Abstract:
:The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences. We demonstrate >40% reduction in the in vitro proliferation index and cell viability in radiation-primed MGMT-expressing human solid tumor cells treated with a single dose of AMONs and temozolomide. We further demonstrate the feasibility of using a non-ablative dose of radiation in vivo to guide and enhance the delivery of intravenously administered AMONs to achieve 50% MGMT knockdown only at radiation-primed tumor sites in a subcutaneous tumor model. Local upregulation of physiological endocytosis after radiation may have a role in radiation-guided uptake of AMONs. This approach holds direct translational significance in glioblastoma and brain metastases where radiation is part of the standard of care; our approach to silence MGMT could overcome the significant problem of MGMT-mediated chemoresistance.
journal_name
Cancer Gene Therjournal_title
Cancer gene therapyauthors
Ambady P,Wu YJ,Walker JM,Kersch C,Pagel MA,Woltjer RL,Fu R,Muldoon LL,Neuwelt EAdoi
10.1038/cgt.2017.27subject
Has Abstractpub_date
2017-08-01 00:00:00pages
348-357issue
8eissn
0929-1903issn
1476-5500pii
cgt201727journal_volume
24pub_type
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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doi:10.1038/cgt.2011.12
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journal_title:Cancer gene therapy
pub_type: 杂志文章
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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journal_title:Cancer gene therapy
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doi:10.1038/sj.cgt.7700161
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