Login Register Cart 0
Research Article

Teratogenic Toxicity Evaluation of Bladder Cancer-Specific Oncolytic Adenovirus on Mice

Author(s): Keqing Lu, Fang Wang*, Baoliang Ma, Wenjuan Cao, Qi Guo, Hanzhang Wang, Ronald Rodriguez and Zhiping Wang*

Volume 21, Issue 2, 2021

Published on: 17 December, 2020

Page: [160 - 166] Pages: 7

DOI: 10.2174/1566523220999201217161258

Price: $65

Abstract

Background: In our previous studies, we had demonstrated the efficiency and specificity of constructed bladder tissue-specific adenovirus Ad-PSCAE-UPII-E1A-AR (APU-EIA-AR) on bladder cancer. The virus biodistribution and body toxicity in nude mice have also been investigated. However, the safety of the bladder cancer-specific oncolytic adenovirus on fetal mice and F1 mice should be under intense investigation.

Objective: In order to evaluate the teratogenic toxicity of bladder cancer-specific oncolytic adenovirus APU-EIA-AR on mice, in this study, we investigated the fetal mice weight, fetal body length and tail length, fetal skeleton development, as well as the F1 mice weight, growth curve, and major organ pathology. These teratogenic toxicity data of bladder tissue-specific adenovirus Ad-PSCAE- UPII-E1A-AR (AD) would provide safe information prior to embarking on clinical trials.

Methods: On the sixth day of being fertilized, the pregnant mice began to be intramuscularly administrated with AD (1×107VP, 1×108VP, 1×109VP) every other day for ten days. The pregnant mice were then divided into two groups. One group was euthanized on the seventeenth day; the fetal mice were taken out, and the bone structure of the infants was observed. The other group was observed until natural childbirth. The Filial Generation (F1) is fed for 30 days; the variations in the growth progress and development were assessed. The mice were then euthanized; The tissues from major organs were harvested and observed under the microscope.

Results: In the process of teratogenic toxicity test, the Placenta weight, fetal mice weight, body length, and a tail length of mice fetal in adenovirus treated group did not reveal any alteration. Meanwhile, comparing with the PBS group, there is no obvious change in the skeleton of fetal mice treated with adenovirus. During the development process of F1 mice treated with adenovirus, the changes in mice weight show statistical significance. However, in the progress of the growth curve, this difference is not very obvious. Furthermore, the pathological section showed no obvious alteration in major organs.

Conclusion: Our study demonstrated that bladder cancer-specific adenovirus Ad-PSCAE-UPII- E1A-AR appears safe in pregnant mice without any discernable effects on fetal mice and F1 development. Hence, it is relatively safe for tumor gene therapy.

Keywords: Gene therapy, teratogenic toxicity evaluation, biosafety, bladder cancer, oncolytic adenovirus, animal model.

« Previous Next »
Graphical Abstract

[1]
Bhanvadia SK. Bladder Cancer Survivorship. Curr Urol Rep 2018; 19(12): 111.
[http://dx.doi.org/10.1007/s11934-018-0860-6] [PMID: 30414013]
[2]
Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet 2009; 374(9685): 239-49.
[http://dx.doi.org/10.1016/S0140-6736(09)60491-8] [PMID: 19520422]
[3]
Ghoneim MA, Abol-Enein H. Management of muscle-invasive bladder cancer: an update. Nat Clin Pract Urol 2008; 5(9): 501-8.
[http://dx.doi.org/10.1038/ncpuro1202] [PMID: 18769377]
[4]
Hussain SA, James ND. The systemic treatment of advanced and metastatic bladder cancer. Lancet Oncol 2003; 4(8): 489-97.
[http://dx.doi.org/10.1016/S1470-2045(03)01168-9] [PMID: 12901963]
[5]
Rosewell Shaw A, Suzuki M. Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol 2016; 21: 9-15.
[http://dx.doi.org/10.1016/j.coviro.2016.06.009] [PMID: 27379906]
[6]
Man YKS, Davies JA, Coughlan L, et al. The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells. Mol Cancer Ther 2018; 17(2): 575-87.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0671] [PMID: 29367266]
[7]
Pascual-Pasto G, Bazan-Peregrino M, Olaciregui NG, et al. Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01. Sci Transl Med 2019; 11(476): eaat9321.
[http://dx.doi.org/10.1126/scitranslmed.aat9321] [PMID: 30674657]
[8]
He XD, Wang ZP, Wei HY, et al. Construction of urothelium-specific recombinant adenovirus and its inhibition in bladder cancer cell. Urol Int 2009; 82(2): 209-13.
[http://dx.doi.org/10.1159/000200802] [PMID: 19322012]
[9]
Hoti N, Li Y, Chen CL, et al. Androgen receptor attenuation of Ad5 replication: implications for the development of conditionally replication competent adenoviruses. Molecular therapy : the journal of the American Society of Gene Therapy 2007; 15(8): 1495-503.
[http://dx.doi.org/10.1038/sj.mt.6300223]
[10]
Zhai Z, Wang Z, Fu S, et al. Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer. Gene Ther 2012; 19(11): 1065-74.
[http://dx.doi.org/10.1038/gt.2011.180] [PMID: 22218302]
[11]
Wang L, Zhang Y, Zhao J, et al. Combination of bladder cancer-specific oncolytic adenovirus gene therapy with cisplatin on bladder cancer in vitro. Tumour Biol 2014; 35(11): 10879-90.
[http://dx.doi.org/10.1007/s13277-014-2353-7] [PMID: 25085582]
[12]
Li S, Wang F, Zhai Z, et al. Synergistic effect of bladder cancer-specific oncolytic adenovirus in combination with chemotherapy. Oncol Lett 2017; 14(2): 2081-8.
[http://dx.doi.org/10.3892/ol.2017.6416] [PMID: 28781650]
[13]
Zhang H, Wang F, Mao C, et al. Effect of combined treatment of radiation and tissue-specific recombinant oncolytic adenovirus on bladder cancer cells. Int J Radiat Biol 2017; 93(2): 174-83.
[http://dx.doi.org/10.1080/09553002.2017.1231942] [PMID: 27600610]
[14]
Chang J, Zhao X, Wu X, et al. A Phase I study of KH901, a conditionally replicating granulocyte-macrophage colony-stimulating factor: armed oncolytic adenovirus for the treatment of head and neck cancers. Cancer Biol Ther 2009; 8(8): 676-82.
[http://dx.doi.org/10.4161/cbt.8.8.7913] [PMID: 19242097]
[15]
Kimball KJ, Preuss MA, Barnes MN, et al. A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases. Clin Cancer Res 2010; 16(21): 5277-87.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-0791]
[16]
Schenk E, Essand M, Bangma CH, et al. GIANT FP6 Consortium. Clinical adenoviral gene therapy for prostate cancer. Hum Gene Ther 2010; 21(7): 807-13.
[http://dx.doi.org/10.1089/hum.2009.206] [PMID: 20001452]
[17]
Kuryk L, Vassilev L, Ranki T, et al. Toxicological and bio-distribution profile of a GM-CSF-expressing, double-targeted, chimeric oncolytic adenovirus ONCOS-102 - Support for clinical studies on advanced cancer treatment. PLoS One 2017; 12(8): e0182715.
[http://dx.doi.org/10.1371/journal.pone.0182715] [PMID: 28796812]
[18]
Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic Virotherapy for the Treatment of Malignant Glioma. Neurotherapeutics 2017; 14(2): 333-44.
[http://dx.doi.org/10.1007/s13311-017-0516-0] [PMID: 28265902]
[19]
Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 1992; 326(10): 663-7.
[http://dx.doi.org/10.1056/NEJM199203053261003] [PMID: 1310525]
[20]
de Jong EP, de Haan TR, Kroes AC, Beersma MF, Oepkes D, Walther FJ. Parvovirus B19 infection in pregnancy. J Clin Virol 2006; 36(1): 1-7.
[http://dx.doi.org/10.1016/j.jcv.2006.01.004]
[21]
Wang F, Wang Z, Tian H, et al. Biodistribution and safety assessment of bladder cancer specific recombinant oncolytic adenovirus in subcutaneous xenografts tumor model in nude mice. Curr Gene Ther 2012; 12(2): 67-76.
[http://dx.doi.org/10.2174/156652312800099599] [PMID: 22384806]
[22]
Machiels JP, Salazar R, Rottey S, et al. A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE). J Immunother Cancer 2019; 7(1): 20.
[http://dx.doi.org/10.1186/s40425-019-0510-7] [PMID: 30691536]
[23]
Philbrick B, Adamson DC. DNX-2401: an investigational drug for the treatment of recurrent glioblastoma. Expert Opin Investig Drugs 2019; 28(12): 1041-9.
[http://dx.doi.org/10.1080/13543784.2019.1694000] [PMID: 31726894]
[24]
Yokoda RT, Nagalo BM, Borad MJ. Oncolytic Adenoviruses in Gastrointestinal Cancers. Biomedicines 2018; 6(1): E33.
[http://dx.doi.org/10.3390/biomedicines6010033] [PMID: 29534501]
[25]
Terao S, Shirakawa T, Kubo S, et al. Midkine promoter-based conditionally replicative adenovirus for targeting midkine-expressing human bladder cancer model. Urology 2007; 70(5): 1009-13.
[http://dx.doi.org/10.1016/j.urology.2007.07.003] [PMID: 17919690]
[26]
Ramesh N, Ge Y, Ennist DL, et al. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor armed oncolytic adenovirus for the treatment of bladder cancer. Clin Cancer Res 2006; 12(1): 305-13.
[27]
Ramesh N, Memarzadeh B, Ge Y, et al. Identification of pretreatment agents to enhance adenovirus infection of bladder epithelium. Mol Ther 2004; 10(4): 697-705.
[http://dx.doi.org/10.1016/j.ymthe.2004.07.002]
[28]
Wang H, Satoh M, Abe H, et al. Oncolytic viral therapy by bladder instillation using an E1A, E1B double-restricted adenovirus in an orthotopic bladder cancer model. Urology 2006; 68(3): 674-81.
[http://dx.doi.org/10.1016/j.urology.2006.04.021] [PMID: 16979729]
[29]
Ahi YS, Bangari DS, Mittal SK. Adenoviral vector immunity: its implications and circumvention strategies. Curr Gene Ther 2011; 11(4): 307-20.
[http://dx.doi.org/10.2174/156652311796150372] [PMID: 21453277]
[30]
Campos SK, Barry MA. Current advances and future challenges in Adenoviral vector biology and targeting. Curr Gene Ther 2007; 7(3): 189-204.
[http://dx.doi.org/10.2174/156652307780859062] [PMID: 17584037]
[31]
Tamura RE, de Luna IV, Lana MG, Strauss BE. Improving adenoviral vectors and strategies for prostate cancer gene therapy. Clinics 2018; 73(Suppl. 1): e476s.
[http://dx.doi.org/10.6061/clinics/2018/e476s] [PMID: 30133562]
[32]
Goradel NH, Mohajel N, Malekshahi ZV, et al. Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches. J Cell Physiol 2019; 234(6): 8636-46.
[http://dx.doi.org/10.1002/jcp.27850] [PMID: 30515798]
[33]
Demmler GJ. Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 1991; 13(2): 315-29.
[http://dx.doi.org/10.1093/clinids/13.2.315] [PMID: 1645882]
[34]
Chisaka H, Morita E, Yaegashi N, Sugamura K. Parvovirus B19 and the pathogenesis of anaemia. Rev Med Virol 2003; 13(6): 347-59.
[http://dx.doi.org/10.1002/rmv.395] [PMID: 14625883]
[35]
Norbeck O, Papadogiannakis N, Petersson K, Hirbod T, Broliden K, Tolfvenstam T. Revised clinical presentation of parvovirus B19-associated intrauterine fetal death. Clin Infect Dis 2002; 35(9): 1032-8.
[http://dx.doi.org/10.1086/342575] [PMID: 12384835]

Rights & Permissions Print Cite
Article Metrics
44
1
World Hemophilia Day
© 2024 Bentham Science Publishers | Privacy Policy