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Analyses of Dose-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell Lines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is a disease with poor response rates on available treatments. Problems with resistance and intolerance against cancer drugs are major reasons for failure of the drugs. The need to discover new cancer drugs is important. In this thesis screening of new cancer drugs and evaluation of their mechanism of action are discussed. The aim of the thesis was to find new compounds active against neuroendocrine tumors (NETs).

In paper I, we screened 1280 substances on two bronchial carcinoid cell lines and one pancreatic carcinoid cell line. Eleven of these compounds were found to have antitumor activity at low concentrations. The most active agents were brefeldin A, emetine, bortezomib and idarubicin, having IC50 values (the concentration of the drug where > 50% of the cells die) < 1μM. In addition, sanguinarine, Bay11-7085, mitoxantrone, doxorubicin, β-lapachone, NSC 95397 and CGP- 74514A were active with IC50 values < 10 μM.

 In paper II, additional studies have been undertaken to investigate the combination effect of the most active drugs with conventional cytotoxic drugs used in clinical practice. If synergistic or additive effects are found, drugs with different mechanism of action and toxicity profiles may be combined, making it possible to reduce the toxic effects yet maintaining the antitumor activity.

In paper III, studies were undertaken to find the mechanistic action, apoptosis or necrosis, of the drugs NSC 95397, brefeldin A, bortezomib and sanguinarine in NETs. All four drugs were shown to induce caspase-3 activity and nuclear fragmentation/condensation in the neuroendocrine tumor cell lines, indicating that their antitumor activity was induction of apoptosis.

In paper IV, the mechanism of action was studied for CGP-74514A and emetine. Both drugs worked by induction of apoptosis. In addition, their cytotoxic activity was studied in a three-dimensional model, the in vitro hollow fiber model. The Hollow Fiber model permits more realistic simulation of in vivo drug effects in a controlled system providing data that more accurately reflects biological responses. Our results showed that the hollow fiber model may be suitable for studies of new drugs in the neuroendocrine tumor cell lines.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , p. 45
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 704
Keyword [en]
Cancer drugs, Screening, Hollow Fiber model, Apoptosis
National Category
Cancer and Oncology Other Basic Medicine
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-158833ISBN: 978-91-554-8159-9 (print)OAI: oai:DiVA.org:uu-158833DiVA, id: diva2:441595
Public defence
2011-10-29, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Note
Title corrected from: Analyses of Dos-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell LinesAvailable from: 2011-10-06 Created: 2011-09-16 Last updated: 2018-01-12Bibliographically approved
List of papers
1. Identification and evaluation of potential anti-cancer drugs on human neuroendocrine tumor cell lines
Open this publication in new window or tab >>Identification and evaluation of potential anti-cancer drugs on human neuroendocrine tumor cell lines
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2006 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 6B, p. 4125-4129Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate drug sensitivity in neuroendocrine tumor cell lines. Materials and Methods: In vitro drug sensitivity screening was performed using the fluorometric microculture cytotoxicity assay in one human pancreatic carcinoid and two human bronchial carcinoid cell lines. In addition, a normal human retinal pigment epithelial cell line was used for comparison. A total of 18 drugs with different mechanisms of action were tested. Results: The most active agents were brefeldin A, emetine, bortezomib and idarubicin, having IC50 values < 1 μM in all four cell lines. In addition, the three tumor cell lines showed sensitivity for sanguinarine, Bay11-7085, mitoxantrone, doxorubicin, β-lapachone, NSC 95397 and CGP-74514A. Conclusion: The cell lines were sensitive for several drugs acting in different ways, covering a broad spectrum of mechanisms of action. Some of these compounds may possibly be used in clinical trials and show therapeutic effect in patients with neuroendocrine tumors.

Keyword
Drug sensitivity, FMCA, Neuroendocrine tumors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-24875 (URN)000243040300005 ()17201123 (PubMedID)
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2017-12-07Bibliographically approved
2. Combination analyses of anti-cancer drugs on human neuroendocrine tumor cell lines
Open this publication in new window or tab >>Combination analyses of anti-cancer drugs on human neuroendocrine tumor cell lines
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2009 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 65, no 1, p. 5-12Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

There is a large need for better pharmacological treatment of neuroendocrine tumors. The aim of this study was to investigate and quantify the cytotoxic potentiating effects resulting from a combination of five substances, NSC 95397, emetine, CGP-74514A hydrochloride, Brefeldin A and sanguinarine chloride, chosen from a previous screening of 1,280 pharmacologically active agents on neuroendocrine tumor cells, with standard cytotoxic agents currently used in the treatment of neuroendocrine tumors.

METHOD:

The human pancreatic carcinoid cell line BON-1, human typical bronchial carcinoid cell line NCI-H727 and the human atypical bronchial carcinoid cell line NCI-H720 were used. Combinations between doxorubicin, etoposide, oxaliplatin, docetaxel, and each one of the five agents were studied and simultaneous exposures were explored using the median-effect method.

RESULTS:

Most of the combinations of NSC-95397 and emetine with doxorubicin, etoposide, docetaxel, and oxaliplatin showed synergism, and their remaining combinations were additive. Almost all of the CGP-74514A hydrochloride interactions were additive, while brefeldin A and sanguinarine displayed less synergy but more additive and antagonistic interactions in combination with the standard drugs.

CONCLUSION:

The synergistic and additive interactions make NSC-95397, emetine, and CGP-74514A hydrochloride potential candidates for incorporation into combination chemotherapy regimens and these drugs might be the suitable candidates for further clinical studies in patients with bronchial carcinoids and pancreatic endocrine tumors.

Keyword
Neuroendocrine tumors, Combination, Chemotherapy, Drug-sensitivity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102564 (URN)10.1007/s00280-009-0997-6 (DOI)000269916800002 ()19381631 (PubMedID)
Available from: 2009-05-08 Created: 2009-05-08 Last updated: 2017-12-13Bibliographically approved
3. The Cytotoxic Agents NSC-95397, Brefeldin A, Bortezomib and Sanguinarine Induce Apoptosis in Neuroendocrine Tumors In Vitro
Open this publication in new window or tab >>The Cytotoxic Agents NSC-95397, Brefeldin A, Bortezomib and Sanguinarine Induce Apoptosis in Neuroendocrine Tumors In Vitro
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2010 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 30, no 1, p. 149-156Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate the apoptosis resulting from NSC 95397, brefeldin A, bortezomib and sanguinarine in neuroendocrine tumor cell lines. Materials and Methods: A multiparametric high-content screening assay for measurement of apoptosis was used. The human pancreatic carcinoid cell line, BON-1, human typical bronchial carcinoid cell line NCI-H727 and the human atypical bronchial carcinoid cell line NCI-H720 were tested. After incubation with cytotoxic drugs, the DNA-binding dye Hoechst 33342, fluorescein-tagged probes that covalently bind active caspase-3 and chloromethyl-X-rosamine to detect mitochondrial membrane potential were added. Image acquisition and quantitative measurement of fluorescence was performed using automated image capture and analysis instrument ArrayScan. In addition, nuclear morphology was examined on microscopic slides stained with May-Grunewald-Giemsa. Results: A time- and dose-dependent activation of caspase-3 and increase in nuclear fragmentation and condensation were observed for the drugs using a multiparametric apoptosis assay. These results were confirmed with nuclear morphological examination on microscopic slides. Conclusion: NSC 95397, brefeldin A, bortezomib and sanguinarine induced caspase-3 activation with modest changes in nuclear morphology.

Keyword
Apoptosis, caspase activity, NSC 95397, brefeldin A
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-137871 (URN)000274537400020 ()20150630 (PubMedID)
Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2017-12-11Bibliographically approved
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