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Model for time dependency of the cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
2001 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 299, no 3, 1140-1147 p.Article in journal (Refereed) Published
Abstract [en]

CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.

Place, publisher, year, edition, pages
2001. Vol. 299, no 3, 1140-1147 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-92449PubMedID: 11714905OAI: oai:DiVA.org:uu-92449DiVA: diva2:165529
Available from: 2004-11-24 Created: 2004-11-24 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Methods for Preclinical Evaluation of Cytotoxic Drugs: With Special Reference to the Cyanoguanidine CHS 828 and Hollow Fiber Method
Open this publication in new window or tab >>Methods for Preclinical Evaluation of Cytotoxic Drugs: With Special Reference to the Cyanoguanidine CHS 828 and Hollow Fiber Method
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The novel cyanoguanidine CHS 828 has shown promising antitumor activity in many in vitro and in vivo studies.

The long-term 14 days in vitro hollow fiber cultures, where tumor cells from different tumor cell lines were cultured inside semipermeable fibers, were more resistant to CHS 828 and other cytotoxic drugs than the shorter-term 3 days cultures. CHS 828 was generally more effective against haematological than solid tumor cells from both cell lines and patients samples.

In vivo, the hollow fibers were implanted into immunocompetent rats and the pharmacokinetics, tumor response and/or toxicity (pharmacodynamics) of CHS 828 were successfully assayed. CHS 828 showed higher activity in this model when a more protracted schedule was used. The quantitative relationships between dose, plasma concentration and response (PK/PD model) developed for CHS 828 explained this phenomenon partly by dose-dependent fraction absorbed and partly by a schedule-dependent pharmacodynamic effect.

Modelling of the in vitro CHS 828 and standard cytotoxic drugs concentration-time effect data in different tumor cell types and characterization of pattern of change of the potency and the slope of the concentration-time effect curves were performed. The results suggest two different mechanisms of action for CHS 828 and that CHS 828 cytotoxicity may depend on the schedule used.

The NF-kB pathway that regulates the transcription of anti-apoptotic genes proved to be inhibited by CHS 828 in different tumor cell lines and the inhibition was correlated to the cell death induced by this agent. CHS 828 did not seem to induce the NF-kB inhibition by affecting the proteasome activity.

The in vitro and in vivo hollow fiber methods were also used successfully to evaluate the new paclitaxel formulation, Pacliex. Pacliex had a similar activity to that of the clinically used formulation Taxol®.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 48 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1395
Keyword
Pharmacology, CHS 828, in vitro, in vivo, hollow fiber, models, NF-kB, Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-4696 (URN)91-554-6113-1 (ISBN)
Public defence
2004-12-16, Rudbecsalen, Rudbeck laboratory, SE-751 85, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-11-24 Created: 2004-11-24Bibliographically approved

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