Evidence for intrathecal sodium butyrate as a novel option for leptomeningeal metastasis
Abstract
Introduction
The prognosis for leptomeningeal metastasis (LM) remains extremely poor regardless of intrathecal chemotherapy with various drugs, and thus, new treatments are necessary. Butyrate is an endogenous 4-carbon saturated fatty acid, has been investigated as an anti-tumor agent because of its multiple suppressive effects on several tumors. In this study, we investigated the cellular basis of sodium butyrate (SB), a sodium salt compound of butyrate, in vitro and evaluated the clinical potential of intrathecal SB administration for LM in vivo.
Methods
We examined SB’s effects on Walker 256 rat mammary tumor cells with regard to cytotoxicity, cell morphology, colony formation, migration, and invasion. We also examined SB’s neurotoxicity for primary neurons and primary astrocytes. We finally evaluated the potency of continuous intrathecal SB administration in rats with intrathecally transplanted breast tumors as an LM model.
Results
Physiological SB concentrations (2–4 mM) induced growth suppression, morphological changes, and inhibition of migration and invasion, but did not exhibit neurotoxic effects on primary neurons and astrocytes. Continuous intrathecal SB administration in a rat LM model significantly increased survival periods with little neurotoxicity.
Conclusions
Continuous intrathecal SB administration significantly improved prognoses in a rat LM model, which suggests that SB is a promising therapy for LM.
Keywords
Intrathecal administration Sodium butyrate Neurotoxicity Leptomeningeal metastasisAbbreviations
- Ara-C
Cytosine arabinoside
- DAPI
4′,6-Diamidino-2-phenylindole
- DMEM
Dulbecco modified essential medium
- FBS
Fetal bovine serum
- MEM
Minimum essential medium
- MTX
Methotrexate
- PBS
Phosphate buffer saline
Supplementary material
References
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