Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• American journal of translational research, 2014, Vol.6 (2), p.169-178

Ort / Verlag

United States

Erscheinungsjahr

2014

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.