Front-line glioblastoma chemotherapeutic temozolomide is toxic to Trypanosoma brucei and potently enhances melarsoprol and eflornithine

Steverding, Dietmar and Rushworth, Stuart A. (2017) Front-line glioblastoma chemotherapeutic temozolomide is toxic to Trypanosoma brucei and potently enhances melarsoprol and eflornithine. Experimental Parasitology, 178. 45–50. ISSN 0014-4894

[img]
Preview
PDF (Accepted manuscript) - Submitted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (392kB) | Preview

Abstract

Sleeping sickness is an infectious disease that is caused by the protozoan parasite Trypanosoma brucei. The second stage of the disease is characterised by the parasites entering the brain. It is therefore important that sleeping sickness therapies are able to cross the blood-brain barrier. At present, only three medications for chemotherapy of the second stage of the disease are available. As these trypanocides have serious side effects and are difficult to administer, new and safe anti-trypanosomal brain-penetrating drugs are needed. For these reasons, the anti-glioblastoma drug temozolomide was tested in vitro for activity against bloodstream forms of T. brucei. The concentration of the drug required to reduce the growth rate of the parasites by 50% was 29.1 μM and to kill all trypanosomes was 125 μM. Importantly, temozolomide did not affect the growth of human HL-60 cells up to a concentration of 300 μM. Cell cycle analysis revealed that temozolomide induced DNA damage and subsequent cell cycle arrest in trypanosomes exposed to the compound. As drug combination regimes often achieve greater therapeutic efficacy than monotherapies, the interactions of temozolomide with the trypanocides eflornithine and melarsoprol, respectively, was determined. Both combinations were found to produce an additive effect. In conclusion, these results together with well-established pharmacokinetic data provide the basis for in vivo studies and potentially for clinical trials of temozolomide in the treatment of T. brucei infections and a rationale for its use in combination therapy, particularly with eflornithine or melarsoprol.

Item Type: Article
Uncontrolled Keywords: trypanosoma brucei,temozolomide,trypanocides,drug combination
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 24 May 2017 05:04
Last Modified: 15 Nov 2020 00:49
URI: https://ueaeprints.uea.ac.uk/id/eprint/63594
DOI: 10.1016/j.exppara.2017.05.006

Actions (login required)

View Item View Item