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Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics)
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2007 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 21, no 6, 1174-1181 p.Article in journal (Refereed) Published
Abstract [en]

Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50–300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.

Place, publisher, year, edition, pages
2007. Vol. 21, no 6, 1174-1181 p.
Keyword [en]
Animals, Antineoplastic Agents/*toxicity, Cell Survival/drug effects, Cells; Cultured, Dogs, Female, Fluorometry, Humans, Leukocytes; Mononuclear/*drug effects, Male, Mice, Mice; Inbred BALB C, Rats, Rats; Inbred Strains, Species Specificity, Toxicity Tests/methods
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-15582DOI: 10.1016/j.tiv.2007.03.009ISI: 000249542300022PubMedID: 17481850OAI: oai:DiVA.org:uu-15582DiVA: diva2:43353
Available from: 2008-02-21 Created: 2008-02-21 Last updated: 2017-12-08Bibliographically approved
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

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Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17481850&dopt=Citation

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Haglund, CarolineÅleskog, AnnaLarsson, RolfLindhagen, Elin

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