A triple suicide gene strategy that improves therapeutic effects and incorporates multimodality molecular imaging for monitoring gene functions

Xing, Ligang; Sun, Xuejun; Deng, Xuelong; Kotedia, Khushali; Zanzonico, Pat; Ackerstaff, Ellen; Koutcher, Jason A.; Ling, C. Clifton; Li, Gloria C.

doi:10.1038/cgt.2013.28

Cited by 4 publications

(3 citation statements)

References 21 publications

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“…Furthermore, our studies demonstrated that hypoxia-targeted expression of bifunctional suicide gene CDUPRT enhanced the cytotoxicity of 5-FC treatments and radiosensitization under hypoxic conditions ( 15 ). We also found the superior antitumor effects of triple suicide gene approach-TKCDUPRT over double gene approach-TKCD in a rat prostate tumor model ( 16 ).…”

Section: Introductionmentioning

confidence: 80%

Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells

et al. 2014

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The hypoxic microenvironment, an important feature of human solid tumors but absent in normal tissue, may provide an opportunity for cancer-specific gene therapy. The purpose of the present study was to investigate whether hypoxia-driven triple suicide gene TK/CD/UPRT expression enhances cytotoxicity to ganciclovir (GCV) and 5-fluorocytosine (5-FC), and sensitizes human colorectal cancer to radiation in vitro and in vivo. Stable transfectant of human colorectal HCT8 cells was established which expressed hypoxia-inducible vectors (HRE-TK/eGFP and HRE-CD/UPRT/mDsRed). Hypoxia-induced expression/function of TK, CD and UPRT was verified by western blot analysis, flow cytometry, fluorescent microscopy and cytotoxicity assay of GCV and 5-FC. Significant radiosensitization effects were detected after 5-FC and GCV treatments under hypoxic conditions. In the tumor xenografts, the distribution of TK/eGFP and CD/UPRT/mDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC and GCV in mice in combination with local irradiation resulted in tumor regression, as compared with prodrug or radiation treatments alone. Our data suggest that the hypoxia-inducible TK/GCV+CDUPRT/5-FC triple suicide gene therapy may have the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy.

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Section: Introductionmentioning

confidence: 80%

Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells

et al. 2014

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“…NMI and MR spectroscopy Gene-directed enzyme prodrug therapy has shown promise in clinical practice. Xing et al 152 designed a triple-suicide-gene (TK, cytosine deaminase [CD] and uracil phosphoribosyltransferase [UPRT]). As an effector, TK converts the prodrug GCV into toxic products.…”

Section: Preclinical Applications Of Multimodality Reporter Gene Imagmentioning

confidence: 99%

“…(E) Surviving fractions of TKCDUPRT (left panel) or TKCD (right panel) cells treated with different doses of GCV, 5-FC or GCV + 5-FC for 24 h. (F) Tumor growth kinetics in mice bearing TKCDUPRT tumors or TKCD tumors untreated or treated with different doses of GCV and 5-FC. (A-D adapted with permission from 152 , copyright 2013 Nature Publishing Group)…”

Section: Figurementioning

confidence: 99%

Multimodality reporter gene imaging: Construction strategies and application

Li¹,

Wang²,

Liu³

et al. 2018

Theranostics

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Molecular imaging has played an important role in the noninvasive exploration of multiple biological processes. Reporter gene imaging is a key part of molecular imaging. By combining with a reporter probe, a reporter protein can induce the accumulation of specific signals that are detectable by an imaging device to provide indirect information of reporter gene expression in living subjects. There are many types of reporter genes and each corresponding imaging technique has its own advantages and drawbacks. Fused reporter genes or single reporter genes with products detectable by multiple imaging modalities can compensate for the disadvantages and potentiate the advantages of each modality. Reporter gene multimodality imaging could be applied to trace implanted cells, monitor gene therapy, assess endogenous molecular events, screen drugs, etc. Although several types of multimodality imaging apparatus and multimodality reporter genes are available, more sophisticated detectors and multimodality reporter gene systems are needed.

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