D Toomey

Publications (13)51.77 Total impact

• Article: Breast 08

  S.G. Maher, D. Toomey, C.M. Condron, D.J. Bouchier‐Hayes
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  ABSTRACT: Background: Interleukin-2 is used in immunotherapy of melanoma and renal cell carcinoma and results in a transient reduction in circulating T-lymphocytes. The mechanism underlying this reduction in lymphocytes is unknown. In vitro prolonged exposure to IL-2 and costimulation of T-cells results in AICD, mediated by interaction between Fas and FasL on T-cells. Intracellular taurine levels are known to be important in regulation of T-cell death. We hypothesize that IL-2 increases Fas/FasL expression on T-cells, which results in T-cell apoptosis, and that preloading T-cells with taurine attenuates T-cell apoptosis induced by IL-2 through regulation of Fas/FasL.Methods: T-cells were treated with anti-CD3 mAb and IL-2 to induce Fas and FasL expression. Some groups were preloaded with taurine. Fas and FasL expression, apoptosis and survival were assessed via flow cytometry.Results: Conclusions: The simultaneous administration of anti-CD3 and IL-2 increases FasL expression and apoptosis of T-cells. Preloading T-cells with taurine reduces Fas and FasL expression and apoptosis induced via anti-CD3 and IL-2. IL-2 receptor levels were not altered by treatment with taurine. Treatment of T-cells with anti-CD3 and IL-2 in the presence of Fas:Fc inhibitor resulted in a similar attenuation of apoptosis compared to that observed with taurine preloading, indicating that the reduction in apoptosis attributed to taurine is dependent on the FasL pathway.
  British Journal of Surgery 01/2009; 89(S1):52 - 52. · 4.61 Impact Factor
• Source

  Available from: Claire Condron

  Article: Correction of anaemia through the use of darbepoetin alfa improves chemotherapeutic outcome in a murine model of Lewis lung carcinoma.

  A M Shannon, D J Bouchier-Hayes, C M Condron, D Toomey
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  ABSTRACT: Darbepoetin alfa (Aranesp), Amgen) is a novel erythropoiesis-stimulating protein with a serum half-life longer than recombinant human erythropoietin (Epo), used in the treatment of cancer-associated anaemia. Anaemia is known to adversely affect prognosis and response to treatment in cancer patients. Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction. Although hypoxic stress usually results in cell death, hypoxia-resistant tumour cells are genetically unstable and often acquire a drug-resistant phenotype. Increasing tumour oxygenation and perfusion during treatment could have the doubly beneficial outcome of reducing the fraction of treatment-resistant cells, while increasing drug delivery to previously hypoxic tissue. In this study, we examined the effect of darbepoetin alfa on chemotherapy sensitivity and delivery in an in vivo model of Lewis lung carcinoma, shown here to express the Epo receptor (EpoR). We identified that weekly darbepoetin alfa treatment, commencing 10 days before chemotherapy, resulted in a significant reduction in tumour volume compared to chemotherapy alone. This was mediated by the prevention of anaemia, a reduction in tumour hypoxia and a concomitant increase in drug delivery. Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells. This study identifies an important role for darbepoetin alfa in increasing the therapeutic index of chemotherapy.
  British Journal of Cancer 08/2005; 93(2):224-32. · 5.04 Impact Factor
• Article: Effect of neoadjuvant chemoradiotherapy on angiogenesis in oesophageal cancer.

  C O McDonnell, D J Bouchier-Hayes, D Toomey, D Foley, E W Kay, E Leen, T N Walsh
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  ABSTRACT: Vascular endothelial growth factor (VEGF) levels are raised in the serum of patients with oesophageal carcinoma. The aim of this study was to evaluate the tumour microvasculature and the role of tumour-associated macrophages in VEGF production after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer. Sections from 92 consecutively resected oesophageal tumours were stained for VEGF, von Willebrand factor and CD68. Twenty-seven patients received preoperative chemoradiation and 65 underwent surgical excision alone. The cellular source of VEGF was determined by parallel-section staining. Microvessel density and macrophage count were determined for each tumour by means of image analysis software. There were no significant differences between the two groups in age, sex or tumour type. Local downstaging of disease was evident in most specimens of tumours that had received preoperative chemoradiation. All tumours stained positive for VEGF, including those demonstrating a complete pathological response. Staining of parallel sections confirmed macrophages as the principal source of VEGF. Mean microvessel density was 6.4 per high-power field (h.p.f.) in tumours that received preoperative chemoradiation compared with 5.3 per h.p.f. in those treated by surgery alone (P = 0.130). A significant increase in tumour-associated macrophage infiltration was noted in tumours treated with neoadjuvant chemoradiation (22.1 per h.p.f.) compared with those treated by surgery alone (14.3 per h.p.f.) (P = 0.042). Preoperative chemoradiation had little effect on the local angiogenic profile of the tumour in patients with oesophageal cancer. Tumour-infiltrating macrophages seem to be the source of persistent VEGF production after chemoradiotherapy and might explain the raised serum levels. Addition of an antiangiogenic agent to this regimen may be worthwhile in patients with oesophageal carcinoma.
  British Journal of Surgery 12/2003; 90(11):1373-8. · 4.61 Impact Factor
• Article: Neutrophil bactericidal function is defective in patients with recurrent urinary tract infections.

  C Condron, D Toomey, R G Casey, M Shaffii, T Creagh, D Bouchier-Hayes
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  ABSTRACT: Urinary tract infection (UTI), most frequently caused by Escherichia coli, is one of the most common bacterial infections in humans. It is a host inflammatory response to bacterial invasion in which large numbers of neutrophils are recruited into the bladder in response to cytokines secreted by the infected bladder epithelium. We hypothesise that an impaired host neutrophil response leads to susceptibility to recurrent UTI (rUTI). Therefore, the neutrophil inflammatory response of patients with a history of rUTI was compared to healthy controls. No difference in neutrophil adhesion receptor expression or complement receptor expression following bacterial stimulus was detected between the two groups. However, the expression of the IgG receptor CD16, bacterial phagocytosis and reactive oxygen intermediate (ROI) production were significantly reduced in UTI patient neutrophils compared to controls. Neutrophils from rUTI patients have a significantly reduced bactericidal function when compared to healthy controls, with the former showing a reduced capacity for activation. This reduced neutrophil function may result in defective bacterial clearance and lead to susceptibility to recurrent infection.
  Urological Research 11/2003; 31(5):329-34. · 1.23 Impact Factor
• Article: Immune function, telomerase, and angiogenesis in patients with primary, operable nonsmall cell lung carcinoma: tumor size and lymph node status remain the most important prognostic features.

  D Toomey, G Smyth, C Condron, E Kay, R Conroy, D Foley, C Hong, B Hogan, S Toner, P McCormick, P Broe, C Kelly, D Bouchier-Hayes
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  ABSTRACT: Lung carcinoma usually is advanced at the time of presentation and frequently shows metastatic spread. In recent times, prognostic factors such as c-erbB-2 in patients with breast carcinoma have provided useful information and beneficial therapeutic targets. The objective of this study was to evaluate angiogenesis, immune function, and telomerase expression in patients with nonsmall cell lung carcinoma (NSCLC) to determine their prognostic significance. Immunohistochemistry was used to evaluate the expression of human telomerase reverse transcriptase (hTERT; n = 115 patients), interleukin-2r (IL-2r; n = 40 patients), microvessel density (MVD; n = 81 patients), and vascular endothelial growth factor (VEGF; n = 61 patients). Three-year survival follow-up information was available for most patients, and a comprehensive review of clinicopathologic features was carried out. Fifty percent of tumors showed nuclear staining for hTERT, 55% of tumors showed some degree of lymphocyte IL-2r expression, 33% of tumors were recorded with an MVD that was higher than average, and VEGF staining was detected in 85% of tumors. None of the parameters measured had an impact on survival. hTERT expression was correlated with lymph node status. Lymph node status and tumor size were identified as independent prognostic factors. This study failed to identify a marker of prognosis for patients with NSCLC other than tumor size and lymph node status in this population. Telomerase expression was associated with metastases, raising the possibility that this enzyme is involved in the metastatic process. Tumor cell VEGF expression was identified frequently: This growth factor may have potential as a target for antiangiogenic therapy. Lung carcinoma typically is the result of large numbers of mutations. Further understanding of the biologic implications of these mutations will lead to the development of effective prognostic markers and treatments for patients with NSCLC.
  Cancer 12/2001; 92(10):2648-57. · 4.77 Impact Factor
• Article: TGF-beta1 is elevated in breast cancer tissue and regulates nitric oxide production from a number of cellular sources during hypoxia re-oxygenation injury.

  D Toomey, C Condron, Q D Wu, E Kay, J Harmey, P Broe, C Kelly, D Bouchier-Hayes
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  ABSTRACT: Cellular response to treatment is dependent on the metabolic preconditioning of individual cells, which is a reflection of environmental conditions. Within solid tumours there are areas of different oxygen tension, which, we hypothesise, may indicate that cells are exposed to conditions that change continually. Other characteristics of the solid-tumour microenvironment include the production of growth factors, one of which is transforming growth factor (TGF)-beta1. As part of this study, we measured TGF-beta1 and found it raised in the serum of breast cancer patients compared with controls (98.24+/-13.25 vs. 48.87+/-12.14 ng/mL; P < 0.05; n = 7), and in the conditioned medium of breast tumour explant tissue compared with matched normal tissue (21.1+/-5.3 vs. 4.7+/-1.2 ng TGF-beta1/gram of tissue; P < 0.05; n = 11). Nitric oxide (NO) is a cytotoxic molecule produced by a large number of cells and thought to have antimetastatic properties. In order to observe the effect of conditions within breast tumours on NO production, we exposed macrophages, endothelial cells and tumour cells to hypoxia re-oxygenation in vitro, both in the presence and absence of TGF-beta1. Hypoxia stimulated increased NO production in both macrophages (normoxia: 0.34+/-0.04 nmol/L nitrite vs. hypoxia: 1.04+/-0.18 nmol/L nitrite; P < 0.05) and endothelial cells (normoxia: 0.02+/-0.01 nmol/L nitrite vs. hypoxia: 0.21+/-0.07 nmol/L nitrite; P < 0.05). NO production in macrophages, endothelial cells and tumour cells was reduced significantly following hypoxia in the presence of TGF-beta1 in a concentration-dependent manner. These results suggest that, within breast tumours, tumour-derived TGF-beta1 in combination with environmental conditions may result in decreased local NO production, which could have implications for tumour growth.
  British journal of biomedical science 01/2001; 58(3):177-83. · 0.92 Impact Factor
• Article: Crystallization and preliminary crystallographic analysis of an NADH oxidase that functions in peroxide reduction in Thermus aquaticus YT-1.

  A Mac Sweeney, A D'Arcy, T M Higgins, S G Mayhew, D Toomey, M A Walsh
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  ABSTRACT: NADH oxidase from Thermus aquaticus is a thermostable flavoenzyme that is similar in amino-acid sequence and other properties to the flavoenzyme component of the NADH peroxidase systems from Salmonella typhimurium and Amphibacillus xylanus. The enzyme has been isolated from T. aquaticus and crystallized using the hanging-drop method of vapour diffusion with sodium citrate as a precipitant at pH 8.5. The crystals belong to the hexagonal space group P622 with unit-cell dimensions a = b = 89.9, c = 491.6 A, and diffract to 2.5 A resolution.
  Acta Crystallographica Section D Biological Crystallography 02/1999; 55(Pt 1):297-8. · 12.62 Impact Factor
• Article: Phenotyping of immune cell infiltrates in breast and colorectal tumours.

  D Toomey, J Harmey, C Condron, E Kay, D Bouchier-Hayes
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  ABSTRACT: White cell infiltration of solid tumors is an important prognostic indicator in malignant disease. Although macrophage infiltration is associated with good outcome in colorectal cancer, a high macrophage content is associated with poor prognosis in breast cancer. Suppressor macrophages prevent T cell activation in normal tissues such as mucosal linings exposed to continuous antigenic challenge. Interleukin 10 (IL-10), an immunosuppressive cytokine, inhibits macrophage co-stimulation of T cells. Suppressor macrophage numbers, T cell numbers and T cell activation status were assessed in cell suspensions obtained from fresh specimens of breast and colorectal tumours and matched normal tissues. IL-10 production by both malignant and matched normal tissue was also assessed. This study identified elevated numbers of suppressor macrophages in breast tumors compared to matched normal breast tissue. Colorectal tumors did not contain significant numbers of these cells. Although T cell numbers are increased in breast tumors, these cells do not appear to be fully activated, as assessed by major histocompatibility complex class II and Interleukin 2 receptor expression. In contrast, T cells in colorectal tumors exhibit greater expression levels of these markers. Breast tumors produce significantly higher levels of IL-10 than normal breast tissue whereas IL-10 levels in colorectal tumors are similar to normal colon tissue. Our findings of high suppressor macrophage numbers, high levels of IL-10 and poorly activated T cells in breast tumors compared to low suppressor macrophage numbers, low IL-10 and fully activated T cells in colorectal tumors may explain why high macrophage content is associated with poor prognosis in breast cancer and good prognosis in colorectal malignancy.
  Immunological investigations 02/1999; 28(1):29-41. · 1.16 Impact Factor
• Article: Purification and characterisation of NADH oxidase from Thermus aquaticus YT-1 and evidence that it functions in a peroxide-reduction system.

  D Toomey, S G Mayhew
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  ABSTRACT: A thermostable enzyme previously identified as an NADH oxidase has been purified from Thermus aquaticus YT-1 by chromatography on DEAE-cellulose and AMP-Sepharose. The enzyme is dimeric with subunits of 54 kDa and one molecule FAD/subunit. The FAD is tightly bound, but it can be removed reversibly by hydrophobic chromatography at low pH. The blue flavin semiquinone is stabilised during photo-chemical reduction of the enzyme. Chemical reduction by static titration with dithionite ion showed that the enzyme requires about 5 mol dithionite/mol FAD for full reduction, and that reduction occurs in four phases. Reduction by the substrate NADH is incomplete, with the formation of a new long-wavelength absorption underlying the semiquinone absorption. Amino acid sequencing showed that the T aquaticus enzyme resembles other microbial flavoenzymes that function in two-enzyme systems for the reduction of peroxides, and which contain two redox-active disulphide groups in addition to the flavin. The enzyme catalyses the reduction of O2, ferricyanide ion, 2,6-dichloroindophenol, and 5,5'dithiobis(2,2'-dinitrobenzoate), and of cumene hydroperoxide in the presence of the small protein component (AhpC) of the peroxide-reducing system of Salmonella typhimurium. The reduction of O2 is slow in the absence of exogenous flavin while dye reduction is fast, suggesting that the free flavin that is added to the usual assay for T. aquaticus NADH oxidase functions by mediating electron transfer from enzyme-bound reduced flavin to O2. The physiological function of the enzyme is probably in peroxide reduction with a small protein analogous to AhpC as the natural electron acceptor.
  European Journal of Biochemistry 03/1998; 251(3):935-45. · 3.58 Impact Factor
• Article: TGF beta-1 regulation of VEGF production by breast cancer cells.

  D Donovan, J H Harmey, D Toomey, D H Osborne, H P Redmond, D J Bouchier-Hayes
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  ABSTRACT: Angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor identified to date. TGF beta-1 acts as an indirect angiogenic agent. VEGF and TGF beta-1 were measured in the serum of breast cancer patients and age-matched controls and in tumor tissue of cancer patients by ELISA. VEGF protein and mRNA expression by breast tumor cell lines were examined, and the effect of TGF beta-1 on VEGF production in these cells was assessed. VEGF levels were significantly higher (P = .03) in the serum of patients with breast cancer compared to age-matched controls. A positive correlation was found between serum (r = 0.539) and tumor tissue (r = 0.688) levels of VEGF and TGF beta-1. Metastatic MDA-MB-231 breast cancer cells produce more VEGF than do the primary BT474 cells. TGF beta-1 significantly (P < .05) increased production of VEGF. Breast cancer cells constitutively produce VEGF protein and mRNA. There is a relationship between VEGF and TGF beta-1 levels in breast cancer patients, and TGF beta-1 regulates VEGF expression by breast cancer cells.
  Annals of Surgical Oncology 12/1997; 4(8):621-7. · 4.17 Impact Factor
• Article: Comparison of the N-terminal sequence of NADH oxidase from Thermus aquaticus with those of other flavoenzymes.

  D Toomey, S G Mayhew, A J Lanzetti, K F Geoghegan
  Biochemical Society Transactions 03/1996; 24(1):25S. · 3.71 Impact Factor
• Article: Mechanisms mediating cancer cachexia.

  D Toomey, H P Redmond, D Bouchier-Hayes
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  ABSTRACT: Cancer cachexia encompasses a wide range of metabolic, hormonal, and cytokine-related abnormalities that result in a wasting syndrome possibly accounting for up to 30% of cancer-related deaths. A literature search was performed to review those pathways of metabolic interference involved in cancer cachexia. An elevated basal metabolic rate and increased energy expenditure combined with systemic catabolism of muscle and adipose tissue are the predominant manifestations of the metabolic and physiologic perturbations noted in this pathologic state. To date, although some of the cachexia-related metabolic abnormalities have been elucidated, there has been little success in relation to therapeutic manipulation of these pathways. This review evaluates current knowledge relating to cancer cachexia and cautions against generalizations concerning treatment regimens.
  Cancer 01/1996; 76(12):2418-26. · 4.77 Impact Factor
• Article: Potentiation of the therapeutic index of interleukin-2 immunotherapy by combination with taurine in a syngeneic murine tumour model.

  N Finnegan, D Toomey, C Condron, H P Redmond, M Da Costa, D J Bouchier-Hayes
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  ABSTRACT: Administration of interleukin-2 (IL-2) is limited by the induction of the vascular leak syndrome (VLS). To examine the effect of taurine on the toxicity and antitumour activity of IL-2 in a B16 melanoma pulmonary metastases model. B16 melanoma cells were injected into female C57BL/6 mice. Macroscopic melanoma pulmonary foci were established by day 10 in untreated mice. Treated mice were randomised into treatment by rIL-2 alone, rIL-2 plus taurine or taurine alone. Control animals received saline. Mice were sacrificed on day 18. Lung metastases were counted in a blinded fashion with the aid of a dissecting microscope. Wet to dry lung weight was measured following lung removal. In another experiment animals were treated as above (n = 15 per group) and survival following treatment monitored. Treatment with IL-2 and taurine significantly reduced lung nodules compared with IL-2 alone. Host survival was significantly enhanced. The wet to dry (w/d) ratios of lung weights in the group receiving IL-2/taurine were significantly less than IL-2 alone. Bronchoalveolar lavage protein fluid was reduced indicating reduced pulmonary injury. These findings indicate that the combination of taurine with IL-2 augments the efficacy of this immunotherapy while reducing its associated dose-limiting toxicity.
  Irish Journal of Medical Science 171(2):85-8. · 0.58 Impact Factor