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Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells

Glioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the eff... Full description

Journal Title: Gene Therapy Nov 2010, Vol.17(11), pp.1363-71
Main Author: Kato, T
Other Authors: Natsume, A , Toda, H , Iwamizu, H , Sugita, T , Hachisu, R , Watanabe, R , Yuki, K , Motomura, K , Bankiewicz, K , Wakabayashi, T
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 09697128 ; DOI: 10.1038/gt.2010.88
Link: http://search.proquest.com/docview/763661729/?pq-origsite=primo
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title: Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells
format: Article
creator:
  • Kato, T
  • Natsume, A
  • Toda, H
  • Iwamizu, H
  • Sugita, T
  • Hachisu, R
  • Watanabe, R
  • Yuki, K
  • Motomura, K
  • Bankiewicz, K
  • Wakabayashi, T
subjects:
  • Animals–Administration & Dosage
  • Antineoplastic Agents, Alkylating–Toxicity
  • Antineoplastic Agents, Alkylating–Drug Therapy
  • Brain Neoplasms–Therapy
  • Brain Neoplasms–Administration & Dosage
  • Cell Line, Tumor–Analogs & Derivatives
  • Combined Modality Therapy–Toxicity
  • DNA Repair–Drug Therapy
  • Dacarbazine–Therapy
  • Dacarbazine–Antagonists & Inhibitors
  • Dacarbazine–Genetics
  • Drug Delivery Systems–Metabolism
  • Glioblastoma–Administration & Dosage
  • Glioblastoma–Administration & Dosage
  • Liposomes–Administration & Dosage
  • Mice–Administration & Dosage
  • Mice, Inbred Nod–Administration & Dosage
  • Mice, Scid–Administration & Dosage
  • O(6)-Methylguanine-DNA Methyltransferase–Administration & Dosage
  • O(6)-Methylguanine-DNA Methyltransferase–Administration & Dosage
  • O(6)-Methylguanine-DNA Methyltransferase–Administration & Dosage
  • RNA, Small Interfering–Administration & Dosage
  • Brain Cancer
  • Gene Therapy
  • Chemotherapy
  • Lipids
  • Cellular Biology
  • Gene Expression
  • Proteins
  • DNA Repair
  • Antineoplastic Agents, Alkylating
  • Liposomes
  • RNA, Small Interfering
  • Dacarbazine
  • Temozolomide
  • O(6)-Methylguanine-DNA Methyltransferase
ispartof: Gene Therapy, Nov 2010, Vol.17(11), pp.1363-71
description: Glioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that small-interfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced glioma-initiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations. [PUBLICATION ]
language: eng
source:
identifier: ISSN: 09697128 ; DOI: 10.1038/gt.2010.88
fulltext: fulltext
issn:
  • 09697128
  • 0969-7128
url: Link


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titleEfficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells
creatorKato, T ; Natsume, A ; Toda, H ; Iwamizu, H ; Sugita, T ; Hachisu, R ; Watanabe, R ; Yuki, K ; Motomura, K ; Bankiewicz, K ; Wakabayashi, T
ispartofGene Therapy, Nov 2010, Vol.17(11), pp.1363-71
identifierISSN: 09697128 ; DOI: 10.1038/gt.2010.88
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descriptionGlioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that small-interfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced glioma-initiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations. [PUBLICATION ]
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titleEfficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells
descriptionGlioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that small-interfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced glioma-initiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations. [PUBLICATION ]
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titleEfficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells
authorKato, T ; Natsume, A ; Toda, H ; Iwamizu, H ; Sugita, T ; Hachisu, R ; Watanabe, R ; Yuki, K ; Motomura, K ; Bankiewicz, K ; Wakabayashi, T
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3Brain Neoplasms–Therapy
4Brain Neoplasms–Administration & Dosage
5Cell Line, Tumor–Analogs & Derivatives
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7DNA Repair–Drug Therapy
8Dacarbazine–Therapy
9Dacarbazine–Antagonists & Inhibitors
10Dacarbazine–Genetics
11Drug Delivery Systems–Metabolism
12Glioblastoma–Administration & Dosage
13Liposomes–Administration & Dosage
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18RNA, Small Interfering–Administration & Dosage
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20Gene Therapy
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22Lipids
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abstractGlioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that small-interfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced glioma-initiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations. [PUBLICATION ABSTRACT]
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doi10.1038/gt.2010.88
urlhttp://search.proquest.com/docview/763661729/
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date2010-11-01