long-term safety. They are usually performed in a single or just a few institutions. Due to the novelty of the regimen and the fact that safety is considered a major concern, it is sometimes the case that patient selection in such trials is rather conservative. If phase I and II trials are performed appropriately, the safety aspect should become less of a concern in phase III trials since investigators will know what to expect, how to manage the observed side-effects, and how to avoid entering patients that should not be entered in view of organ dysfunction, poor clinical condition and other factors. Nevertheless, since phase III studies have a different aim, and are mostly multi-centre, it is possible that the population becomes less well selected, whilst remaining within the limits of the protocol criteria. Most of the time, phase I and II studies have indeed appropriately predicted side-effects and designed ways to manage them. Fortunately, exceptions are truly rare. However, that does not mean that such exceptions do not occur. Whether this means that ‘‘Early mortality detected in a clinical trial is one of the most important parameters for assessing the safety of chemotherapy regimes’’, as indicated by Katopodis and colleagues [1], in their paper in the current issue of European Journal of Cancer entitled ‘‘60-Day all-cause mortality rates in patients treated for gastrointestinal cancers, in randomised
- Published
- 2004
50. CA125 response and disease stabilisation are associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer
- Author
-
A. Bowman, A B Young, Hani Gabra, John F. Smyth, M. Stewart, Simon P. Langdon, and A. Lessels
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Letrozole ,Estrogen receptor ,Disease ,medicine.disease ,Internal medicine ,medicine ,business ,Ovarian cancer ,medicine.drug - Published
- 2001
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