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Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity

Cowan, Noemi and Raimondo, Alessia and Keiser, Jennifer. (2016) Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity. Parasitology research, 115 (11). pp. 4443-4446.

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Official URL: http://edoc.unibas.ch/44559/

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Abstract

Infections with soil-transmitted helminths (STHs) are considered among the most persistent global health problems. The few available drugs have limitations including low efficacy against Trichuris trichiura infections. As a starting point toward drug repositioning, we studied a set of FDA-approved oncology drugs for activity against Trichuris muris since targets relevant to cancer therapy might have a function in helminth biology. Drugs were tested in vitro on the larval and adult stage of T. muris. Compounds active in vitro were tested in the T. muris mouse model at single oral dosages of 200-400 mg/kg. Of the 114 drugs tested in vitro, 12 showed activity against T. muris larvae (>80 % drug effect at 50 μM). Ten of these drugs were also active on the adult worm stage (>80 % drug effect at 50 μM), of which six revealed IC50 values between 1.8 and 5.0 μM. Except for tamoxifen citrate, all in vitro active drugs were protein kinase inhibitors. None of the drugs tested in vivo showed efficacy, revealing worm burden reductions of 0-24 % and worm expulsion rates of 0-7.9 %. The promising in vitro activities of protein kinases could not be confirmed in vivo. Drug discovery against STH should be strengthened including the definition of compound progression criteria. Follow-up structure-activity relationship studies with modified compounds might be considered.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Keiser, Jennifer
Item Type:Article, refereed
Publisher:Springer-Verlag
ISSN:0932-0113
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:12 Dec 2016 14:25
Deposited On:12 Dec 2016 14:25

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