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Identification of A...
Identification of Agents that Induce Apoptosis of Multicellular Tumour Spheroids : Enrichment for Mitotic Inhibitors with Hydrophobic Properties
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Fayad, Walid (författare)
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- Rickardson, Linda (författare)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics/Rolf Larsson
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- Haglund, Caroline (författare)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics/Rolf Larsson
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- Hägg Olofsson, Maria (författare)
- Karolinska Institutet
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- D'Arcy, Padraig (författare)
- Karolinska Institutet
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- Larsson, Rolf (författare)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics/Rolf Larsson
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- Linder, Stig (författare)
- Karolinska Institutet
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- Fryknäs, Mårten (författare)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics/Rolf Larsson
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(creator_code:org_t)
- 2011-07-29
- 2011
- Engelska.
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 78:4, s. 547-557
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Cell-based anticancer drug screening generally utilizes rapidly proliferating tumour cells grown as monolayer cultures. Hit compounds from such screens are not necessarily effective on hypoxic and slowly proliferating cells in 3-D tumour tissue. The aim of this study was to examine the potential usefulness of 3-D cultured tumour cells for anticancer drug screening. We used colon carcinoma multicellular spheroids containing hypoxic and quiescent cells in core areas for this purpose. Three libraries (similar to 11 000 compounds) were screened using antiproliferative activity and/or apoptosis as end-points. Screening of monolayer and spheroid cultures was found to identify different sets of hit compounds. Spheroid screening enriched for hydrophobic compounds: median XLogP values of 4.3 and 4.4 were observed for the hits in two independent screening campaigns. Mechanistic analysis revealed that the majority of spheroid screening hits were microtubuli inhibitors. One of these inhibitors was examined in detail and found to be effective against non-dividing cells in the hypoxic centres of spheroids. Spheroid screening represents a conceptually new strategy for anticancer drug discovery. Our findings have implications for drug library design and hit selection in projects aimed to develop drugs for the treatment of solid tumours.
Nyckelord
- anticancer drugs
- apoptosis
- microtubuli inhibitors
- solid tumours
- XLogP
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- ref (ämneskategori)
- art (ämneskategori)
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