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Inhibitory action of benzimidazole fungicides on the in vivo incorporation of [3H]thymidine in various organs of the mouse
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Cancer pharmacology)
1990 (English)In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 10, no 28, 701-706 p.Article in journal (Refereed) Published
Abstract [en]

The effect of benomyl on the DNA turnover in various organs of the mouse was evaluated by measuring the incorporation of [3H]thymidine 24 hr after oral administration of different doses (1.3, 2.55 and 5.1 nmol/kg body weight) of benomyl. In the thymus, spleen and testis there was a clear relationship between dose and effect, the no-observed-effect level being 1.3 mmol/kg body weight. However, in the liver and kidney there was no obvious relationship between dose and effect, the [3H]thymidine incorporation being inhibited even at the lowest dose. Equimolar amounts of the closely related fungicide carbendazim inhibited the [3H]thymidine incorporation only in the testis. The observed differences between the two compounds was not a result of different absorption rates. Whole-body autoradiography indicated a rapid absorption and a similar distribution pattern for [phenyl(U)-14C)benomyl and [phenyl(U)-14C]carbendazim. Apart from an accumulation in the retina, liver and kidney, most other organs were almost devoid of [14C]benomyl- and [14C]carbendazim-associated radioactivity.

Place, publisher, year, edition, pages
1990. Vol. 10, no 28, 701-706 p.
National Category
Pharmacology and Toxicology
Research subject
URN: urn:nbn:se:uu:diva-130187DOI: 10.1016/0278-6915(90)90146-EISI: A1990EU64600006OAI: oai:DiVA.org:uu-130187DiVA: diva2:347926
Available from: 2010-09-03 Created: 2010-09-03 Last updated: 2010-09-29Bibliographically approved
In thesis
1. Preclinical Characterization in vivo and in vitro of Novel Agents for Cancer Chemotherapy: Studies on Benomyl, Carbendazim, Cryptolepine and Acriflavine
Open this publication in new window or tab >>Preclinical Characterization in vivo and in vitro of Novel Agents for Cancer Chemotherapy: Studies on Benomyl, Carbendazim, Cryptolepine and Acriflavine
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Preclinical methods for the identification and characterization of molecules for development into new cancer drugs were investigated. Based on repurposing, i.e. the exploration of currently prescribed drugs for new indications, and as a result of a new high throughput screening (HTS) approach, the benzimidazoles benomyl and carbendazim, the alkaloid cryptolepine and the acridine acriflavine were found interesting to characterize using these methods.

In mice the benzimidazoles inhibited 3H-thymidine incorporation in tissues with high cell renewal, with benomyl being more active than carbendazim.  They were rapidly absorbed with highest amounts seen in the liver, kidneys and gastro-intestinal lumen as evidenced from distribution of 14C-labeled drugs. In human tumour cell lines, the benzimidazoles showed a similar activity pattern but benomyl was more potent. This was true also in tumour cells from patients but carbendazim was relatively more active against solid tumours. Analyses of drug activity cross-resistance patterns and of drug activity – gene expression correlations in a cell line panel suggested multiple mechanisms of action for the benzimidazoles.

Cryptolepine was widely distributed to tissues in vivo in the mice. It was more potent than the benzimidazoles in tumour cells, with highest activity in haematological malignancies but some patient samples of breast, colon and non small-cell lung cancer were sensitive. Cross-resistance analysis indicated cryptolepine to be a topoisomerase II inhibitor whereas drug activity – gene expression correlations suggested additional mechanisms of action.

HTS on 2 000 molecules in colon cancer cell lines and normal cells identified acriflavine as a hit molecule, subsequently shown to have unprecedented activity against colorectal cancer tumour cells in patient tumour samples. Connectivity map analysis, based on drug induced gene expression perturbation patterns in a tumour cell line, indicated acriflavine to be a topoisomerase inhibitor, subsequently confirmed in a plasmid relaxation assay. In conclusion, repurposing of drugs and HTS using stringent activity criteria followed by preclinical characterization might contribute to more efficient development of new cancer drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 593
Benzimidazoles, cryptolepine, acriflavine, cancer, high throughput screening, cytotoxic drug, gene expression
urn:nbn:se:uu:diva-130330 (URN)978-91-554-7882-7 (ISBN)
Public defence
2010-10-15, Enghoffsalen, Entrance 50, Ground Floor, Uppsala University Hospital, Uppsala, 13:15 (English)
Available from: 2010-09-28 Created: 2010-09-06 Last updated: 2010-09-30Bibliographically approved

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