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Tsujiuchi T, Natsume A, Motomura K, et al. Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. Am J Transl Res. 2014;6(2):169-78
Tsujiuchi, T., Natsume, A., Motomura, K., Kondo, G., Ranjit, M., Hachisu, R., Sugimura, I., Tomita, S., Takehara, I., Woolley, M., Barua, N. U., Gill, S. S., Bienemann, A. S., Yamashita, Y., Toyokuni, S., & Wakabayashi, T. (2014). Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. American journal of translational research, 6(2), 169-78.
Tsujiuchi, Takashi, et al. "Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains." American journal of translational research vol. 6,2 (2014): 169-78.
Tsujiuchi T, Natsume A, Motomura K, Kondo G, Ranjit M, Hachisu R, Sugimura I, Tomita S, Takehara I, Woolley M, Barua NU, Gill SS, Bienemann AS, Yamashita Y, Toyokuni S, Wakabayashi T. Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. Am J Transl Res. 2014 Jan 15;6(2):169-78. eCollection 2014. PMID: 24489997; PMCID: PMC3902228.
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Am J Transl Res. 2014 Jan 15;6(2):169-78. eCollection 2014.

Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains.

American journal of translational research

Takashi Tsujiuchi, Atsushi Natsume, Kazuya Motomura, Goro Kondo, Melissa Ranjit, Rei Hachisu, Itsuro Sugimura, Shinpei Tomita, Isao Takehara, Max Woolley, Neil U Barua, Steven S Gill, Alison S Bienemann, Yoriko Yamashita, Shinya Toyokuni, Toshihiko Wakabayashi

Affiliations

  1. Department of Neurosurgery, Nagoya University School of Medicine Nagoya, Aichi, Japan.
  2. Hokkaido System Science Sapporo, Hokkaido, Japan.
  3. New Drug Development Research Center Eniwa, Hokkaido, Japan.
  4. Renishaw Advanced Materials New Mills, Wotton-under-Edge, Gloucestershire, GL 12 8JR, United Kingdom.
  5. Functional Neurosurgery Research Group, University of Bristol United Kingdom.
  6. Functional Neurosurgery Research Group, University of Bristol, United Kingdom.
  7. Department of Pathology and Biological Responses, Nagoya University School of Medicine, Nagoya, Japan.

PMID: 24489997 PMCID: PMC3902228

Abstract

The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O(6)-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O(6)-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

Keywords: Glioblastoma; MGMT; cationic liposome; convection-enhaced delivery; si-RNA

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