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Undifferentiated monocytoid U937-1 cells accumulate boron-10 after administration of BPA in vitro
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (Other academic)
Abstract [en]

A tumour influences it’s surrounding and is at the same time influenced by surrounding cells. It is established that a majority of malignant tumours are infiltrated by macrophages, so called tumour-associated macrophages (TAMs) and that this infiltration is associated with poor prognosis. The role of TAMs is not completely revealed but evidence has emerged for a symbiotic relationship between tumour cells and TAMs. In this context, one may consider the importance of TAMs during tumour eradication. In this study, undifferentiated human monocytoid U937-1 cells were used as a model of normal monocytes and analysed regarding accumulation of boronophenylalanine (BPA) in vitro. BPA is a compound used extensively in vitro, in vivo and in clinical trials for boron neutron capture therapy (BNCT). The high energy ionizing radiation utilized in the BNCT process may also affect TAMs; directly if TAMs accumulate boron or through bystander effects initiated by the irradiation. Undifferentiated cells were incubated in BPA-containing cell culture medium at boron concentrations of 0-5 μg 10B/ml. A rapid oil filtration method was used for separation of extracellular and cellassociated boron. Boron content was analysed using inductively coupled plasma atomic emission spectroscopy (ICP-AES). It was shown that undifferentiated U937-1 cells accumulate boron in a clinical relevant concentration range. Further investigations are needed to reveal the role of TAMs in tumours and eventual interaction during the treatment, here specifically when utilizing BNCT.

Keyword [en]
Monocyte, macrophage, U937-1, boronophenylalanine, BPA, in vitro, accumulation, ICP-AES, tumour-associated macrophages, TAMs, bystander effect
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-18469OAI: oai:DiVA.org:liu-18469DiVA: diva2:219692
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Aspects of Tumour Targeting: Preclinical Studies on Human Malignant Cells in vitro
Open this publication in new window or tab >>Aspects of Tumour Targeting: Preclinical Studies on Human Malignant Cells in vitro
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Exclusive eradication of tumour cells causing minimal damage to healthy tissue, a concept referred to as targeting, is an interesting approach to improve the outcome for patients afflicted with cancer.

The general aim of this thesis was to highlighten aspects that could be of importance in developing novel treatment regimens based on specific targeting of tumour cells. Two variants of targeting strategies, boron neutron capture therapy (BNCT) and platelet-derived growth factor receptor (PDGFR) tumour targeting were studied in vitro.

In BNCT, the ability of boron-10, 10B, to capture neutrons is utilized. The capture reaction initiate emission of high linear energy transfer (LET) particles which exerts potential damaging effects on exposed cells. A preferential accumulation of at least 10 μg 10B/g tumour tissue is suggested to be required for effective clinical outcome. Here, the accumulation of boronophenylalanine, BPA, was investigated in human glioma, synovial sarcoma, fibroblast and monocytoid cells in vitro. For the purpose of quick and effective separation of extracellular and cell-associated boron, a rapid cell filtration method was developed. Inductively coupled plasma atomic emission spectroscopy, ICP-AES, was used to analyse the amount of boron associated to the cells.

Over-expression of PDGFRs may render the possibility to target certain tumours using PDGF-based conjugates for a specific delivery of cytotoxic agents. PDGF-AA was conjugated to dextran of two different sizes, 10 and 40 kDa, and compared with 125I-radiolabelled PDGF-AA regarding accumulation, retention and localisation in human glioma cells in vitro.

A boron concentration of >10 μg 10B/g tumour tissue was found in all human cell lines studied. For the two glioma cell lines, the results extend differences between the two although originating from the same human tumour material. Since fibroblasts and monocytoid cells, here used to represent normal cells, accumulated boron at a clinically relevant amount one may have to consider the role of these cells in/at the tumour site during treatment. Regarding results for the human synovial sarcoma cells, further investigations may state the potential of BNCT as a treatment modality and explore the possibilities of a directed delivery of boron-containing substances to receptors specifically expressed in this malignancy.

PDGF-AA-based dextran conjugates, preferentially 10 kDa dextran conjugates, showed in vitro properties that were superior to radiolabelled unconjugated PDGF-AA. A prolonged retention time was observed for the conjugates. Radiolabelled PDGF-AA was mainly determined to be located intracellular but the localisation, internalised or membrane-associated, of radiolabelled conjugates seemed to be dependent on the composition of the conjugate. It is of interest to explore the potential of dextran conjugates carrying toxic substances for therapeutic purpose.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1118
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18471 (URN)978-91-7393-649-1 (ISBN)
Public defence
2009-06-04, Aulan, Hälsans Hus, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2009-06-22Bibliographically approved

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Dahlström Wester, MariaHallbeck, Anna-Lotta Lindström, Annelie

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