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Evidence for intrathecal sodium butyrate as a novel option for leptomeningeal metastasis

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  • Published:
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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.

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Abbreviations

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

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Author information

Authors and Affiliations

  1. Department of Neurosurgery, Nozaki Tokushukai Hospital, Tanigawa 2-10-50, Daito, Osaka, 574-0074, Japan

    Hidemitsu Nakagawa

  2. Research Institute, Nozaki Tokushukai Hospital, Tanigawa 2-10-50, Daito, Osaka, Japan

    Hidemitsu Nakagawa, Yoshihiro Yui, Satoru Sasagawa & Kazuyuki Itoh

Authors
  1. Hidemitsu Nakagawa
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  2. Yoshihiro Yui
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  3. Satoru Sasagawa
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  4. Kazuyuki Itoh
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Corresponding author

Correspondence to Hidemitsu Nakagawa.

Electronic supplementary material

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Figure S1. Surgical osmotic pump implantation into the medullary cavity

. a. The osmotic mini-pump. Bar = 1 cm. b. Schematic of osmotic mini-pump implantation (JPG 1041 KB)

Figure S2. Effect of MTX treatment on neuronal cells and astrocyte

. a. Neuron viability in the presence of MTX. We treated primary isolated neurons with various MTX concentrations and observed cell viability. b. Astrocyte viability in the presence of MTX. We treated primary isolated astrocytes with various MTX concentrations and observed cell viability. *: P < 0.01; abbreviations: MTX, methotrexate (JPG 414 KB)

Figure S3. Histological confirmation of SB-induced brain damage

. An SB-treated rat brain was sectioned and stained with hematoxylin and eosin or with the Klüver-Barrera method. No obviously damaged regions were observed. Bar = 50 µm. Abbreviation: SB, sodium butyrate (JPG 1712 KB)

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Nakagawa, H., Yui, Y., Sasagawa, S. et al. Evidence for intrathecal sodium butyrate as a novel option for leptomeningeal metastasis. J Neurooncol 139, 43–50 (2018). https://doi.org/10.1007/s11060-018-2852-2

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  • DOI: https://doi.org/10.1007/s11060-018-2852-2

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