Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press67710.17650/2313-805X-2024-11-2-63-73REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИModern approaches in suicidal gene therapy of malignant neoplasmsСовременные подходы к суицидальной генотерапии злокачественных новообразованийhttps://orcid.org/0000-0002-2817-1384DudkinaE. V.ДудкинаЕ. В.
Russian Federation

18 Kremlevskaya St., Kazan 420008

420008; ул. Кремлевская, 18; Казань

https://orcid.org/0000-0003-1768-3314UlyanovaV. V.УльяноваВ. В.
Russian Federation

Vera Vladimirovna Ulyanova

18 Kremlevskaya St., Kazan 420008

Вера Владимировна Ульянова

420008; ул. Кремлевская, 18; Казань

ulyanova.vera@gmail.comhttps://orcid.org/0000-0001-6936-2032IlinskayaO. N.ИльинскаяО. Н.
Russian Federation

18 Kremlevskaya St., Kazan 420008

420008; ул. Кремлевская, 18; Казань

Kazan (Volga Region) Federal UniversityФГАОУ ВО «Казанский (Приволжский) федеральный университет»1505202411263732806202428062024Copyright ©; 2024, Dudkina E.V., Ulyanova V.V., Ilinskaya O.N.Copyright ©; 2024, Дудкина Е.В., Ульянова В.В., Ильинская О.Н.2024Dudkina E.V., Ulyanova V.V., Ilinskaya O.N.Дудкина Е.В., Ульянова В.В., Ильинская О.Н.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/677

   One of the promising directions in antitumor therapy is suicidal gene therapy based on the introduction of cytotoxic genes into tumor cells. Most often, these genes encode for enzymes of bacterial or viral origin, capable of direct or indirect killing of tumor cells. This review provides information about modern strategies for suicidal cancer gene therapy, discusses their advantages and disadvantages, and analyzes the properties of a potential candidate for creating a new highly effective suicidal system, combining the advantages of existing approaches.

   Одним из перспективных направлений противоопухолевой терапии является суицидальная генотерапия, основанная на внедрении в опухолевые клетки цитотоксических генов. Чаще всего это гены ферментов бактериального или вирусного происхождения, способные напрямую или опосредованно уничтожать клетки опухоли. В настоящем обзоре представлены сведения о современных стратегиях суицидальной генотерапии злокачественных новообразований, описаны их достоинства и недостатки, а также проанализированы свойства потенциального кандидата для создания на его основе новой высокоэффективной суицидальной системы, совмещающей в себе достоинства уже существующих подходов.

NaPi2bSLC34A2malignant neoplasmgene expressionmutationонкологическое заболеваниегенотерапиясуицидальный генцитотоксичностьбиназаThis work was supported by the Russian Science Foundation (project No. 21-74-10036) within the framework of the Strategic Academic Leadership Program of the Kazan (Volga Region) Federal University (“Priority-2030”)Работа выполнена при финансовой поддержке Российского научного фонда (проект № 21-74-10036) в рамках Программы стратегического академического лидерства ФГАОУ ВО «Казанский (Приволжский) федеральный университет» («Приоритет-2030»)Pottier C., Fresnais M., Gilon M. et al. Tyrosine kinase inhibitors in cancer: breakthrough and challenges of targeted therapy. Cancers (Basel) 2020;12(3):731. DOI: 10.3390/cancers12030731Zinn S., Vazquez-Lombardi R., Zimmermann C. et al. Advances in antibody-based therapy in oncology. Nat Cancer 2023;4(2):165–80. DOI: 10.1038/s43018-023-00516-zWeiss F., Lauffenburger D., Friedl P. Towards targeting of shared mechanisms of cancer metastasis and therapy resistance. Nat Rev Cancer 2022;22(3):157–73. DOI:10.1038/s41568-021-00427-0Sun W., Shi Q., Zhang H. et al. Advances in the techniques and methodologies of cancer gene therapy. Discov Med 2019;27(146): 45–55.Cesur-Ergün B., Demir-Dora D. Gene therapy in cancer. J Gene Med 2023;25(11):e3550. DOI: 10.1002/jgm.3550Navarro S.A., Carrillo E., Griñán-Lisón C. et al. Cancer suicide gene therapy : a patent review. Expert Opin Ther Pat 2016;26:1095–104. DOI: 10.1080/13543776.2016.1211640Sheikh S., Ernst D., Keating A. Prodrugs and prodrug-activated systems in gene therapy. Mol Ther 2021;29(5):1716–28. DOI: 10.1016/j.ymthe.2021.04.006Ardini M., Vago R., Fabbrini M.S., Ippoliti R. From immunotoxins to suicide toxin delivery approaches: is there a clinical opportunity? Toxins (Basel) 2022;14(9):579. DOI: 10.3390/toxins14090579Tamura R., Miyoshi H., Yoshida K. et al. Recent progress in the research of suicide gene therapy for malignant glioma. Neurosurg Rev 2021;44(1):29–49. DOI: 10.1007/s10143-019-01203-3Hong S., Zhang P., Zhang H. et al. Enforced effect of tk-MCP-1 fusion gene in ovarian cancer. J Exp Clin Cancer Res 2012;31(1):74. DOI: 10.1186/1756-9966-31-74Alekseenko I.V., Snezhkov E.V., Chernov I.P. et al. Therapeutic properties of a vector carrying the HSV thymidine kinase and GM-CSF genes and delivered as a complex with a cationic copolymer. J Transl Med 2015;13:78. DOI: 10.1186/s12967-015-0433-0Liu Y., Sukumar U.K., Jugniot N. et al. Inhaled gold nano-star carriers for targeted delivery of triple suicide gene therapy and therapeutic microRNAs to lung metastases: development and validation in a small animal model. Adv Ther (Weinh) 2022;5(8):2200018. DOI: 10.1002/adtp.202200018Ding Y., Fan J., Deng L. et al. Antitumor efficacy of cytosine deaminase-armed vaccinia virus plus 5-fluorocytosine in colorectal cancers. Cancer Cell Int 2020;20:243. DOI: 10.1186/s12935-020-01340-6Emamian M., Abbaspour A., Shahani T et al. Non-viral suicide gene therapy: cytosine deaminase gene directed by VEGF promoter and 5-fluorocytosine as a gene directed enzyme/prodrug system in breast cancer model. Drug Res (Stuttg) 2021;71(7):395–406. DOI: 10.1055/a-1488-6054Takahashi M., Valdes G., Hiraoka K. et al. Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. Cancer Gene Ther 2014;21(10):405–10. DOI: 10.1038/cgt.2014.38El-Sayed A.S.A., Mohamed N.Z., Yassin M.A. et al. Microbial cytosine deaminase is a programmable anticancer prodrug mediating enzyme: antibody, and gene directed enzyme prodrug therapy. Heliyon 2022;8(9):e10660. DOI: 10.1016/j.heliyon.2022.e10660Ostertag D., Amundson K.K., Lopez Espinoza F. et al. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol 2012;14(2):145–59. DOI: 10.1093/neuonc/nor199Vermes A., Guchelaar H.J., Dankert J. Flucytosine : a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 2000;46(2):171–9. DOI: 10.1093/jac/46.2.171Mitchell L.A., Lopez Espinoza F., Mendoza D. et al. Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. Neuro Oncol 2017;19(7):930–9. DOI: 10.1093/neuonc/nox037Cloughesy T.F., Petrecca K., Walbert T. et al. Effect of vocimagene amiretrorepvec in combination with flucytosine vs standard of care on survival following tumor resection in patients with recurrent high-grade glioma: a randomized clinical trial. JAMA Oncol 2020;6(12):1939–46. DOI: 10.1001/jamaoncol.2020.3161Kazlauskas A., Darinskas A., Meškys R. et al. Isocytosine deaminase Vcz as a novel tool for the prodrug cancer therapy. BMC Cancer 2019;19(1):197. DOI: 10.1186/s12885-019-5409-7Vosough P., Vafadar A., Naderi S. et al. Escherichia coli cytosine deaminase: structural and biotechnological aspects. Biotechnol Appl Biochem 2024;71(1):5–16. DOI: 10.1002/bab.2516Aučynaitė A., Rutkienė R., Tauraitė D. et al. Discovery of bacterial deaminases that convert 5-fluoroisocytosine into 5-fluorouracil. Front Microbiol 2018;9:2375. DOI: 10.3389/fmicb.2018.02375Ho Y.K., Woo J.Y., Tu G.X.E. et al. A highly efficient non-viral process for programming mesenchymal stem cells for gene directed enzyme prodrug cancer therapy. Sci Rep 2020;10(1):14257. DOI: 10.1038/s41598-020-71224-2Xu N., Tian H., Po Fung C. et al. Inhibition of human oral squamous cell carcinoma proliferation and migration by prodrug-activating suicide gene therapies. Exp Ther Med 2023;25(2):92. DOI: 10.3892/etm.2023.11790Horikawa M., Koizumi S., Oishi T. et al. Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth. Cancer Gene Ther 2023;30(1):85–95. DOI: 10.1038/s41417-022-00527-5Tanaka T., Duflot-Dancer A., Tiraby M. et al. Bystander effect from cytosine deaminase and uracil phosphoribosyl transferase genes in vitro: a partial contribution of gap junctions. Cancer Lett 2009;282(1):43–7. DOI: 10.1016/j.canlet.2009.02.050Oishi T., Ito M., Koizumi S. et al. Efficacy of HSV-TK/GCV system suicide gene therapy using SHED expressing modified HSV-TK against lung cancer brain metastases. Mol Ther Methods Clin Dev 2022;26:253–65. DOI: 10.1016/j.omtm.2022.07.001Rainov N.G. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 2000;11(17):2389–401. DOI: 10.1089/104303400750038499Fabbrini M.S., Katayama M., Nakase I., Vago R. Plant ribosomeinactivating proteins: progesses, challenges and biotechnological applications (and a few digressions). Toxins (Basel) 2017;9(10):314. DOI: 10.3390/toxins9100314Pahle J., Menzel L., Niesler N. et al. Rapid eradication of colon carcinoma by Clostridium perfringens enterotoxin suicidal gene therapy. BMC Cancer 2017;17(1):129. DOI: 10.1186/s12885-017-3123-xPiontek A., Eichner M., Zwanziger D. et al. Targeting claudinoverexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin. Mol Oncol 2020;14(2):261–76. DOI: 10.1002/1878-0261.12615Pahle J., Kobelt D., Aumann J. et al. Effective oncoleaking treatment of pancreatic cancer by claudin-targeted suicide gene therapy with Clostridium perfringens enterotoxin (CPE). Cancers (Basel) 2021;13(17):4393. DOI: 10.3390/cancers13174393Bagga S., Seth D., Batra J.K. The cytotoxic activity of ribosomeinactivating protein saporin-6 is attributed to its rRNA N-glycosidase and internucleosomal DNA fragmentation activities. J Biol Chem 2003;278(7):4813–20. DOI: 10.1074/jbc.M207389200Sama S., Woith E., Walther W. et al. Targeted suicide gene transfections reveal promising results in nu/nu mice with aggressive neuroblastoma. J Control Release 2018;275:208–16. DOI: 10.1016/j.jconrel.2018.02.031Herawati I.E., Lesmana R., Levita J., Subarnas A. Cytotoxicity, apoptosis, migration inhibition, and autophagy-induced by crude ricin from ricinus communis seeds in a549 lung cancer cell lines. Med Sci Monit Basic Res 2022;28:e936683. DOI: 10.12659/MSMBR.936683Morgan R.N., Saleh S.E., Farrag H.A., Aboshanab K.M. New insights on Pseudomonas aeruginosa exotoxin A-based immunotoxins in targeted cancer therapeutic delivery. Ther Deliv 2023;14(1):31–60. DOI: 10.4155/tde-2022-0055Dai L., Yu X., Huang S. et al. The therapeutic potential of attenuated diphtheria toxin delivered by an adenovirus vector with survivin promoter on human lung cancer cells. Cancer Biol Ther 2021;22(1):79–87. DOI: 10.1080/15384047.2020.1859870Zinser E., Rössner S., Littmann L. et al. The IL-2 diphtheria toxin fusion protein denileukin diftitox modulates the onset of diabetes in female nonobese diabetic animals in a time-dependent manner and breaks tolerance in male nonobese diabetic animals. J Immunol 2012;189(3):1173–81. DOI: 10.4049/jimmunol.1102691Pemmaraju N., Konopleva M. Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. Blood Adv 2020;4(16):4020–7. DOI: 10.1182/bloodadvances.2019000173Dhillon S. Moxetumomab pasudotox: first global approval. Drugs 2018;78(16):1763–7. DOI: 10.1007/s40265-018-1000-9Dieffenbach M., Pastan I. Mechanisms of resistance to immunotoxins containing Pseudomonas exotoxin a in cancer therapy. Biomolecules 2020;10(7):979. DOI: 10.3390/biom10070979Cerise A., Bera T.K., Liu X. et al. Anti-mesothelin recombinant immunotoxin therapy for colorectal cancer. Clin Colorectal Cancer 2019;18(3):192–9. DOI: 10.1016/j.clcc.2019.06.006Granot-Matok Y., Ezra A., Ramishetti S. et al. Lipid nanoparticles-loaded with toxin mRNA represents a new strategy for the treatment of solid tumors. Theranostics 2023;13(11):3497–508. DOI: 10.7150/thno.82228Nakashima I., Saito S., Akahoshi E. et al. Non-viral inducible caspase 9 mRNA delivery using lipid nanoparticles against breast cancer: an in vitro study. Biochem Biophys Res Commun 2022;635:144–53. DOI: 10.1016/j.bbrc.2022.09.105Pathak S., Singh V., Kumar N., Jayandharan G.R. Inducible caspase 9-mediated suicide gene therapy using AAV6 vectors in a murine model of breast cancer. Mol Ther Methods Clin Dev 2023;31:101166. DOI: 10.1016/j.omtm.2023.101166Long Q., Yang R., Lu W. et al. Adenovirus-mediated truncated Bid overexpression induced by the Cre/LoxP system promotes the cell apoptosis of CD133+ ovarian cancer stem cells. Oncol Rep 2017;37(1):155–62. DOI: 10.3892/or.2016.5263Garg H., Salcedo R., Trinchieri G., Blumenthal R. Improved nonviral cancer suicide gene therapy using survivin promoter-driven mutant Bax. Cancer Gene Ther 2010;17(3):155–63. DOI: 10.1038/cgt.2009.63Rossignoli F., Grisendi G., Spano C. et al. Inducible Caspase9-mediated suicide gene for MSC-based cancer gene therapy. Cancer Gene Ther 2019;26(1–2):11–6. DOI: 10.1038/s41417-018-0034-1Moradi-Mehr S., Khademy M., Akbari-Birgani S. et al. Comparative evaluation of the therapeutic strategies using a minimal model of luminal-A breast cancer. Biochem Biophys Res Commun 2023;666:107–14. DOI: 10.1016/j.bbrc.2023.05.028Shariat S.F., Desai S., Song W. et al. Adenovirus-mediated transfer of inducible caspases: a novel “death switch” gene therapeutic approach to prostate cancer. Cancer Res 2001;61(6):2562–71.Kemper K., Rodermond H., Colak S. et al. Targeting colorectal cancer stem cells with inducible caspase-9. Apoptosis 2012;17(5):528–37. DOI: 10.1007/s10495-011-0692-zMontaño-Samaniego M., Bravo-Estupiñan D.M., Méndez-Guerrero O. et al. Strategies for targeting gene therapy in cancer cells with tumor-specific promoters. Front Oncol 2020;10:605380. DOI: 10.3389/fonc.2020.605380Ji X., Zhang J., Cheng L. et al. Oncolytic adenovirus delivering herpes simplex virus thymidine kinase suicide gene reduces the growth of human retinoblastoma in an in vivo mouse model. Exp Eye Res 2009;89(2):193–9. DOI: 10.1016/j.exer.2009.03.007Peng W., Chen J., Huang Y.H., Sawicki J.A. Tightly-regulated suicide gene expression kills PSA-expressing prostate tumor cells. Gene Ther 2005;12(21):1573–80. DOI: 10.1038/sj.gt.3302580Yahya E.B., Alqadhi A.M. Recent trends in cancer therapy : a review on the current state of gene delivery. Life Sci 2021;269:119087. DOI: 10.1016/j.lfs.2021.119087Li X., Le Y., Zhang Z. et al. Viral vector-based gene therapy. Int J Mol Sci 2023;24(9):7736. DOI: 10.3390/ijms24097736Greig J.A., Martins K.M., Breton C. et al. Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration. Nat Biotechnol 2023. DOI: 10.1038/s41587-023-01974-7Zweiri J., Christmas S.E. Demonstration of anti-tumour bystander killing with prodrug-preloaded suicide gene-engineered tumour cells: a potential improvement for cancer therapeutics. Cancer Cell Int 2020;20:26. DOI: 10.1186/s12935-020-1115-4Srivastava A., Mallela K.M.G., Deorkar N., Brophy G. Manufacturing challenges and rational formulation development for AAV viral vectors. J Pharm Sci 2021;110(7):2609–24. DOI: 10.1016/j.xphs.2021.03.024Nguyen Q.M., Dupré P.F., Haute T. et al. Suicide gene strategies applied in ovarian cancer studies. Cancer Gene Ther 2023;30(6):812–21. DOI: 10.1038/s41417-023-00590-6Ghasempour E., Hesami S., Movahed E. et al. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy in the brain tumors. Stem Cell Res Ther 2022;13(1):527. DOI: 10.1186/s13287-022-03212-4Oraee-Yazdani S., Tavanaei R., Rostami F. et al. Suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cell gene delivery vehicles in recurrent glioblastoma multiforme: a first-in-human, dose-escalation, phase I clinical trial. J Transl Med 2023;21(1):350. DOI: 10.1186/s12967-023-04213-4Hendijani F., Javanmard S.H., Sadeghi-aliabadi H. Human Wharton’s jelly mesenchymal stem cell secretome display antiproliferative effect on leukemia cell line and produce additive cytotoxic effect in combination with doxorubicin. Tissue Cell 2015;47(3):229–34. DOI: 10.1016/j.tice.2015.01.005Makarov A.A., Kolchinsky A., Ilinskaya O.N. Binase and other microbial RNases as potential anticancer agents. Bioessays 2008;30(8):781–90. DOI: 10.1002/bies.20789Dudkina E.V., Ulyanova V.V., Ilinskaya O.N. Supramolecular organization as a factor of ribonuclease cytotoxicity. Acta Naturae 2020;12(3):24–33. DOI: 10.32607/actanaturae.11000Mitkevich V.A., Burnysheva K.M, Petrushanko I.Y. et al. Binase treatment increases interferon sensitivity and apoptosis in SiHa cervical carcinoma cells by downregulating E6 and E7 human papilloma virus oncoproteins. Oncotarget 2017;8(42): 72666–75. DOI: 10.18632/oncotarget.20199Mitkevich V.A., Kretova O.V., Petrushanko I.Y. et al. Ribonuclease binase apoptotic signature in leukemic Kasumi-1 cells. Biochimie 2013;95(6):1344–9. DOI: 10.1016/j.biochi.2013.02.016Ilinskaya O.N., Singh I., Dudkina E. et al. Direct inhibition of oncogenic KRAS by Bacillus pumilus ribonuclease (binase). Biochim Biophys Acta 2016;1863(7 Pt. A):1559–67. DOI: 10.1016/j.bbamcr.2016.04.005Mironova N.L., Petrushanko I.Y., Patutina O.A. et al. Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells. Cell Cycle 2013;12(13):2120–31. DOI: 10.4161/cc.25164Dudkina E., Ulyanova V., Asmandiyarova V. et al. Two main cancer biomarkers as molecular targets of binase antitumor activity. Biomed Res Int 2024;2024:8159893. DOI: 10.1155/2024/8159893Mitkevich V.A., Tchurikov N.A., Zelenikhin P.V. et al. Binase cleaves cellular noncoding RNAs and affects coding mRNAs. FEBS J 2010;277(1):186–96. DOI: 10.1111/j.1742-4658.2009.07471.xSokurenko J.V., Zelenikhin P.V., Ulyanova V.V. et al. Identification of 2’,3’-cGMP as an intermediate of RNA catalytic cleavage by binase and evaluation of its biological action. Bioorg Khim 2015;41(1):37–43. DOI: 10.1134/s1068162015010136Azarashvili T., Krestinina O., Galvita A. et al. Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2’,3’-cyclic nucleotides and 2’,3’-cyclic nucleotide 3’-phosphodiesterase. Am J Physiol Cell Physiol 2009;296(6):C1428–39. DOI: 10.1152/ajpcell.00006.2009Cabrera Fuentes H.A., Kalacheva N.V., Mukhametshina R.T. et al. Binase penetration into alveolar epithelial cells does not induce cell death. Biomed Khim 2012;58(3):272–80. DOI: 10.18097/pbmc20125803272Ilinskaya O.N., Zelenikhin P.V., Petrushanko I.Y. et al. Binase induces apoptosis of transformed myeloid cells and does not induce T-cell immune response. Biochem Biophys Res Commun 2007;361(4):1000–5. DOI: 10.1016/j.bbrc.2007.07.143