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Combination of CHS 828 and etoposide in vitro - from cytotoxic synergy to complete inhibition of apoptosis
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-89535OAI: oai:DiVA.org:uu-89535DiVA: diva2:161085
Available from: 2001-11-01 Created: 2001-11-01 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Pharmacological Studies of CHS 828 and Etoposide Induced Tumour Cell Death
Open this publication in new window or tab >>Pharmacological Studies of CHS 828 and Etoposide Induced Tumour Cell Death
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antitumour properties of the cyanoguanidine CHS 828 and analogues were discovered in 1997. CHS 828 is presently in clinical phase I/II trials. This thesis encompasses in vitro studies of the kinetics and mode of cell death induced in the human cell line U-937 GTB, by CHS 828 and the standard antitumour drug etoposide.

Etoposide induces apoptosis in U-937 GTB within 4 h. The cells exhibited apoptotic morphology, including condensed and fragmented nuclei and formation of apoptotic bodies, activation of caspase 3 and 8, and DNA fragmentation, visualised by TdT-mediated dUTP nick end-labelling (TUNEL).

CHS 828 induced few and weak signs of apoptosis. Metabolic activity was the only parameter affected during the first 24 h of exposure. After ~30 h, proliferation (DNA synthesis) and protein synthesis ceased, and viability started to decrease towards 10% at 72 h. Morphology and ultrastructure of dying/dead cells showed predominant necrosis. The decrease in viability was postponed by protein synthesis inhibition or maintenance of ATP levels by 3-aminobenzamide. In addition, 3-aminobenzamide switched morphology towards apoptosis.

Continuous co-exposure to CHS 828 and etoposide resulted in impressive cell kill synergy in U-937 GTB cells at effect levels of 30-70%. Pre-exposure to CHS 828 for 18 h or more, on the other hand, resulted in diminished cell kill and inability to activate the apoptotic machinery upon etoposide stimulation, evaluated by morphology and caspase activity.

In summary, CHS 828 induced cell death is predominantly non-apoptotic, does not involve caspases and can be postponed by maintained protein synthesis and ATP levels.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 53 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1095
Medical sciences, Cancer chemotherapy, cell death, caspase, etoposide, CHS 828, MEDICIN OCH VÅRD
National Category
Medical and Health Sciences
Research subject
Clinical Pharmacology
urn:nbn:se:uu:diva-1500 (URN)91-554-5157-8 (ISBN)
Public defence
2001-11-24, Auditorium Minus, Gustavianum, Uppsala, 09:15
Available from: 2001-11-01 Created: 2001-11-01Bibliographically approved

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