Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Teng, Guangju; Ju, Yuanrong; Yang, Ye; Hua, Hui‐Ming; Chi, Jing-yu; Mu, Xiuan

doi:10.3892/mmr.2016.5917

Cited by 10 publications

(11 citation statements)

References 17 publications

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“…This enzyme converts the prodrug into a bifunctional alkylating agent, resulting in DNA cross-links and cell apoptosis. [188][189][190][191] In combination with RT, the combination of NTR and 41 was found to induce synergistic cytotoxicity in HeLa cells. Phase I/II clinical trials for virus directed enzyme-prodrug therapy (VDEPT) with 41 were carried out in patients with prostate-specific antigen (PSA).…”

Section: 171mentioning

confidence: 99%

Hypoxia-targeted drug delivery

Sharma¹,

Arambula

Koo³

et al. 2019

Chem. Soc. Rev.

378

287

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Section: 171mentioning

confidence: 99%

Hypoxia-targeted drug delivery

Sharma¹,

Arambula

Koo³

et al. 2019

Chem. Soc. Rev.

378

287

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show abstract

“…These results show that HSV-TK could enhance sensitivity of radiation, and RT could enhance the effect of a suicide gene to inhibit tumors [92]. The same happens with the combination of a NTR/CB1954 suicide gene system based on the conversion of prodrug CB1954 into an alkylating agent by Escherichia coli NTR, leading to DNA crosslinks and the apoptosis of cancer cells-and γ-rays on HeLa cells [82].…”

Section: Suicide Gene Therapymentioning

confidence: 77%

“…There are two types of suicide genes: genes that encode toxic molecules to the cell, and genes that encode for enzymes not found in mammals, that convert an inactive substance into toxic metabolites [79,80]. Different gene-directed enzyme prodrug systems such as cytosine deaminase (CD)/5-flurocytosine (5-FC), herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir enzyme (GCV) [81], nitroreductase (NTR)/CB1954 [82], and uracil phosphoribosyltransferase (UPRT)/5FU [83] have been used as therapeutic weapons in cervix cancer. These systems focus on the conversion of a non-toxic prodrug into a highly toxic metabolite, and are able to induce cell death.…”

Section: Suicide Gene Therapymentioning

confidence: 99%

Targeted Gene Delivery Therapies for Cervical Cancer

Ayén

Martínez

Boulaiz

2020

Cancers

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Despite being largely preventable through early vaccination and screening strategies, cervical cancer is the most common type of gynecological malignancy worldwide and constitutes one of the leading causes of cancer deaths in women. Patients with advanced or recurrent disease have a very poor prognosis; hence, novel therapeutic modalities to improve clinical outcomes in cervical malignancy are needed. In this regard, targeted gene delivery therapy is presented as a promising approach, which leads to the development of multiple strategies focused on different aspects. These range from altered gene restoration, immune system potentiation, and oncolytic virotherapy to the use of nanotechnology and the design of improved and enhanced gene delivery systems, among others. In the present manuscript, we review the current progress made in targeted gene delivery therapy for cervical cancer, the advantages and drawbacks and their clinical application. At present, multiple targeted gene delivery systems have been reported with encouraging preclinical results. However, the translation to humans has not yet shown a significant clinical benefit due principally to the lack of efficient vectors. Real efforts are being made to develop new gene delivery systems, to improve tumor targeting and to minimize toxicity in normal tissues.

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“…74 Similarly, combining NTR/CB1954 and g-rays has been shown to lead to a synergistic effect on HeLa cells in vitro, leading to enhanced radiosensitivity of tumor cells. 75 Molecular modeling studies may furthermore allow optimization of the prodrug for the NTR system, and cell viability studies with a series of nitro-substituted benzamide prodrugs have led to the discovery of novel prodrug candidates with promising kinetic and molecular docking profiles for NTR-based therapy. 76 Other PAGT approaches/systems…”

Section: Ntr Systemsmentioning

confidence: 99%

Prodrugs and prodrug-activated systems in gene therapy

2021

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The inclusion of genes that control cell fate (so-called suicide, or kill-switch, genes) into gene therapy vectors is based on a compelling rationale for the safe and selective elimination of aberrant transfected cells. Prodrug-activated systems were developed in the 1980s and 1990s and rely on the enzymatic conversion of non-active prodrugs to active metabolites that lead to cell death. Although considerable effort and ingenuity has gone into vector design for gene therapy, less attention has been directed at the efficacy or associated adverse effects of the prodrug systems employed. In this review, we discuss prodrug systems employed in clinical trials and consider their role in the field of gene therapy. We highlight potential drawbacks associated with the use of specific prodrugs, such as systemic toxicity of the activated compound, the paucity of data on biodistribution of prodrugs, bystander effects, and destruction of genetically modified cells, and how these can inform future advances in cell therapies. Prodrug-activated gene therapyEarly gene therapy trials carried out for monogenic diseases, such as severe combined immune deficiency (SCID) and alpha 1-antitypsin deficiency, initially focused on replacing a single deficient or mutated gene with a normal copy. However, the safety concerns inherent in cellular therapy were highlighted when 4 of 10 patients treated with gene therapy for SCID developed acute T cell lymphoblastic leukemia as the result of insertional mutagenesis into the host genome. 4 One strategy to mitigate potential adverse effects (AEs) caused by genetically modified cells is to include a cell-fate control system, such as a suicide gene, in the transfer vector; thus, a second transgene accompanies the gene of interest and acts as a suicide switch that allows transduced cells to be destroyed when exposed to a particular signal. 1,5 Several mechanisms can be used to control cell fate in this way (Figure 1). Prodrug-activated gene therapy (PAGT) strategies aim to enable the selective, on-demand destruction of transduced cells. A suicide transgene that encodes an enzyme is introduced into a target cell, and the transduced cell then becomes able to convert

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Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Cited by 10 publications

References 17 publications

Hypoxia-targeted drug delivery

Hypoxia-targeted drug delivery

Targeted Gene Delivery Therapies for Cervical Cancer

Prodrugs and prodrug-activated systems in gene therapy

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