Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors.

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 Ther

journal_title

Cancer gene therapy

authors

Ambady P,Wu YJ,Walker JM,Kersch C,Pagel MA,Woltjer RL,Fu R,Muldoon LL,Neuwelt EA

doi

10.1038/cgt.2017.27

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

348-357

issue

8

eissn

0929-1903

issn

1476-5500

pii

cgt201727

journal_volume

24

pub_type

杂志文章
  • Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand.

    abstract::The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the i...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-00239-8

    authors: Yu J,Yang K,Zheng J,Zhao W,Sun X

    更新日期:2020-10-13 00:00:00

  • Oral contrast enhances the resolution of in-life NIS reporter gene imaging.

    abstract::Sodium iodide symporter (NIS) reporter gene imaging is an excellent technology for noninvasive cell fate determination in living animals unless the NIS-transduced cells reside in perigastric organs such as the spleen, liver, diaphragm, omentum, pancreas, perigastric lymph nodes or perigastric tumor deposits. Here we r...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2013.57

    authors: Suksanpaisan L,Pham L,McIvor S,Russell SJ,Peng KW

    更新日期:2013-11-01 00:00:00

  • circRACGAP1 promotes non-small cell lung cancer proliferation by regulating miR-144-5p/CDKL1 signaling pathway.

    abstract::Circular RNAs (circRNAs) are involved in the regulation of many pathophysiological processes as non-coding RNAs. This study focuses on the role of circRACGAP1 in the development of non-small cell lung cancer (NSCLC). Expression patterns of circRACGAP1 and miR-144-5p in NSCLC tissues and cell lines were quantified by q...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-00209-0

    authors: Lu M,Xiong H,Xia ZK,Liu B,Wu F,Zhang HX,Hu CH,Liu P

    更新日期:2020-08-11 00:00:00

  • The role of natural killer cells in combinatorial anti-cancer therapy using Sindbis viral vectors and irinotecan.

    abstract::Oncolytic viruses (OVs) have shown great anti-cancer potential in animal models, but only modest success in early clinical trials. A better understanding of the mechanisms underlining OV efficacy is needed to resolve this discrepancy. In the clinic, OV therapy will likely be combined with traditional chemotherapy, und...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2012.33

    authors: Granot T,Meruelo D

    更新日期:2012-08-01 00:00:00

  • microRNA-9-5p regulates the mitochondrial function of hepatocellular carcinoma cells through suppressing PDK4.

    abstract::Due to the lack of early diagnostic and effective treatment modalities, hepatocellular carcinoma (HCC) is still the most lethal cancer with a high mortality on a global scale. Recent studies have highlighted the key roles of microRNAs (miRs) in HCC development. In the study, we attempted to investigate the potential r...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-00253-w

    authors: Si T,Ning X,Zhao H,Zhang M,Huang P,Hu Z,Yang L,Lin L

    更新日期:2020-11-30 00:00:00

  • Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors.

    abstract::Endothelial cells and endothelial cell precursors encoding a therapeutic gene have induced antitumor responses in preclinical models. Culture of peripheral blood provides a rich supply of autologous, highly proliferative endothelial cells, also referred to as blood outgrowth endothelial cells (BOECs). The aim of this ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2010.42

    authors: Bodempudi V,Ohlfest JR,Terai K,Zamora EA,Vogel RI,Gupta K,Hebbel RP,Dudek AZ

    更新日期:2010-12-01 00:00:00

  • Virotherapy clinical trials for regional disease: in situ immune modulation using recombinant poxvirus vectors.

    abstract::The ability of viruses to readily infect tumor cells both in vitro and in vivo has resulted in their study as antitumor agents through a variety of strategies. Replicating and conditionally replicating viruses and recombinant viruses encoding genes for toxins and/or prodrugs have been studied for their direct antitumo...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/sj.cgt.7700538

    authors: Mastrangelo MJ,Lattime EC

    更新日期:2002-12-01 00:00:00

  • Mdr1 promoter-driven tumor necrosis factor-alpha expression for a chemotherapy-controllable combined in vivo gene therapy and chemotherapy of tumors.

    abstract::Cancer gene therapy approaches are often designed as single-agent treatments; however, greater therapeutic effect might be obtained if combined with an established conventional treatment regimen such as chemotherapy. In this context, conditional promoters are useful tools, because they may be induced by therapeutic mo...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700196

    authors: Walther W,Stein U,Fichtner I,Alexander M,Shoemaker RH,Schlag PM

    更新日期:2000-06-01 00:00:00

  • Transfection of NF-κB decoy oligodeoxynucleotide suppresses pulmonary metastasis by murine osteosarcoma.

    abstract::Nuclear factor-kappa B (NF-κB) has a pivotal role in the progression and distant metastasis of cancers, including malignant bone tumors. To inhibit NF-κB activation, a new molecular therapy using synthetic double-stranded oligodeoxynucleotide (ODN) as a 'decoy' cis element against NF-κB has been developed. To determin...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2010.75

    authors: Nishimura A,Akeda K,Matsubara T,Kusuzaki K,Matsumine A,Masuda K,Gemba T,Uchida A,Sudo A

    更新日期:2011-04-01 00:00:00

  • Eliciting protective immune responses against murine myeloma challenge in lymphopenia mice through adoptive transfer of tumor antigen-specific lymphocytes and immunization of tumor vaccine secreting mIL-21.

    abstract::Previous studies have indicated that the cytokine interleukin (IL)-21 may induce both innate and adaptive immune responses against tumors. The goal of this study was to evaluate a new adoptive immunotherapy strategy that combined lymphocytes from mice immunized with a murine myeloma vaccine secreting murine IL-21 (mIL...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2010.23

    authors: Dou J,Wu Y,Wang J,Zhao F,Chu L,Liu C,Wen P,Hu W,Hu K,He XF,Gu N

    更新日期:2010-10-01 00:00:00

  • Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells.

    abstract::The aim of the present study is to identify the optimal anticancer agents for use in combination with gene therapy using wild-type (wt) p53 gene transfer. We used adenoviral vectors expressing human wt p53 (AdCAp53) and investigated the effects of wt p53 gene transfer in combination with 12 anticancer agents on a huma...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700096

    authors: Osaki S,Nakanishi Y,Takayama K,Pei XH,Ueno H,Hara N

    更新日期:2000-02-01 00:00:00

  • Sustained cytokine production and immunophenotypic changes in human neuroblastoma cell lines transduced with a human gamma interferon vector.

    abstract::The majority of human neuroblastomas express low to undetectable levels of major histocompatibility complex (MHC) class I and II antigens (MHC-I and -II). We studied the effects of gamma interferon (gamma-IFN) transduction on expression of these antigens in six human neuroblastoma cell lines with and without genomic a...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:

    authors: Uçar K,Seeger RC,Challita PM,Watanabe CT,Yen TL,Morgan JP,Amado R,Chou E,McCallister T,Barber JR

    更新日期:1995-09-01 00:00:00

  • Suppression of the Ewing's sarcoma phenotype by FLI1/ERF repressor hybrids.

    abstract::Fusion of the 5' half of the Ewing's sarcoma (ES) gene EWS with the DNA-binding domain of several transcription factors has been detected in many human tumors. The t(11;22)(q24;q12) chromosomal translocation is specifically linked to ES and primitive neuroectodermal tumors and results, in the majority of cases, in the...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700220

    authors: Athanasiou M,LeGallic L,Watson DK,Blair DG,Mavrothalassitis G

    更新日期:2000-08-01 00:00:00

  • Mining the adenovirus virome for oncolytics against multiple solid tumor types.

    abstract::Although there are 55 serotypes of adenovirus (Ad) that infect humans, Ad serotype 5 (Ad5) is the most widely studied because of the availability of commercial kits for its genetic manipulation. In fact, engineered Ad 5 is currently being used in all of the 87 global clinical trials utilizing Ad for the treatment of c...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2011.47

    authors: Chen CY,Weaver EA,Khare R,May SM,Barry MA

    更新日期:2011-10-01 00:00:00

  • Enhancement of antitumor immunity by expression of CD70 (CD27 ligand) or CD154 (CD40 ligand) costimulatory molecules in tumor cells.

    abstract::CD70 (CD27 ligand (CD27L)), CD153 (CD30L), and CD154 (CD40L) are members of the tumor necrosis factor family of costimulatory molecules and expressed on the surface of T cells that are important for both T- and B-cell help. We examined the capacity for expression of these tumor necrosis factor family members on tumor ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:

    authors: Couderc B,Zitvogel L,Douin-Echinard V,Djennane L,Tahara H,Favre G,Lotze MT,Robbins PD

    更新日期:1998-05-01 00:00:00

  • Human growth hormone gene transfer into tumor cells may improve cancer chemotherapy.

    abstract::Chemotherapy remains the main tool for the treatment of cancers, but is often hampered by tumor cell resistance. In this context, the transfer of genes able to accentuate the effect of anticancer drugs may constitute a useful approach, as exemplified by inactivation of nuclear factor (NF)-kappa B via direct transfer o...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700467

    authors: Cherbonnier C,Déas O,Vassal G,Merlin JL,Haeffner A,Senik A,Charpentier B,Dürrbach A,Bénard J,Hirsch F

    更新日期:2002-06-01 00:00:00

  • Role of temperature-independent lipoplex-cell membrane interactions in the efficiency boost of multicomponent lipoplexes.

    abstract::Multicomponent lipoplexes have recently emerged as especially promising transfection candidates, as they are from 10 to 100 times more efficient than binary complexes usually employed for gene delivery purposes. Previously, we investigated a number of chemical-physical properties of DNA-lipid complexes that were propo...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2011.12

    authors: Marchini C,Pozzi D,Montani M,Alfonsi C,Amici A,Candeloro De Sanctis S,Digman MA,Sanchez S,Gratton E,Amenitsch H,Fabbretti A,Gualerzi CO,Caracciolo G

    更新日期:2011-08-01 00:00:00

  • An HSVtk-mediated local and distant antitumor bystander effect in tumors of head and neck origin in athymic mice.

    abstract::The "bystander effect," produced by ganciclovir-mediated killing of cells transduced with a herpes simplex virus thymidine kinase (HSVtk) gene, defines the cooperative killing of non-HSVtk-transduced cells. In vitro, a major contributor to this phenomenon is metabolic cooperation involving transfer of cytotoxic small ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:

    authors: Bi W,Kim YG,Feliciano ES,Pavelic L,Wilson KM,Pavelic ZP,Stambrook PJ

    更新日期:1997-07-01 00:00:00

  • Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells.

    abstract::Replication-selective oncolytic viruses are being developed for human cancer therapy. We previously developed an attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site. OBP-301...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2012.57

    authors: Watanabe Y,Hashimoto Y,Kagawa S,Kawamura H,Nagai K,Tanaka N,Urata Y,Fujiwara T

    更新日期:2012-11-01 00:00:00

  • Triplex-forming oligodeoxynucleotides targeting survivin inhibit proliferation and induce apoptosis of human lung carcinoma cells.

    abstract::Survivin is expressed in most cancers but is undetectable in differentiated adult cells, and plays an important role both in the suppression of apoptosis and mitotic spindle checkpoint; thus it has attracted great interest as a potential drug target. In this study, we investigated the antigene and antiproliferative ef...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700581

    authors: Shen C,Buck A,Polat B,Schmid-Kotsas A,Matuschek C,Gross HJ,Bachem M,Reske SN

    更新日期:2003-05-01 00:00:00

  • Suppression of mammary carcinoma growth in vitro and in vivo by inducible expression of the Cdk inhibitor p21.

    abstract::Mammary carcinomas that develop in C3 (1)/SV40 T- antigen (TAg) transgenic mice have lost the p53-mediated induction of p21, leading to increased cellular proliferation and significant elevations of cyclins and Cdks. To test whether p21 could serve as a target for anticancer therapy for this mammary cancer model, a re...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700275

    authors: Shibata MA,Yoshidome K,Shibata E,Jorcyk CL,Green JE

    更新日期:2001-01-01 00:00:00

  • T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines.

    abstract::CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700584

    authors: Tada Y,O-Wang J,Yu L,Shimozato O,Wang YQ,Takiguchi Y,Tatsumi K,Kuriyama T,Takenaga K,Sakiyama S,Tagawa M

    更新日期:2003-06-01 00:00:00

  • Bone marrow stromal cells-derived microRNA-181-containing extracellular vesicles inhibit ovarian cancer cell chemoresistance by downregulating MEST via the Wnt/β-catenin signaling pathway.

    abstract::Cisplatin (DDP)-based strategies are the first-line treatment for cancers; however, resistance to DDP remains a major obstacle to cancer treatment. The current study set out to investigate the effects of microRNA-181c (miR-181c) on the resistance of ovarian cancer cells to DDP. Ovarian cancer-associated miRs as well a...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-0195-6

    authors: Ruan Z,Lu L,Zhang L,Dong M

    更新日期:2020-07-07 00:00:00

  • Immunosuppression promotes reovirus therapy of colorectal liver metastases.

    abstract::Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic virus. The efficacy of ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700949

    authors: Smakman N,van der Bilt JD,van den Wollenberg DJ,Hoeben RC,Borel Rinkes IH,Kranenburg O

    更新日期:2006-08-01 00:00:00

  • Fusion protein from RGD peptide and Fc fragment of mouse immunoglobulin G inhibits angiogenesis in tumor.

    abstract::Targeting tumor vasculature represents an interesting approach for the treatment of solid tumors. The alpha v beta 3 integrins have been found to be specifically associated with angiogenesis in tumors. By using bacteriophage display technology, Ruoslahti et al found that a group of peptides containing the RGD (Arg-Gly...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700707

    authors: Li J,Ji J,Holmes LM,Burgin KE,Barton LB,Yu X,Wagner TE,Wei Y

    更新日期:2004-05-01 00:00:00

  • PiggyBac as a novel vector in cancer gene therapy: current perspective.

    abstract::Selection of suitable delivery system is one of the crucial aspects in gene therapy that determines the efficiency of gene therapy. The past two decades have witnessed extensive efforts for finding safe and efficient vectors to overcome the limitations of viral vectors. The utilization of DNA transposon-based vectors ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2015.68

    authors: Mirzaei H,Sahebkar A,Jaafari MR,Hadjati J,Javanmard SH,Mirzaei HR,Salehi R

    更新日期:2016-02-01 00:00:00

  • Gene therapy of metastatic colon carcinoma: regression of multiple hepatic metastases by adenoviral expression of bacterial cytosine deaminase.

    abstract::Colon carcinoma accounts for 20% of deaths due to malignancies in the Western world. Once metastases occur, therapeutic options are limited, with an approximate 5-year survival of only 5%. To investigate the potential of new gene therapeutic approaches, a hepatic micrometastasis model of colon carcinoma in BALB/c mice...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700131

    authors: Block A,Freund CT,Chen SH,Nguyen KP,Finegold M,Windler E,Woo SL

    更新日期:2000-03-01 00:00:00

  • Development of a novel adenovirus-alphavirus hybrid vector with RNA replicon features for malignant hematopoietic cell transduction.

    abstract::To improve the expression levels of transgenes in malignant hematopoietic cells, we developed a novel adenoviral-alphavirus hybrid vector Ad5/F11p-SFV-GFP that contains a Semliki Forest Virus (SFV) replicon and chimeric fibers of Ad5 and Ad11p. Ad5/F11p-SFV-GFP infected >95% of K562, U937 or Jurkat cells and 23.65% of...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2013.37

    authors: Yang Y,Xiao F,Lu Z,Li Z,Zuo H,Zhang Q,Li Q,Wang H,Wang LS

    更新日期:2013-08-01 00:00:00

  • Neuregulin receptor-mediated gene transfer by human epidermal growth factor receptor 2-targeted antibodies and neuregulin-1.

    abstract::The human epidermal growth factor receptors 2, 3, and 4 (HER2, HER3, and HER4, respectively) are frequently overexpressed in many human cancers, and therefore may be potential targets for receptor-mediated gene transfer. To evaluate this possibility, we constructed a series of HER-targeted gene transfer vehicles by co...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700069

    authors: Kern JA,Wakita R,Sliwkowski MX

    更新日期:1999-11-01 00:00:00

  • Redirected cellular cytotoxicity by infection of effector cells with a recombinant vaccinia virus encoding a tumor-specific monoclonal antibody.

    abstract::Cytotoxicity is an important function of the immune system that results in the destruction of cellular targets by humoral and/or cellular mechanisms. We wanted to assess the possibility of targeting the lytic function of immune cells toward cancer cells, which express the gene coding for a known tumor antigen (Ag) (GA...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700161

    authors: Paul S,Bizouarne N,Dott K,Ruet L,Dufour P,Acres RB,Kieny MP

    更新日期:2000-04-01 00:00:00