Chemotherapeutic agent 5-fluorouracil increases survival of SOD1 mouse model of ALS.

Amaya Rando,Sara Hernández,Anna Martinez-Muriana,Pilar Zaragoza,Janne M Toivonen,Rosario Osta,Miriam De La Torre,Antonio Musaro,Xavier Navarro,Hoon Ryu

doi:10.1371/journal.pone.0210752

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease with no cure. Currently there are only two ALS drugs approved by the FDA, both with a limited therapeutic effect. In the search for drug candidates for ALS, we studied the effect of known stem cell mobilizing agents (treatment) and antimetabolite 5-fluorouracil (5-FU) (anti-treatment) in SOD1G93A model of ALS. Surprisingly, we found that anti-cancer drug 5-FU increases lifespan, delays the disease onset and improves motor performance in ALS mice. Although we were not able to demonstrate the mechanistic basis of the beneficial 5-FU action in ALS mice, our findings suggest that 5-FU or similar drugs are possible drug candidates for the treatment of motor neuron diseases through drug repurposing.

Highlights

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by upper and lower motor neuron (MN) degeneration, progressive muscle paralysis and atrophy [1]
Granulocyte colony stimulating factor (GCSF) and its analog Pegfilgrastim increase the mobilization of hematopoietic stem cells and blood white blood cell (WBC) count [6, 7]
To confirm the expected action of 5-FU, we measured the effect of 5-FU administration on the number of the circulating white blood cells (WBC) in the SOD1G93A mice following the treatment with a single dose of 5-FU at 150 mg/kg

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by upper and lower motor neuron (MN) degeneration, progressive muscle paralysis and atrophy [1]. ALS patients typically die from cardiorespiratory failure within 2–5 years after the diagnosis. The only FDA accepted treatments for ALS, riluzole and edaravone, appear to provide only limited benefit to the patients. New treatments are desperately needed for fighting ALS [2]. Cell-based therapies and gene targeting are being investigated for clinical use, the progress is slow because of bottlenecks in the therapeutic development process. Drug repurposing (using an agent already commercialized to treat one disease for the treatment of other diseases)

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