Document Detail


Optimizing glioblastoma temozolomide chemotherapy employing lentiviral-based anti-MGMT shRNA technology.
MedLine Citation:
PMID:  23319055     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Despite treatments combining surgery, radiation-, and chemotherapy, patients affected by glioblastoma (GBM) have a limited prognosis. Addition of temozolomide (TMZ) to radiation therapy is the standard therapy in clinical application, but effectiveness of TMZ is limited by the tumor's overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). The goal of this study was to use the highly specific and efficient RNA interference (RNAi) pathway to modulate MGMT expression to increase TMZ efficiency in chemotherapy resistant GBM. Using lentiviral-based anti-MGMT small hairpin RNA (shRNA) technology we observed a specific inhibition of the MGMT expression in GBM cell lines as well as in subcutaneous tumors. Tumor growth inhibition was observed following TMZ treatment of xenografts with low MGMT expression in contrast to xenografts with high MGMT expression. Bioluminescence imaging (BLI) measurements indicated that luciferase and shRNA-expressing lentiviruses were able to efficiently transduce the GBM xenografts in vivo. Treatment combining injection of a lentivirus expressing an anti-MGMT shRNA and TMZ induced a reduction of the size of the tumors, in contrast with treatment combining the lentivirus expressing the control shRNA and TMZ. Our data suggest that anti-MGMT shRNA therapy could be used in combination with TMZ chemotherapy in order to improve the treatment of resistant GBM.
Authors:
Thomas Viel; Parisa Monfared; Sonja Schelhaas; Inga B Fricke; Michael T Kuhlmann; Cornel Fraefel; Andreas H Jacobs
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-15
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-10-22     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  570-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents, Alkylating / therapeutic use
Cell Line, Tumor
DNA Modification Methylases / antagonists & inhibitors*,  genetics,  metabolism
DNA Repair Enzymes / antagonists & inhibitors*,  genetics,  metabolism
Dacarbazine / analogs & derivatives*,  therapeutic use
Drug Resistance, Neoplasm / drug effects,  genetics
Gene Expression Regulation
Genetic Vectors
Glioblastoma / drug therapy*,  radiotherapy
Humans
Lentivirus / genetics*
Mice
Mice, Nude
RNA, Small Interfering / therapeutic use*
Transduction, Genetic
Tumor Suppressor Proteins / antagonists & inhibitors*,  genetics,  metabolism
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/RNA, Small Interfering; 0/Tumor Suppressor Proteins; 7GR28W0FJI/Dacarbazine; 85622-93-1/temozolomide; EC 2.1.1.-/DNA Modification Methylases; EC 2.1.1.63/MGMT protein, human; EC 6.5.1.-/DNA Repair Enzymes
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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