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

Parasitol Res. 2016 Nov;115(11):4443-4446. doi: 10.1007/s00436-016-5225-9. Epub 2016 Aug 8.

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.

Keywords: Oncology drugs; Protein kinases; Trichuriasis; Trichuris muris.

MeSH terms

  • Animals
  • Antinematodal Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Disease Models, Animal
  • Female
  • Larva / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Structure-Activity Relationship
  • Trichuriasis / drug therapy*
  • Trichuriasis / parasitology
  • Trichuris / drug effects*

Substances

  • Antinematodal Agents
  • Antineoplastic Agents