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Vector-Mediated Cancer Gene Therapy Reduces Toxicity and Inhibition of Lung Carcinoma Growth in Nude Mice

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Abstract

Replication-competent oncolytic adenovirus (TOA2) gene therapy is a recently introduced anti-tumor treatment regimen with superior results. The biodistribution studies of virus vector-based medicine seem more cautious and have been given much attention recently in terms of its quality and safety in preclinical trials. The current study determined the biodistribution and safety of a replication-competent adenovirus in different organs to predict its toxicity threshold. The present study has used TOA2, while biodistribution analysis was performed in human lung carcinoma A549-induced tumor-bearing nude mice model. Intratumoral injection was applied onto tumor-bearing mice with the adenovirus (3×1010 VP per mouse). Mice were sacrificed at the end of the experiment and the organs were dissected. Biodistribution analysis was done with complete hexon gene detection in each organ using quantitative real-time polymerase chain reaction (qRT-PCR). The biodistribution and concentration profiles showed that the TOA2 is well distributed in the entire tumor tissue. After dose 3 at day 11, the concentration of the virus has increased in the tumor tissue from 2240.54 (± 01.69) copies/100 ng genome to 13,120.28 (± 88.21) copies/100 ng genome on the 18th day, which eventually approached 336.45 (± 23.41) copies/100ng genome on the day 36. On the contrary, the concentration of the same decreased in the order of the liver, kidney, spleen, lung, and heart over time but no distributional traces in gonads. But the concentration found decreased dramatically in blood and other organs, while at the end of the experiment no detectable distribution was seen besides tumor tissue. The study confirms that adenovirus-based tumor therapy using conditionally replicating competent oncolytic TOA2 exhibited great efficiency with no toxicity at all.

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The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary material.

References

  1. Marelli, G., et al. (2018). Oncolytic viral therapy and the immune system: A double-edged sword against cancer. Frontiers in Immunology, 9, 866.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Larson, C., et al. (2015). Going viral: A review of replication-selective oncolytic adenoviruses. Oncotarget, 6(24), 19976.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Su, C., et al. (2006). Immune gene–viral therapy with triplex efficacy mediated by oncolytic adenovirus carrying an interferon-γ gene yields efficient antitumor activity in immunodeficient and immunocompetent mice. Molecular Therapy, 13(5), 918–927.

    Article  CAS  PubMed  Google Scholar 

  4. Wang, L., et al. (2015). TOA02, a recombinant adenovirus with tumor-specific granulocyte macrophage colony-stimulating factor expression, has limited biodistribution and low toxicity in rhesus monkeys. Human Gene Therapy Methods, 26(2), 62–70.

    Article  CAS  PubMed  Google Scholar 

  5. Huebner, R., et al. (1964). Induction by adenovirus type 7 of tumors in hamsters having the antigenic characteristics of SV40 virus. Proceedings of the National Academy of Sciences of the United States of America, 52(6), 1333–1340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fueyo, J., et al. (2000). A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene, 19(1), 2–12.

    Article  CAS  PubMed  Google Scholar 

  7. Lei, N., et al. (2009). An oncolytic adenovirus expressing granulocyte macrophage colony-stimulating factor shows improved specificity and efficacy for treating human solid tumors. Cancer Gene Therapy, 16(1), 33–43.

    Article  CAS  PubMed  Google Scholar 

  8. Xia, Z.-J., et al. (2004). Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai zheng= Aizheng=Chinese Journal of Cancer, 23(12), 1666–1670.

    PubMed  Google Scholar 

  9. Miao, Y., Wang, X., & Huo, Y. (2010). Key points for non-clinical biodistribution study of virus vector vaccines. Chinese Pharmaceutical Affairs, 24(7), 655–658.

    CAS  Google Scholar 

  10. Patel, A. G., et al. (2012). Enhanced killing of cancer cells by poly (ADP-ribose) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes. Journal of Biological Chemistry, 287(6), 4198–4210.

    Article  CAS  PubMed  Google Scholar 

  11. Murali, V., et al. (2014). Adenovirus death protein (ADP) is required for lytic infection of human lymphocytes. Journal of Virology, 88(2), 903–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mangerich, A., & Bürkle, A. (2011). How to kill tumor cells with inhibitors of poly (ADP-ribosyl) ation. International Journal of Cancer, 128(2), 251–265.

    Article  CAS  PubMed  Google Scholar 

  13. Demarest, T. G., et al. (2019). NAD+ metabolism in aging and cancer. Annual Review of Cancer Biology, 3, 105–130.

    Article  Google Scholar 

  14. Ujie, M., et al. (2019). Long-term culture of human lung adenocarcinoma A549 cells enhances the replication of human influenza A viruses. The Journal of General Virology, 100(10), 1345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gonin, P., & Gaillard, C. (2004). Gene transfer vector biodistribution: Pivotal safety studies in clinical gene therapy development. Gene Therapy, 11(1), S98–S108.

    Article  CAS  PubMed  Google Scholar 

  16. Wilkening, S., & Bader, A. (2004). Quantitative real-time polymerase chain reaction: Methodical analysis and mathematical model. Journal of Biomolecular Techniques: JBT, 15(2), 107.

    PubMed  PubMed Central  Google Scholar 

  17. Heise, C. C., et al. (1999). Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection: Intratumoral spread and distribution effects. Cancer Gene Therapy, 6(6), 499–504.

    Article  CAS  PubMed  Google Scholar 

  18. Wang, P., Qu, Z. Y., & Zhang, H. Y. (2007). Analysis of the antigenicity of a conserved region of hexon protein from human adenovirus. International Journal of Immunology, 30(3), 135–138.

    Google Scholar 

  19. Wang, X., Miao, Y. F., & Zhou, X. B. (2008). Biodistribution of gag gene transferred by adenovirus vector in Mice. Chinese Journal of Biologicals, 21(11), 938–940.

    CAS  Google Scholar 

  20. Miao, Y. F., Wang, X., & Li, B. (2012). Biodistribution evaluation of adenovirus vector HIV vaccine in C57BL/6 mice. Chinese Journal of New Drugs, 2(10), 1085–1087.

    Google Scholar 

  21. Feng, Y., et al. (2018). Hexon and fiber of adenovirus type 14 and 55 are major targets of neutralizing antibody but only fiber-specific antibody contributes to cross-neutralizing activity. Virology, 518, 272–283.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Special thanks to the staff of the college of clinical medical laboratory.

Funding

This research was funded by the Key Laboratory of Pattern Recognition and Intelligent Information Processing, Institutions of Higher Education of Sichuan Province (Grant No. MSSB-2019-11).

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Authors and Affiliations

  1. Basic Medical College, Chengdu University, Chengdu, 610106, Sichuan Province, China

    Ahmad Taha Khalaf & Shen Fubing

  2. Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, 610081, China

    Jun Wan

  3. Key Laboratory of Pattern Recognition and Intelligent Information Processing, Institutions of Higher Education of Sichuan Province, Chengdu University, Sichuan, 610106, Chengdu, China

    Jun Wan

  4. Hospital of Wuhan University, Wuhan, Hubei province, China

    Hu Wei

  5. Widad University College, Pahang, Darul Makmur, Malaysia

    Jamaludin Zainol & Samiah Yasmin Abdul Kadir

  6. Department of Thoracic Surgery, West China Fourth Hospital, Sichuan University, Chengdu, 610041, China

    Min Liang

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  1. Ahmad Taha Khalaf
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  2. Jun Wan
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  3. Hu Wei
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  4. Shen Fubing
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  5. Jamaludin Zainol
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  6. Samiah Yasmin Abdul Kadir
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  7. Min Liang
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The authors contributed equally.

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Correspondence to Min Liang.

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Khalaf, A.T., Wan, J., Wei, H. et al. Vector-Mediated Cancer Gene Therapy Reduces Toxicity and Inhibition of Lung Carcinoma Growth in Nude Mice. Appl Biochem Biotechnol 196, 261–274 (2024). https://doi.org/10.1007/s12010-023-04463-4

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  • DOI: https://doi.org/10.1007/s12010-023-04463-4

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