This gene has been used to target various cancers, including pancreatic cancer, ovarian cancer, glioblastoma, and bladder cancer, in combination with various delivery methods, including an integrase-deficient lentiviral vector and plasmid DNA. The DTA could inactivate elongation factor 2 by adenosine diphosphate ribosylation, as well as inhibit protein translation in the cells and trigger apoptosis. In this paper, we use a diphtheria toxin A (DTA) as a target therapeutic gene, an immunotoxin that is widely used in gene therapy due to its role in protein synthesis inhibition. Suicide gene therapeutic strategies include the following: a combination of transgenes delivery that converts and administers prodrugs, such as herpes simplex virus thymidine kinase and ganciclovir delivery of cytotoxic genes delivery of oncogene silencers, such as siRNA delivery of genes expressing antibodies that block the tumor cell’s vital pathways, specifically into the tumor cells, and control its expression in the tumor cells using such as promoter sensitivity. Among these strategies, we focus on the suicide gene delivery strategy, which was recently reported to be elicited in a tumor-specific manner using transcriptionally targeted retroviral replicating vectors, targeting the genomic rearrangement in the tumor by using the genome-editing approach to insert the suicide gene. The following cancer gene therapies for HCC have been tested in both basic and clinical research: the modification of genes related to tumor suppressors, oncogenes, suicide genes, those encoding the proteins expressed on the tumor cell surface, and the T-cell receptor to target the tumor, as well as genetic immunotherapy. Therefore, innovative basic research and clinical trials focusing on the development of gene therapy for HCC are becoming more common. Recently, cancer gene therapy has developed in parallel with the significant improvement of genomic information using next-generation sequencing (NGS) and advances in the techniques of molecular biology that use two-dimensional culture systems and patient-derived primary cancer cells to target and modify tumor-related genes. Therefore, novel therapies are required for the effective treatment of advanced-staged HCC with poor hepatic reserve functions. This is partly due to the heterogeneity of tumor cells in HCC, which can cause a high risk of recurrence and drug resistance. To be sure, recent developments in the field of molecular targeted agent have shed light on chemotherapy for HCC with respect to molecular expression differences in the tumor and the potential promise for immune checkpoint inhibitors however, current therapies require further modifications to be fully effective. However, since the consideration of the remaining hepatic function is essential in determining therapeutic options, said therapies are insufficient for advanced-stage liver cancer in terms of efficacy. For hepatocellular carcinoma (HCC), which is responsible for >90% of primary liver cancers, various conventional therapeutic options are available, including surgical resection, ablation, chemoembolization, systemic chemotherapy, molecularly targeted agents, and liver transplantation. Liver cancer is responsible for a great number of cancer-related deaths worldwide. These results suggest that DTA gene therapy is effective for HCC. A significant inhibition of HCC occurrence and the suppression of the tumor marker of AFP and des-gamma-carboxy prothrombin can be seen in mice groups treated with hydrodynamic gene delivery of DTA, both 0 and 2 months after the YAP gene delivery. The protein synthesis in DTA transfected cells is inhibited by the disappearance of tdTomato and GFP expression co-transfected upon the delivery of the DTA plasmid the HCC cell growth is inhibited by the expression of DTA in HCC cells in an AFP promoter-selective manner. Moreover, the effect and safety of the AFP promoter-selective DTA expression was examined in vivo using an HCC mice model established by the hydrodynamic gene delivery of the yes-associated protein (YAP)-expressing plasmid. The antitumor effect of DTA expression in HCC cell lines (and alpha-fetoprotein (AFP) promoter selectivity) is assessed in vitro by examining HCC cell growth. We assessed gene therapy for HCC using a diphtheria toxin fragment A (DTA) gene-expressing plasmid, utilizing a non-viral hydrodynamics-based procedure. Accordingly, the development of a novel therapy is essential. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells recurrence is highly probable, and some patients develop resistances to the therapies. Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers.
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