Optimization of an E1A Gene Expression Cassette in an Oncolytic Adenovirus for Efficient Tumor Cell Killing Activity

Sakurai, Fuminori; Nishimae, Fumitaka; Takayama, Kosuke; Mizuguchi, Hiroyuki

doi:10.21873/anticanres.14829

Cited by 4 publications

(4 citation statements)

References 24 publications

(28 reference statements)

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“…E1A is an early-expressed gene related to adenovirus replication [ 5 , 23 , 24 ]. In this experiment, we detected the expression of E1A to evaluate the amount of CRAds entering cells after drug treatment.…”

Section: Resultsmentioning

confidence: 99%

Improving the Transduction Efficiency and Antitumor Effect of Conditionally Replicative Adenovirus by Application of 6-cyclohexyl Methyl-β-D-maltoside

et al. 2023

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As a tumor-targeting oncolytic adenovirus (Ad), conditionally replicating adenovirus (CRAd) can access the cell interior by binding to coxsackievirus-Ad receptors (CARs) and specifically replicate and destroy cancer cells without lethal effects on normal cells. The transduction efficiency of CRAd is highly dependent on the number of CARs on the cell membrane. However, not all tumor cells highly express CARs; therefore, improving the transduction efficiency of CRAd is beneficial for improving its antitumor effect. In this study, 6-cyclohexyl methyl-β-D-maltoside (6-β-D), as maltoside transfection agent, showed several advantages, including high transfection efficiency, low toxicity, and potential for intensive use and easy operation. With pretreatment of cancer cells with low concentration of 6-β-D (≤5 μg/mL), the transduction efficiency of “model” Ad (eGFP-Ad) was improved 18-fold compared to eGFP-Ad alone. 6-β-D improved the antitumor effect of CRAd while being safe for normal cells, in which treatment with 6-β-D helped the lethal effects of CRAd at a multiplicity-of-infection ratio of 10 (MOI 10) achieve the oncolytic outcomes of MOI 50. This means that if CRAd is combined with 6-β-D, the amount of CRAd used in clinical practice could be greatly reduced without diminishing its curative effect or exposing patients to the potential side effects of high-titer CRAd. Finally, the underlying mechanism of antitumor effect of CRAd + 6-β-D was primarily investigated, and we found that 6-β-D increased the virus’s replication in cancer cells at the early stage of infection and activated the apoptosis signaling pathway at the late stage of the cell cycle. This research will provide an effective technical reference for further improving Ad-mediated cancer gene therapy in clinical practice.

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Section: Resultsmentioning

confidence: 99%

Improving the Transduction Efficiency and Antitumor Effect of Conditionally Replicative Adenovirus by Application of 6-cyclohexyl Methyl-β-D-maltoside

et al. 2023

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“…S1, available in the online version of this article). We had previously examined the tumour cell viabilities following infection with OAd-tAIB [8]. We chose the domperidone concentrations and virus litres at which cell viabilities were not severely reduced either by each of domperidone or by OAd-tAIB alone.…”

Section: Domperidone Increased Oad-taib-luc-mediated Luciferase Expre...mentioning

confidence: 99%

“…Among the various types of oncolytic viruses, wider use of oncolytic adenoviruses (OAds) is highly anticipated due to their promising properties, including efficient tumour cell killing activities, high titre production, and relatively large capacities for transgene insertion [4]. In order to enhance the antitumour effects of OAds, combinational use of an OAd and anticancer drugs, including chemical and biological anticancer agents, has been actively performed and has shown promising results against various types of tumours [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

A dopamine antagonist, domperidone enhances the replication of an oncolytic adenovirus in human tumour cells

Nishimae

Sakurai

Ono

et al. 2022

Journal of General Virology

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Oncolytic adenoviruses (OAds) have attracted much attention as novel anticancer agents. Numerous studies have examined the antitumour effects of combinational use of an OAd and anticancer agents; however, few chemical compounds enhancing OAd infection have been reported. In this study, we screened a food and drug administration (FDA)-approved drug library containing 1134 small chemical compounds to identify chemical compounds that enhance OAd replication in human tumour cells. We found that domperidone, a dopamine D2 receptor antagonist, significantly enhanced the replication of an OAd in human tumour cells, including human pancreatic tumour cells, by two–fivefold, resulting in improvement of OAd-mediated tumour cell killing activities. The E1A mRNA levels were significantly increased in domperidone-pre-treated cells following OAd infection, which contributed to the promotion of OAd replication. However, mRNA levels of the dopamine D2 receptor (DRD2), which is known to be a target molecule of domperidone, were undetectable in most of the tumour cells by real-time reverse transcription (RT)-PCR analysis, indicating that domperidone promoted OAd replication by acting on a molecule other than DRD2. This study provides important clues for the improvement of OAd-mediated cancer therapy.

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“…OVs mediate not only direct tumor cell lysis but also activation of antitumor immunity, leading to efficient antitumor effects (10,11). Among the many available types of OVs, an OV based on human adenovirus (Ad) (OAd) is the most widely used due to its attractive properties (12)(13)(14)(15). Clinical trials using OAds for the treatment of pancreatic cancers have been conducted (16)(17)(18) or are ongoing [NCT03225989, NCT02749331].…”

mentioning

confidence: 99%

Treatment of Human Pancreatic Cancers Following Local and Systemic Administration of Oncolytic Adenovirus Serotype 35

et al. 2023

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Background/Aim: Oncolytic adenoviruses (Ads) (OAds) are gaining attention as an effective remedy for pancreatic cancer. Most OAds are based on human Ad serotype 5 (Ad5) (OAd5); however, two major drawbacks of OAd5 have been reported. Expression of coxsackievirus-adenovirus receptor, a primary infection receptor of Ad5, is often decreased on malignant tumor cells, including pancreatic cancers. More than 60% of adults have neutralizing antibodies against Ad5. Previously, we developed an OAd composed of Ad serotype 35 (Ad35) (OAd35). Ad35 recognizes CD46, which is often up-regulated on pancreatic cancers. In addition, only 20% or fewer adults have anti-Ad35 neutralizing antibodies. Materials and Methods: We examined the tumor cell lysis activities of OAd35 in the four human pancreatic cancer cell lines in the presence and absence of human serum. The tumor growth suppression effects of OAd35 after local and systemic administration were evaluated in nude mice bearing human pancreatic tumors. Results: OAd35 showed higher levels of tumor cell lysis activities than OAd5 in the human pancreatic cancer cell lines AsPC-1 and BxPC-3. Although the in vitro tumor cell lysis activities of OAd5 against MIA PaCa-2 and PANC-1 cells were strongly attenuated in the presence of human serum, OAd35 mediated comparable levels of tumor cell lysis in the presence and absence of human serum. Systemic administration of OAd5 did not mediate significant growth inhibition against the subcutaneous BxPC-3 tumor. On the other hand, OAd35 significantly suppressed tumor growth. Conclusion: OAd35 would be suitable as an alternative anticancer agent for pancreatic cancer.Pancreatic cancer is the fourth leading cause of cancerrelated death (1, 2). The 5-year survival rates are about 10% for all stages combined and 15-20% for surgically resected patients (3-6). Due to the lack of effective treatments without severe toxicity profiles, the 5-year survival rates of patients who cannot undergo surgical resection have remained unchanged (7,8). Since pancreatic cancer is often an aggressive malignancy and does not exhibit obvious symptoms, many patients present with unresectable disease or distant metastases at the time of diagnosis. The 5-year survival rate of patients with unresectable disease is less than 5%. Moreover, undetectable distant metastases make a major contribution to the low 5-year survival rate of patients undergoing surgical resection (9). Thus, there is an urgent need for the development of novel, systemically deliverable 537

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Optimization of an E1A Gene Expression Cassette in an Oncolytic Adenovirus for Efficient Tumor Cell Killing Activity

Cited by 4 publications

References 24 publications

Improving the Transduction Efficiency and Antitumor Effect of Conditionally Replicative Adenovirus by Application of 6-cyclohexyl Methyl-β-D-maltoside

Improving the Transduction Efficiency and Antitumor Effect of Conditionally Replicative Adenovirus by Application of 6-cyclohexyl Methyl-β-D-maltoside

A dopamine antagonist, domperidone enhances the replication of an oncolytic adenovirus in human tumour cells

Treatment of Human Pancreatic Cancers Following Local and Systemic Administration of Oncolytic Adenovirus Serotype 35

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