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Combination analyses of anti-cancer drugs on human neuroendocrine tumor cell lines
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. (Department of Endocrine Oncology)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi. (Cancer Pharmacology and Informatics)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi. (Cancer Pharmacology and Informatics)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. (Department of Endocrine Oncology)
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2009 (Engelska)Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 65, nr 1, s. 5-12Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2009. Vol. 65, nr 1, s. 5-12
Nyckelord [en]
Neuroendocrine tumors, Combination, Chemotherapy, Drug-sensitivity
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-102564DOI: 10.1007/s00280-009-0997-6ISI: 000269916800002PubMedID: 19381631OAI: oai:DiVA.org:uu-102564DiVA, id: diva2:216383
Tillgänglig från: 2009-05-08 Skapad: 2009-05-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. Analyses of Dose-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell Lines
Öppna denna publikation i ny flik eller fönster >>Analyses of Dose-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell Lines
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2011. s. 45
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 704
Nyckelord
Cancer drugs, Screening, Hollow Fiber model, Apoptosis
Nationell ämneskategori
Cancer och onkologi Annan medicinsk grundvetenskap
Forskningsämne
Onkologi
Identifikatorer
urn:nbn:se:uu:diva-158833 (URN)978-91-554-8159-9 (ISBN)
Disputation
2011-10-29, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 09:15 (Svenska)
Opponent
Handledare
Anmärkning
Title corrected from: Analyses of Dos-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell LinesTillgänglig från: 2011-10-06 Skapad: 2011-09-16 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

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