Application of mRNA regulatory regions to improve tumor specificity of transgene expression

Шепелев, М. В.; Korobko, Elena V.; Georgiev, G.P.; Коробко, И. В.

doi:10.1038/cgt.2011.33

Cited by 11 publications

(4 citation statements)

References 8 publications

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“…Attempts to construct such an ideal promoter remain ongoing. Increased expression can also be achieved by increasing the translation efficiency and stability of mRNA [127].…”

Section: Expression Regulatory Elementmentioning

confidence: 99%

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Alekseenko

Kuzmich

Kondratyeva

et al. 2021

IJMS

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Gene-directed enzyme prodrug gene therapy (GDEPT) theoretically represents a useful method to carry out chemotherapy for cancer with minimal side effects through the formation of a chemotherapeutic agent inside cancer cells. However, despite great efforts, promising preliminary results, and a long period of time (over 25 years) since the first mention of this method, GDEPT has not yet reached the clinic. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. The advent of checkpoint immunotherapy has yielded new highly promising avenues of study in cancer therapy. For such therapy, it seems reasonable to use combinations of different immunomodulators alongside traditional methods, such as chemotherapy and radiotherapy, as well as GDEPT. In this review, we focused on non-viral gene immunotherapy systems combining the intratumoral production of toxins diffused by GDEPT and immunomodulatory molecules. Special attention was paid to the applications and mechanisms of action of the granulocyte-macrophage colony-stimulating factor (GM–CSF), a cytokine that is widely used but shows contradictory effects. Another method to enhance the formation of stable immune responses in a tumor, the use of danger signals, is also discussed. The process of dying from GDEPT cancer cells initiates danger signaling by releasing damage-associated molecular patterns (DAMPs) that exert immature dendritic cells by increasing antigen uptake, maturation, and antigen presentation to cytotoxic T-lymphocytes. We hypothesized that the combined action of this danger signal and GM–CSF issued from the same dying cancer cell within a limited space would focus on a limited pool of immature dendritic cells, thus acting synergistically and enhancing their maturation and cytotoxic T-lymphocyte attraction potential. We also discuss the problem of enhancing the cancer specificity of the combined GDEPT–GM–CSF–danger signal system by means of artificial cancer specific promoters or a modified delivery system.

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“…Attempts to construct such an ideal promoter remain ongoing. Increased expression can also be achieved by increasing the translation efficiency and stability of mRNA [127].…”

Section: Expression Regulatory Elementmentioning

confidence: 99%

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Alekseenko

Kuzmich

Kondratyeva

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…Gene therapy is a strategy that is witnessing dynamic development; several drugs have already been approved for clinical use, many are undergoing various phases of clinical trials, and a vast number of drugs are under development at laboratories. Various approaches to provide specific activity of gene therapy agents in cancer cells have been proposed and validated, including post-transcriptional regulation of the therapeutic transgene expression level in cancer cells via the selective stabilization of the transcript in tumor cells [1] or destabilization of the transcript in normal cells [2]. Along with these relatively new approaches, activation of transgene expression predominantly in tumor cells by tumor-specific promoters remains one of the most frequently used, well-explored, and justified strategies to provide tumor specificity in cancer gene therapy [3].…”

Section: Introductionmentioning

confidence: 99%

A Novel Hybrid Promoter ARE-hTERT for Cancer Gene Therapy

et al. 2017

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describe a novel hybrid tumor-specific promoter, ARE-hTERT, composed of the human TERT gene promoter (hTERT) and the antioxidant response element (ARE) from the human GCLM gene promoter. The hybrid promoter retains the tumor specificity of the basal hTERT promoter but is characterized by an enhanced transcriptional activity in cancer cells with abnormal activation of the Nrf2 transcription factor and upon induction of oxidative stress. In the in vitro enzyme-prodrug cancer gene therapy scheme, ARE-hTERT promoter-driven expression of CD : UPRT (yeast cytosine deaminase : uracil phosphoribosyltransferase) chimeric protein induced a more pronounced death of cancer cells either upon treatment with 5-fluorouracil (5FC) alone or when 5FC was combined with chemotherapeutic drugs as compared to the hTERT promoter. The developed hybrid promoter can be considered a better alternative to the hTERT promoter in cancer gene therapy schemes.

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“…Various approaches to provide specific activity of gene therapy agents in cancer cells have been proposed and validated, including post-transcriptional regulation of the therapeutic transgene expression level in cancer cells via the selective stabilization of the transcript in tumor cells [1] or destabilization of the transcript in normal cells [2]. Along with these relatively new approaches, activation of transgene expression predominantly in tumor cells by tumor-specific promoters remains one of the most frequently used, well-explored, and justified strategies to provide tumor specificity in cancer gene therapy [3].…”

Section: Introductionmentioning

confidence: 99%