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- Dahlström Wester, Maria, 1979-
(författare)
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Aspects of Tumour Targeting : Preclinical Studies on Human Malignant Cells in vitro
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Hallbeck, Anna-Lotta, 1967-
(författare)
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Studies of transforming growth factor alpha in normal and abnormal growth
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Regulation of growth is of fundamental importance for development of the organism and to maintain health. The induction of cell proliferation and matrix production are influenced by several different signaling systems, most importantly by growth factors.The human HER-family of growth factor ligands and receptors is one of the most studied and, at present, one of the most complex including 4 tyrosine kinase receptors and at least 11 different ligands cooperating in the transfer of signals. The HER-family growth responses are also influenced by other intercellular and extracellular signals, including matrix components, cytokines and hormones mediating e.g. inflammation.HER-1 (EGFR) is one of the best known and most extensively studied growth factor receptors. TGF-alpha is possibly the most potent HER-1 ligand and influences wound healing, epidermal maintenance, gastrointestinal function, lactation, pulmonary function and more. Several studies have shown important regulatory functions for some inflammatory cytokines on TGF-alpha production in white blood cells. HER-1 is widespread in epithelial cells but also in mesenchymal cells such as fibroblasts, osteogenic and chondrogenic cells. Consequently, many tumors arising from these cell types express HER family members and often show TGF-alpha and/or HER activation. Indeed, mammary cancer development has been shown when over expressing both TGF-alpha and HER-2 in mouse mammary cells in vivo.In recent years the first HER-1 and HER-2 inhibitors have come into clinical practice for treatment of breast cancer, lung cancer and gastrointestinal cancers, sometimes with great success. However, more knowledge is needed concerning the inflammatory regulation of HER-family expression including where and how the ligands and receptors cooperate. Therefore we were interested in studying the role of TGF-alpha in normal and abnormal growth.First we showed that the acute inflammatory cytokine IL-6 regulates TGF-alpha expression in U-937-1 monocytoid cells. Secondly, we detected a possible long-term enhancing influence of singledose UVR on HER-1 expression in normal human melanocytes. We continued thirdly by revealing TGF-alpha production concomitant with HER-2 in normal human synovia and release of soluble TGF-alpha into the synovial fluid. Both TGF-alpha and HER-2 production were significantly increased in inflammatory joint conditions, e.g. RA. Fourthly, we demonstrated expression of TGF-alpha, HER-1 and HER-2 in synovial sarcoma cells in culture; the observed HER-2 phosphorylation was dependent on ligand induced HER-1 activation.The presented results indicate that TGF-alpha expression can be enhanced by acute inflammatory cytokine IL-6, possibly contributing to growth stimulatory effects assigned to IL-6 itself.The acute effects of UVR on melanocytes mediate up-regulated steady-state expression of HER-1, constituting a potential target for locally produced TGF-alpha that may induce melanocyte proliferation.TGF-alpha and HER-2 seem to have a role in the maintenance ofsynovial joint tissues. Upregulation of TGF-alpha and HER-2 in inflammatory joint conditions, e.g. RA, represents a novel mechanism for synovial proliferation contributing to joint deterioration.TGF-alpha, HER1 and HER-2 may have a role in synovial sarcoma proliferation; further investigation is needed to evaluate HER-family inhibitors as a possible treatment alternative in this type of cancer.
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