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Convection-enhanced delivery of a hydrophilic nitrosourea ameliorates deficits and suppresses tumor growth in experimental spinal cord glioma models

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Abstract

Background

Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier.

Objective

To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model.

Methods

Toxicity studies were performed in 42 rats following the administration of 4 μl of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED (n = 8); saline i.v. (n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically.

Results

The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses (P < 0.05; log-rank test).

Conclusions

ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma.

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Acknowledgements

We thank Ms. Haruka Mitome for her excellent technical assistance. The authors would like to thank Enago for the English language review.

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Authors and Affiliations

  1. Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo Aoba, Sendai, Japan, 980-8574

    Shogo Ogita, Toshiki Endo, Shinichiro Sugiyama, Ryuta Saito, Tomoo Inoue, Yukihiko Sonoda & Teiji Tominaga

  2. Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University Graduate School of Medicine, Sendai, Japan

    Akira Sumiyoshi, Hiroi Nonaka & Ryuta Kawashima

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  1. Shogo Ogita
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Correspondence to Toshiki Endo.

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Funding

This work was supported in part by a research grant from The General Insurance Association of Japan, Grant-in Aid for Scientific Research (C) (KAKENHI 24592151 and KAKENHI 15 K10352), Grant-in-Aid for Young Scientists (B) (KAKENHI 24791483), Japan Brain Foundation, and The MIKIYA Science and Technology Foundation. No author has personal or institutional financial interest in drugs, materials, or devices described in this paper.

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All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Ogita, S., Endo, T., Sugiyama, S. et al. Convection-enhanced delivery of a hydrophilic nitrosourea ameliorates deficits and suppresses tumor growth in experimental spinal cord glioma models. Acta Neurochir 159, 939–946 (2017). https://doi.org/10.1007/s00701-017-3123-2

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