Use of the XRCC2 promoter for in vivo cancer diagnosis and therapy

Chen, Yu; Li, Zhen; Xu, Zhu; Tang, Herman; Guo, Wenbo; Sun, Xian-He; Zhang, Wenjun; Zhang, Jian; Wan, Xiaoping; Jiang, Ying; Mao, Zhiyong

doi:10.1038/s41419-018-0453-9

Cited by 11 publications

(10 citation statements)

References 34 publications

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“…The cytolethal effects after transfection of pXRCC2-DTA and pRAD51-DTA into HeLa cells were very similar (76.7 vs. 82.1%, respectively). Moreover, in vivo evaluation in nude mice, subcutaneously xenografted with HeLa cells, which consisted of 4 intratumoral injections of lentiviral vector containing the XRC22-DTA cassette in 11 days, resulted in a significant reduction in tumor size (Chen Y. et al, 2018).…”

Section: Expression Of Dt Under the Control Of Specific Promotersmentioning

confidence: 99%

Targeted Diphtheria Toxin-Based Therapy: A Review Article

Shafiee¹,

Aucoin²,

Jahanian-Najafabadi³

2019

Front. Microbiol.

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Cancer remains one of the leading causes of death worldwide. Conventional therapeutic strategies usually offer limited specificity, resulting in severe side effects and toxicity to normal tissues. Targeted cancer therapy, on the other hand, can improve the therapeutic potential of anti-cancer agents and decrease unwanted side effects. Targeted applications of cytolethal bacterial toxins have been found to be especially useful for the specific eradication of cancer cells. Targeting is either mediated by peptides or by protein-targeting moieties, such as antibodies, antibody fragments, cell-penetrating peptides (CPPs), growth factors, or cytokines. Together with a toxin domain, these molecules are more commonly referred to as immunotoxins. Targeting can also be achieved through gene delivery and cell-specific expression of a toxin. Of the available cytolethal toxins, diphtheria toxin (DT) is one of the most frequently used for these strategies. Of the many DT-based therapeutic strategies investigated to date, two immunotoxins, OntakTM and TagraxofuspTM, have gained FDA approval for clinical application. Despite some success with immunotoxins, suicide-gene therapy strategies, whereby controlled tumor-specific expression of DT is used for the eradication of malignant cells, are gaining prominence. The first part of this review focuses on DT-based immunotoxins, and it then discusses recent developments in tumor-specific expression of DT.

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Section: Expression Of Dt Under the Control Of Specific Promotersmentioning

confidence: 99%

Targeted Diphtheria Toxin-Based Therapy: A Review Article

Shafiee¹,

Aucoin²,

Jahanian-Najafabadi³

2019

Front. Microbiol.

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“…Additionally, miR-7 interacts with XRCC2 mRNA in colorectal cancer cells; overexpression of miR-7 reduces XRCC2 promoter activity (Xu et al, 2014). Interestingly, XRCC2 promoter activity seems to be highly up-regulated in nearly all types of cancers (Chen et al, 2018).…”

Section: Mutationsmentioning

confidence: 99%

XRCC2 (X-ray repair cross complementing 2)

Andreassen

2019

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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XRCC2 is one of five somatic RAD51 paralogs, all of which have Walker A and B ATPase motifs. Each of the paralogs, including XRCC2, has a function in DNA double-strand break repair by homologous recombination (HR). However, their individual roles are not as well understood as that of RAD51 itself. The XRCC2 protein forms a complex (BCDX2) with three other RAD51 paralogs, RAD51B, RAD51C and RAD51D. It is believed that the BCDX2 complex mediates HR downstream of BRCA2 but upstream of RAD51, as XRCC2 is involved in the assembly of RAD51 into DNA damage foci. XRCC2 can bind DNA and, along with RAD51D, can promote homologous pairing in vitro. Consistent with its role in HR, XRCC2-deficient cells have increased levels of spontaneous chromosome instability, and exhibit hypersensitivity to DNA interstrand crosslinking agents such as mitomycin C and cisplatin as well as ionizing radiation, alkylating agents and aldehydes. XRCC2 also functions in promoting DNA replication and chromosome segregation. Biallelic mutation of XRCC2 (FANCU) causes the FA-U subtype of FA, while heterozygosity for deleterious mutations in XRCC2 may be associated with an increased breast cancer risk. XRCC2 appears to function ‘downstream’ in the FA pathway, since it is not required for FANCD2 monoubiquitination, which is the central step in the FA pathway. Clinically, the only known FA-U patient in the world exhibits severe congenital abnormalities, but had not developed, by seven years of age, the bone marrow failure and cancer that are often seen in patients from other FA complementation groups.

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“…While the HR repair pathway is functionally important for repairing DNA double stranded breaks, cancer cells exploit this pathway to avoid apoptosis. More recently, Chen et al have demonstrated that delivery of the lentiviral vector containing promoter XRCC2 to target cancer-specific tumor cells with hyperactive HR genes holds great promise for in vivo tumor prognosis and therapy [ 63 ]. Lentivirus bearing pXRCC2-luciferase vector was shown to enhance in vivo imaging of the bioluminescence signal, which proved to be significantly greater in xenograft implanted mice, as compared to control cancer-free mice.…”

Section: In Vivo Applications Of Genome Editing Tools In Pre-clinimentioning

confidence: 99%

“…In addition, XRCC2 promoter driving firefly luciferase or diphtheria A (DTA) gene injected subcutaneously to HeLa xenograft mice model demonstrated that pXRCC2-DTA lentivirus significantly inhibited the growth of HeLa xenografts. Hence, this reemphasized the potential of viral-mediated delivery pXRCC2-DTA constructs as an effective tool for attenuating tumor growth in vivo [ 63 ].…”

Section: In Vivo Applications Of Genome Editing Tools In Pre-clinimentioning

confidence: 99%

In Vivo Genome Editing as a Therapeutic Approach

Loh

Chan

et al. 2018

IJMS

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Genome editing has been well established as a genome engineering tool that enables researchers to establish causal linkages between genetic mutation and biological phenotypes, providing further understanding of the genetic manifestation of many debilitating diseases. More recently, the paradigm of genome editing technologies has evolved to include the correction of mutations that cause diseases via the use of nucleases such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs), and more recently, Cas9 nuclease. With the aim of reversing disease phenotypes, which arise from somatic gene mutations, current research focuses on the clinical translatability of correcting human genetic diseases in vivo, to provide long-term therapeutic benefits and potentially circumvent the limitations of in vivo cell replacement therapy. In this review, in addition to providing an overview of the various genome editing techniques available, we have also summarized several in vivo genome engineering strategies that have successfully demonstrated disease correction via in vivo genome editing. The various benefits and challenges faced in applying in vivo genome editing in humans will also be discussed.

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Use of the XRCC2 promoter for in vivo cancer diagnosis and therapy

Cited by 11 publications

References 34 publications

Targeted Diphtheria Toxin-Based Therapy: A Review Article

Targeted Diphtheria Toxin-Based Therapy: A Review Article

XRCC2 (X-ray repair cross complementing 2)

In Vivo Genome Editing as a Therapeutic Approach

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