uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Identification of CB3, a novel inhibitor of the ubiquitin-proteasome system
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-150349OAI: oai:DiVA.org:uu-150349DiVA: diva2:407119
Available from: 2011-03-29 Created: 2011-03-29 Last updated: 2011-05-05
In thesis
1. Integrating Efficacy and Toxicity in Preclinical Anticancer Drug Development: Methods and Applications
Open this publication in new window or tab >>Integrating Efficacy and Toxicity in Preclinical Anticancer Drug Development: Methods and Applications
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Preclinical testing is an important part of cancer drug development. The aim of this thesis was to establish and evaluate preclinical in vitro methods useful in the development of new anticancer drugs.

In paper I, the development of non-clonogenic assays (FMCA-GM) using CD34+ stem cells for assessment of haematological toxicity was described. A high correlation was seen when comparing the 50% inhibitory concentrations (IC50) from FMCA-GM with the IC50 from the established clonogenic assay (CFU-GM).

In paper II, FMCA-GM was complemented with additional cell models, establishing a normal cell panel. In vitro toxicity towards the five normal cell types was compared with known clinical adverse event profiles. The normal cell panel roughly reflected the tissue specific toxicities but was most useful in the prediction of therapeutic index.

In paper III the use of peripheral blood lymphocytes from human, dog, rat and mouse to detect species differences in cellular drug sensitivity was described. Good agreement between our method and the established CFU-GM assay was observed.

In paper II the benefit of using primary tumour cells from patients to predict cancer diagnosis-specific activity was studied. The in vitro activity of fourteen anticancer drugs was tested in tumour samples of both haematological and solid tumour origin. In general, clinical activity was well reflected.

In paper IV, the efficacy and toxicity models were applied for experimental follow-up of a novel inhibitor of the ubiquitin-proteasome system, CB3 (Phosphoric acid, 2,3-dihydro-1,1-dioxido-3-thienyl diphenyl ester). In the preliminary characterization of CB3, antitumour activity and a favourable toxicity profile were displayed, although the exact mechanism of action remains to be elucidated. CB3 will therefore be further investigated.

In conclusion, the work presented here contributes to different parts of the preclinical drug development and the methods may aid in the characterization of anticancer compounds

Place, publisher, year, edition, pages
Uppsala: Acta Unversitatis Upsaliensis, 2011. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 665
Keyword
Anticancer drugs, In vitro assays, Toxicity testing, Haematological toxicity, Primary tumour cells, Species difference
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-150361 (URN)978-91-554-8051-6 (ISBN)
Public defence
2011-05-12, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2011-04-19 Created: 2011-03-29 Last updated: 2011-05-05Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Haglund, Caroline

Search in DiVA

By author/editor
Haglund, Caroline
By organisation
Clinical Pharmacology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 427 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf