Jörgen Carlsson - Academia.edu (original) (raw)
Papers by Jörgen Carlsson
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1987
International journal of oncology, 2005
The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2,... more The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2, HER3, and HER4 were evaluated by immunohistochemistry in 19 cases of metastatic squamous cell carcinoma of the oral cavity and base of tongue. EGFR had a similar and high expression in both primary tumours and the corresponding metastases, while the expression in normal epithelium was lower in most cases. HER2 was not expressed to the same extent as EGFR. However, when HER2 was well expressed, it was in most cases expressed to the same extent and intensity in the primary tumours, metastases, and normal epithelium. The expression of HER3 and HER4 varied and was mainly cytoplasmic in all cases studied. No overexpression of HER3 and HER4 in tumours was seen as compared to normal epithelium. In order to further investigate the distribution of HER3, two HER3 expressing cell lines originating from tongue cancer were analysed in vitro, using radiolabelled anti-HER3 antibodies directed to the e...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
A positron-emitting isotope of bromine, 76Br, with a half-life of 16.2 h, was produced using the ... more A positron-emitting isotope of bromine, 76Br, with a half-life of 16.2 h, was produced using the reaction natBr(p, xn)76Kr. Labelling of mouse epidermal growth factor (EGF) with 76Br was optimized, using the chloramine-T method, obtaining a maximal radiochemical yield of 53%. In tests with receptor-rich, cultured glioma cells, [76Br]EGF and [125I]EGF bound equally well. A study of the distribution and stability of [76Br]EGF and [125I]EGF in normal rat was carried out. The distribution of both radioisotopes was similar, however, the percentage of 76Br bound to the high molecular weight fraction in the plasma, liver and kidney was greater than that of 125I.
International journal of oncology, 1995
The basic metabolism and pO(2) and pH gradients in spheroids were characterized and, in some case... more The basic metabolism and pO(2) and pH gradients in spheroids were characterized and, in some cases, changed by the addition of the pyruvate analogue oxamate. Two human tumour spheroid types, colon adenocarcinoma HT29 and malignant glioma U118MG, were applied as models. Microelectrode measurements in HT29 spheroids showed steep pO(2) gradients with large differences between surface and center, Delta pO(2), and low central pO(2) values. The HT29 spheroids had rather flat pH gradients. The U118MG spheroids had less steep pO(2) gradients but steeper pH gradients. Determinations of 1-C-14 and 2-C-14 pyruvate oxidation rates, for characterization of the oxidative glucose breakdown as well as of lactate dehydrogenase kinetics, showed consistent results with the microelectrode measurements in that there was high oxidative metabolism in the HT29 spheroids whereas the U118MG spheroids relied more on glycolysis. Western blot investigations of the LDH isoenzyme composition showed different isoe...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2005
Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides i... more Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides important diagnostic information, which can influence patient management. The use of PET may enable such detection in vivo by a noninvasive procedure with high sensitivity. The aim of this study was to develop a method for preparation of a positron-emitting tracer based on a natural ligand to EGFR, the recombinant human epidermal growth factor (hEGF), and to perform a preclinical evaluation of the tracer. DOTA-hEGF (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) was prepared by coupling of a N-sulfosuccinimide ester of DOTA to hEGF. The conjugate was labeled with a generator-produced positron-emitting nuclide, (68)Ga (half-life = 68 min), using microwave heating. Binding specificity, affinity, internalization, and retention of (68)Ga-DOTA-hEGF was studied in 2 EGFR-expressing cell lines, U343 glioma cells and A431 cervical carcinoma cells. B...
British journal of cancer, Jan 14, 2004
The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in... more The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in metastases. The HER2 expression in primary tumours and the corresponding lymph node metastases were evaluated in parallel samples from 47 patients. The HercepTest was used for immunohistochemical analyses of HER2 overexpression in all cases. CISH/FISH was used for analysis of gene amplification in some cases. HER2 overexpression (HER2-scores 2+ or 3+) was found in 55% of both the primary tumours and of the lymph node metastases. There were only small changes in the HER2-scores; six from 1+ to 0 and one from 3+ to 2+ when the metastases were compared to the corresponding primary tumours. However, there were no cases with drastic changes in HER2 expression between the primary tumours and the corresponding lymph node metastases. The literature was reviewed for similar investigations, and it is concluded that breast cancer lymph node metastases generally overexpress HER2 to the same extent ...
![Research paper thumbnail of [Radionuclide therapy--a possible way toward an improved treatment of cancer. The obstacle is the shortage of commercially available radionuclides for clinical use]](https://attachments.academia-assets.com/39270499/thumbnails/1.jpg)
](Läkartidningen, Jan 11, 2004
About one third of all cancer develops into a spread disease that is difficult to treat. Radioimm... more About one third of all cancer develops into a spread disease that is difficult to treat. Radioimmunotherapy has during the last years proven to be of help when other therapy modalities fail in e.g. lymphomas. The development in this area is fast mainly due to substantial improvements in molecular biology and in our increasing understanding of specific receptor expressions in cancer cells. However, radionuclides used today, 131I and 90Y, are not optimal in that sense that they emit radiation mainly suitable to treat the bulk tumor and not the single cell and micrometastases present in spread disease. The article stresses the importance that radionuclides with more suitable emission of particles like 177Lu and 211At are made available for clinical research and routine.
International journal of oncology, 2000
The binding of a targeting agent, 125I-EGF-dextran, to epidermal growth factor (EGF) receptors in... more The binding of a targeting agent, 125I-EGF-dextran, to epidermal growth factor (EGF) receptors in tumour spheroids of a human bladder cancer cell line was studied. The accumulation of radioactivity was continuous up to at least 48 h in the peripheral cells of the spheroids, which in comparison with the binding pattern of 125I-EGF indicated that the cells had a limited capacity to degrade the EGF-dextran. The 125I-EGF-dextran was of two different sizes, 28 and 76 kDa, but this did not affect the binding patterns and the results were very similar. The EGF-dextran conjugates had qualities that are of interest for tumour targeting.
Nuclear medicine and biology, 1999
Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direc... more Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direct labeling was done using the conventional chloramine-T method. After optimization of the labeling conditions, a maximum yield (mean +/- max error) of 77 +/- 2% was obtained at pH 6.8. In vitro binding of 76Br-A33 to SW1222 colonic cancer cells showed that the immunoreactivity was retained. Also, the MAbs 38S1 and 3S193 and the peptide hEGF were 76Br-labeled, resulting in labeling yields (mean +/- max error) of 75 +/- 3%, 63 +/- 4%, and 73 +/- 0.1%, respectively. We conclude that antibodies and peptides can be labeled conveniently with 76Br for the purpose of whole-body tumour imaging by positron emission tomography.
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine, 1997
Effects of Pb2+, Ni2+, Hg2+ and Se4+ on cultured human glioma U-343MG cells were investigated con... more Effects of Pb2+, Ni2+, Hg2+ and Se4+ on cultured human glioma U-343MG cells were investigated considering uptake, toxicity and, in combination with radiation, clonogenic cells survival. The cells were exposed to 0-100 microM of the metals for a week before the evaluation. The tests showed a tendency to toxicity with 10 microM nickel although not significant (P > 0.05). Selenium, lead and mercury exerted a significant toxicity (P < 0.05) at 2.5 microM, 10 microM and 1 microM, respectively. To challenge the clonogenic cell survival capacity, the cells were irradiated with 60Co photons after being exposed to the highest nontoxic concentration of the different metals. The clonogenic cell survival tests, after irradiation, showed no significant change if the cells were exposed to 5 microM nickel, 0.5 microM selenium or 5 microM lead compared with those not exposed. Mercury, 0.1 microM, gave a relative reduction in survival compared with only irradiated cells of 58 +/- 17%. Thus, on...
European journal of cancer (Oxford, England : 1990), 1990
Established cell-lines of human glioma origin were cultured as multicellular spheroids or as mono... more Established cell-lines of human glioma origin were cultured as multicellular spheroids or as monolayers. Volume growth and 3H-thymidine labelling were analysed for the spheroids after continuous exposure to drugs interfering with the release of arachidonic acid and the production of prostaglandins and leukotrienes. Comparative measurements were made on monolayer cultures. The cyclo-oxygenase inhibitor indomethacin enhanced growth at intermediate concentrations (0.5-5.0 micrograms/ml) but reduced growth at 50 micrograms/ml. The dual cyclo-oxygenase and lipoxygenase inhibitor ketoprofen had a significant inhibitory effect on growth and cell proliferation of spheroids at high concentration (50 micrograms/ml). The weak lipoxygenase inhibitor NDGA (quinone-form) decreased growth whereas the strong lipoxygenase inhibitor NDGA (hydroquinone-form) did not reduce growth rate but significantly decreased cell proliferation. Quinacrine reduced the spheroid growth rate although dexamethasone had...
Prostaglandins, leukotrienes, and essential fatty acids, 1991
Cell lines of human glioma (U-343 MGa and U-251 MG) and human glia (U-533 CG) origin were culture... more Cell lines of human glioma (U-343 MGa and U-251 MG) and human glia (U-533 CG) origin were cultured as monolayers and exposed to CV-6209, an alkyl-phospholipid analog and antagonist of platelet activating factor. This drug had very potent antiproliferative effects on the studied human glioma cell lines; IC50 was 0.9 microM after 48 h treatment and 0.2 microM after 2 weeks treatment. At these doses no growth inhibitory effect was noted on the normal glia cells. The effects on the glioma cells were reversible in the dose intervals, where cell proliferation, 3H-thymidine and 14C-methionine uptakes were greatly inhibited. The simultaneous administration of platelet activating factor [(R)PAF] did not influence the antiproliferative effects of CV-6209 on the cells cultured as monolayers. The structurally similar analog CV-3988 also had antiproliferative effects, although at 10 times higher concentration than CV-6209. Two other, structurally unrelated, PAF-antagonists (WEB-2086 and TCV-309)...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
Tumour-to-normal tissue ratios of i.p. injected 125I-labelled monoclonal antibodies (MAbs), react... more Tumour-to-normal tissue ratios of i.p. injected 125I-labelled monoclonal antibodies (MAbs), reacting with CEA were determined in nude rats xenografted with human colonic cancer cells (LS 174 T). Two MAbs, I-38S1 and II-16, reactive with the GOLD 1-epitope on CEA were tested. MAb I-38S1 was also tested after additional purification using anion exchange chromatography (thereafter named AEC 38). In the external activity measurements, MAb AEC 38 showed significantly better tumour-to-liver ratios than did MAb II-16 on all 4 days after injection. MAb I-38S1 gave intermediate ratios but was significantly better than II-16 only on day 3. The mean tumour-to-blood ratios were 3.0, 2.6 and 1.5 and the mean tumour-to-liver ratios were 6.6, 4.8 and 3.5 for MAbs AEC 38, I-38S1 and II-16 respectively. Gamma camera registrations in 3 animals on 4 days showed good imaging properties for all three MAbs and the patterns of tissue uptake were consistent with those seen in the external measurements. Fur...
Acta pathologica et microbiologica Scandinavica. Section A, Pathology, 1977
The fine structure of human glioma cells cultivated as three-dimensional colonies in agarose was ... more The fine structure of human glioma cells cultivated as three-dimensional colonies in agarose was investigated during exponential growth. The colonies did not show central degeneration, although they reached diameters of up to 600 mum. Large extra-cellular spaces extended throughout the colonies. The mean volumetric fraction of the spaces increased from about 20 per cent at the periphery up to nearly 40 per cent in the central regions. The quotient between nuclei and cytoplasm showed a slight decrease with depth. A proliferative gradient existed in the colonies, i.e. the mitotic index decreased almost exponentially with the distance from the surface. The distance at which the mitotic index changes by a factor of 2 was about 90 mum, corresponding to nearly five cell diameters. Cytoplasmic extensions, with a ruffling-like appearance, occurred both at the periphery and in the centre of the colonies but were larger and more frequent at the periphery. The fractions of mitochondria and vac...
Acta pathologica et microbiologica Scandinavica. Section A, Pathology, 1978
Human glioma cells, growing as spherical colonies in agarose gel, or as monolayers on glass or pl... more Human glioma cells, growing as spherical colonies in agarose gel, or as monolayers on glass or plastic, were studied with time-lapse cinematography and electron microscopy. The cells in the agarose cultured colonies often had ruffling-like membrane structures which were similar in for, although smaller in size, than those observed on monolayer cultured cells. The ruffling-like structures were more frequent at the periphery than in the central regions of the colonies which was in parallel to the proliferative pattern. In time-lapse cinematography it was seen that pinocytotic vacuoles were formed from ruffling membranes in the monolayer cultures. In the transmission electron microscope, such vacuoles were also found near the ruffling-like structures in the agarose cultured cells. In dense monolayer cultures, ruffling and associated pinocytosis were to a large extent transferred from the margin to the upper surface of the cells. This capacity may be an important property for the abilit...
Anticancer research
The alpha-emitting nuclide 211At is of great interest for radionuclide therapy when coupled to a ... more The alpha-emitting nuclide 211At is of great interest for radionuclide therapy when coupled to a tumor-targeting biomolecule, e.g. epidermal growth factor (EGF) the receptors of which are overexpressed in many malignancies. However, almost no information concerning the cellular processing of astatinated targeting agents is available. We indirectly astatinated EGF ([211At]-benzoate-EGF) and studied its cellular processing in A-431 carcinoma cells in comparison with data concerning [125I]-benzoate-EGF. The biological half-life of astatine (3.5 h) was longer than the half-life of the iodine label (1.5 h). The increase of the half-life was due to longer retention of the internalised astatine radioactivity. The maximum accumulation for the astatine label occurred later (4-6h) than that for the iodine label (2-4h), indicating a slower excretion of astatine that was confirmed in experiment with 211At/1251-benzoate-EGF. The long retention of astatine might be advantageous for radionuclide t...
Current Radiopharmaceuticalse, 2008
International Journal of Oncology, 1997
An epidermal growth factor (EGF) conjugate, with potential for selective delivery of DNA-binding ... more An epidermal growth factor (EGF) conjugate, with potential for selective delivery of DNA-binding compounds to malignancies overexpressing the EGF receptor, is presented. The development of a two-step targeting principle implies that, after cellular binding and internalisation, the conjugate should be degraded and the released toxic agents should be in such chemical forms that they bind to the cellular DNA. Boronated compounds with proved DNA-intercalation, earlier developed for boron neutron capture therapy, could be most suitable as the toxic agents. In this study the amino terminus of I-125-EGF was coupled to the 5' end of double stranded DNA, constructed of a 30-mer self-complementary oligonucleotide, to generate a I-125-EGF-DNA conjugate. Binding, internalisation and retention of the conjugate were investigated in vitro on human glioma cells overexpressing the EGF receptor. The generated I-125-EGF-DNA conjugate was shown to bind specifically to the EGF receptor. The conjugate was thereafter internalised and degraded efficiently. The results indicate that the I-125-EGF-DNA conjugate has suitable biological properties for the planned tests of selective delivery of DNA-binding toxic compounds in a two-step targeting process.
Cancer Neutron Capture Therapy, 1996
The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) g... more The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of ¹°B to tumor cells with an amplified number of
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1987
International journal of oncology, 2005
The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2,... more The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2, HER3, and HER4 were evaluated by immunohistochemistry in 19 cases of metastatic squamous cell carcinoma of the oral cavity and base of tongue. EGFR had a similar and high expression in both primary tumours and the corresponding metastases, while the expression in normal epithelium was lower in most cases. HER2 was not expressed to the same extent as EGFR. However, when HER2 was well expressed, it was in most cases expressed to the same extent and intensity in the primary tumours, metastases, and normal epithelium. The expression of HER3 and HER4 varied and was mainly cytoplasmic in all cases studied. No overexpression of HER3 and HER4 in tumours was seen as compared to normal epithelium. In order to further investigate the distribution of HER3, two HER3 expressing cell lines originating from tongue cancer were analysed in vitro, using radiolabelled anti-HER3 antibodies directed to the e...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
A positron-emitting isotope of bromine, 76Br, with a half-life of 16.2 h, was produced using the ... more A positron-emitting isotope of bromine, 76Br, with a half-life of 16.2 h, was produced using the reaction natBr(p, xn)76Kr. Labelling of mouse epidermal growth factor (EGF) with 76Br was optimized, using the chloramine-T method, obtaining a maximal radiochemical yield of 53%. In tests with receptor-rich, cultured glioma cells, [76Br]EGF and [125I]EGF bound equally well. A study of the distribution and stability of [76Br]EGF and [125I]EGF in normal rat was carried out. The distribution of both radioisotopes was similar, however, the percentage of 76Br bound to the high molecular weight fraction in the plasma, liver and kidney was greater than that of 125I.
International journal of oncology, 1995
The basic metabolism and pO(2) and pH gradients in spheroids were characterized and, in some case... more The basic metabolism and pO(2) and pH gradients in spheroids were characterized and, in some cases, changed by the addition of the pyruvate analogue oxamate. Two human tumour spheroid types, colon adenocarcinoma HT29 and malignant glioma U118MG, were applied as models. Microelectrode measurements in HT29 spheroids showed steep pO(2) gradients with large differences between surface and center, Delta pO(2), and low central pO(2) values. The HT29 spheroids had rather flat pH gradients. The U118MG spheroids had less steep pO(2) gradients but steeper pH gradients. Determinations of 1-C-14 and 2-C-14 pyruvate oxidation rates, for characterization of the oxidative glucose breakdown as well as of lactate dehydrogenase kinetics, showed consistent results with the microelectrode measurements in that there was high oxidative metabolism in the HT29 spheroids whereas the U118MG spheroids relied more on glycolysis. Western blot investigations of the LDH isoenzyme composition showed different isoe...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2005
Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides i... more Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides important diagnostic information, which can influence patient management. The use of PET may enable such detection in vivo by a noninvasive procedure with high sensitivity. The aim of this study was to develop a method for preparation of a positron-emitting tracer based on a natural ligand to EGFR, the recombinant human epidermal growth factor (hEGF), and to perform a preclinical evaluation of the tracer. DOTA-hEGF (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) was prepared by coupling of a N-sulfosuccinimide ester of DOTA to hEGF. The conjugate was labeled with a generator-produced positron-emitting nuclide, (68)Ga (half-life = 68 min), using microwave heating. Binding specificity, affinity, internalization, and retention of (68)Ga-DOTA-hEGF was studied in 2 EGFR-expressing cell lines, U343 glioma cells and A431 cervical carcinoma cells. B...
British journal of cancer, Jan 14, 2004
The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in... more The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in metastases. The HER2 expression in primary tumours and the corresponding lymph node metastases were evaluated in parallel samples from 47 patients. The HercepTest was used for immunohistochemical analyses of HER2 overexpression in all cases. CISH/FISH was used for analysis of gene amplification in some cases. HER2 overexpression (HER2-scores 2+ or 3+) was found in 55% of both the primary tumours and of the lymph node metastases. There were only small changes in the HER2-scores; six from 1+ to 0 and one from 3+ to 2+ when the metastases were compared to the corresponding primary tumours. However, there were no cases with drastic changes in HER2 expression between the primary tumours and the corresponding lymph node metastases. The literature was reviewed for similar investigations, and it is concluded that breast cancer lymph node metastases generally overexpress HER2 to the same extent ...
Läkartidningen, Jan 11, 2004
About one third of all cancer develops into a spread disease that is difficult to treat. Radioimm... more About one third of all cancer develops into a spread disease that is difficult to treat. Radioimmunotherapy has during the last years proven to be of help when other therapy modalities fail in e.g. lymphomas. The development in this area is fast mainly due to substantial improvements in molecular biology and in our increasing understanding of specific receptor expressions in cancer cells. However, radionuclides used today, 131I and 90Y, are not optimal in that sense that they emit radiation mainly suitable to treat the bulk tumor and not the single cell and micrometastases present in spread disease. The article stresses the importance that radionuclides with more suitable emission of particles like 177Lu and 211At are made available for clinical research and routine.
International journal of oncology, 2000
The binding of a targeting agent, 125I-EGF-dextran, to epidermal growth factor (EGF) receptors in... more The binding of a targeting agent, 125I-EGF-dextran, to epidermal growth factor (EGF) receptors in tumour spheroids of a human bladder cancer cell line was studied. The accumulation of radioactivity was continuous up to at least 48 h in the peripheral cells of the spheroids, which in comparison with the binding pattern of 125I-EGF indicated that the cells had a limited capacity to degrade the EGF-dextran. The 125I-EGF-dextran was of two different sizes, 28 and 76 kDa, but this did not affect the binding patterns and the results were very similar. The EGF-dextran conjugates had qualities that are of interest for tumour targeting.
Nuclear medicine and biology, 1999
Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direc... more Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direct labeling was done using the conventional chloramine-T method. After optimization of the labeling conditions, a maximum yield (mean +/- max error) of 77 +/- 2% was obtained at pH 6.8. In vitro binding of 76Br-A33 to SW1222 colonic cancer cells showed that the immunoreactivity was retained. Also, the MAbs 38S1 and 3S193 and the peptide hEGF were 76Br-labeled, resulting in labeling yields (mean +/- max error) of 75 +/- 3%, 63 +/- 4%, and 73 +/- 0.1%, respectively. We conclude that antibodies and peptides can be labeled conveniently with 76Br for the purpose of whole-body tumour imaging by positron emission tomography.
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine, 1997
Effects of Pb2+, Ni2+, Hg2+ and Se4+ on cultured human glioma U-343MG cells were investigated con... more Effects of Pb2+, Ni2+, Hg2+ and Se4+ on cultured human glioma U-343MG cells were investigated considering uptake, toxicity and, in combination with radiation, clonogenic cells survival. The cells were exposed to 0-100 microM of the metals for a week before the evaluation. The tests showed a tendency to toxicity with 10 microM nickel although not significant (P > 0.05). Selenium, lead and mercury exerted a significant toxicity (P < 0.05) at 2.5 microM, 10 microM and 1 microM, respectively. To challenge the clonogenic cell survival capacity, the cells were irradiated with 60Co photons after being exposed to the highest nontoxic concentration of the different metals. The clonogenic cell survival tests, after irradiation, showed no significant change if the cells were exposed to 5 microM nickel, 0.5 microM selenium or 5 microM lead compared with those not exposed. Mercury, 0.1 microM, gave a relative reduction in survival compared with only irradiated cells of 58 +/- 17%. Thus, on...
European journal of cancer (Oxford, England : 1990), 1990
Established cell-lines of human glioma origin were cultured as multicellular spheroids or as mono... more Established cell-lines of human glioma origin were cultured as multicellular spheroids or as monolayers. Volume growth and 3H-thymidine labelling were analysed for the spheroids after continuous exposure to drugs interfering with the release of arachidonic acid and the production of prostaglandins and leukotrienes. Comparative measurements were made on monolayer cultures. The cyclo-oxygenase inhibitor indomethacin enhanced growth at intermediate concentrations (0.5-5.0 micrograms/ml) but reduced growth at 50 micrograms/ml. The dual cyclo-oxygenase and lipoxygenase inhibitor ketoprofen had a significant inhibitory effect on growth and cell proliferation of spheroids at high concentration (50 micrograms/ml). The weak lipoxygenase inhibitor NDGA (quinone-form) decreased growth whereas the strong lipoxygenase inhibitor NDGA (hydroquinone-form) did not reduce growth rate but significantly decreased cell proliferation. Quinacrine reduced the spheroid growth rate although dexamethasone had...
Prostaglandins, leukotrienes, and essential fatty acids, 1991
Cell lines of human glioma (U-343 MGa and U-251 MG) and human glia (U-533 CG) origin were culture... more Cell lines of human glioma (U-343 MGa and U-251 MG) and human glia (U-533 CG) origin were cultured as monolayers and exposed to CV-6209, an alkyl-phospholipid analog and antagonist of platelet activating factor. This drug had very potent antiproliferative effects on the studied human glioma cell lines; IC50 was 0.9 microM after 48 h treatment and 0.2 microM after 2 weeks treatment. At these doses no growth inhibitory effect was noted on the normal glia cells. The effects on the glioma cells were reversible in the dose intervals, where cell proliferation, 3H-thymidine and 14C-methionine uptakes were greatly inhibited. The simultaneous administration of platelet activating factor [(R)PAF] did not influence the antiproliferative effects of CV-6209 on the cells cultured as monolayers. The structurally similar analog CV-3988 also had antiproliferative effects, although at 10 times higher concentration than CV-6209. Two other, structurally unrelated, PAF-antagonists (WEB-2086 and TCV-309)...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
Tumour-to-normal tissue ratios of i.p. injected 125I-labelled monoclonal antibodies (MAbs), react... more Tumour-to-normal tissue ratios of i.p. injected 125I-labelled monoclonal antibodies (MAbs), reacting with CEA were determined in nude rats xenografted with human colonic cancer cells (LS 174 T). Two MAbs, I-38S1 and II-16, reactive with the GOLD 1-epitope on CEA were tested. MAb I-38S1 was also tested after additional purification using anion exchange chromatography (thereafter named AEC 38). In the external activity measurements, MAb AEC 38 showed significantly better tumour-to-liver ratios than did MAb II-16 on all 4 days after injection. MAb I-38S1 gave intermediate ratios but was significantly better than II-16 only on day 3. The mean tumour-to-blood ratios were 3.0, 2.6 and 1.5 and the mean tumour-to-liver ratios were 6.6, 4.8 and 3.5 for MAbs AEC 38, I-38S1 and II-16 respectively. Gamma camera registrations in 3 animals on 4 days showed good imaging properties for all three MAbs and the patterns of tissue uptake were consistent with those seen in the external measurements. Fur...
Acta pathologica et microbiologica Scandinavica. Section A, Pathology, 1977
The fine structure of human glioma cells cultivated as three-dimensional colonies in agarose was ... more The fine structure of human glioma cells cultivated as three-dimensional colonies in agarose was investigated during exponential growth. The colonies did not show central degeneration, although they reached diameters of up to 600 mum. Large extra-cellular spaces extended throughout the colonies. The mean volumetric fraction of the spaces increased from about 20 per cent at the periphery up to nearly 40 per cent in the central regions. The quotient between nuclei and cytoplasm showed a slight decrease with depth. A proliferative gradient existed in the colonies, i.e. the mitotic index decreased almost exponentially with the distance from the surface. The distance at which the mitotic index changes by a factor of 2 was about 90 mum, corresponding to nearly five cell diameters. Cytoplasmic extensions, with a ruffling-like appearance, occurred both at the periphery and in the centre of the colonies but were larger and more frequent at the periphery. The fractions of mitochondria and vac...
Acta pathologica et microbiologica Scandinavica. Section A, Pathology, 1978
Human glioma cells, growing as spherical colonies in agarose gel, or as monolayers on glass or pl... more Human glioma cells, growing as spherical colonies in agarose gel, or as monolayers on glass or plastic, were studied with time-lapse cinematography and electron microscopy. The cells in the agarose cultured colonies often had ruffling-like membrane structures which were similar in for, although smaller in size, than those observed on monolayer cultured cells. The ruffling-like structures were more frequent at the periphery than in the central regions of the colonies which was in parallel to the proliferative pattern. In time-lapse cinematography it was seen that pinocytotic vacuoles were formed from ruffling membranes in the monolayer cultures. In the transmission electron microscope, such vacuoles were also found near the ruffling-like structures in the agarose cultured cells. In dense monolayer cultures, ruffling and associated pinocytosis were to a large extent transferred from the margin to the upper surface of the cells. This capacity may be an important property for the abilit...
Anticancer research
The alpha-emitting nuclide 211At is of great interest for radionuclide therapy when coupled to a ... more The alpha-emitting nuclide 211At is of great interest for radionuclide therapy when coupled to a tumor-targeting biomolecule, e.g. epidermal growth factor (EGF) the receptors of which are overexpressed in many malignancies. However, almost no information concerning the cellular processing of astatinated targeting agents is available. We indirectly astatinated EGF ([211At]-benzoate-EGF) and studied its cellular processing in A-431 carcinoma cells in comparison with data concerning [125I]-benzoate-EGF. The biological half-life of astatine (3.5 h) was longer than the half-life of the iodine label (1.5 h). The increase of the half-life was due to longer retention of the internalised astatine radioactivity. The maximum accumulation for the astatine label occurred later (4-6h) than that for the iodine label (2-4h), indicating a slower excretion of astatine that was confirmed in experiment with 211At/1251-benzoate-EGF. The long retention of astatine might be advantageous for radionuclide t...
Current Radiopharmaceuticalse, 2008
International Journal of Oncology, 1997
An epidermal growth factor (EGF) conjugate, with potential for selective delivery of DNA-binding ... more An epidermal growth factor (EGF) conjugate, with potential for selective delivery of DNA-binding compounds to malignancies overexpressing the EGF receptor, is presented. The development of a two-step targeting principle implies that, after cellular binding and internalisation, the conjugate should be degraded and the released toxic agents should be in such chemical forms that they bind to the cellular DNA. Boronated compounds with proved DNA-intercalation, earlier developed for boron neutron capture therapy, could be most suitable as the toxic agents. In this study the amino terminus of I-125-EGF was coupled to the 5' end of double stranded DNA, constructed of a 30-mer self-complementary oligonucleotide, to generate a I-125-EGF-DNA conjugate. Binding, internalisation and retention of the conjugate were investigated in vitro on human glioma cells overexpressing the EGF receptor. The generated I-125-EGF-DNA conjugate was shown to bind specifically to the EGF receptor. The conjugate was thereafter internalised and degraded efficiently. The results indicate that the I-125-EGF-DNA conjugate has suitable biological properties for the planned tests of selective delivery of DNA-binding toxic compounds in a two-step targeting process.
Cancer Neutron Capture Therapy, 1996
The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) g... more The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of ¹°B to tumor cells with an amplified number of