Dual-vector Prodrug Activator Gene Therapy Using Retroviral Replicating Vectors

Overview

Journal Cancer Gene Ther

Specialties Genetics
Oncology
Pharmacology

Date 2018 Oct 24

PMID 30348946

Citations 8

Authors

Shuji Kubo

Misato Takagi-Kimura

Masatoshi Tagawa

Noriyuki Kasahara

Affiliations

Soon will be listed here.

Abstract

Retroviral replicating vectors (RRVs) have been shown to achieve efficient tumor transduction and enhanced therapeutic benefits in a variety of cancer models. In the present study, we evaluated a possible combinatorial effect of prodrug activator genes delivered by two different RRVs derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV) on human hepatocellular carcinoma Hep3B cells. Both RRVs showed efficient replicative spread in culture and can overcame superinfection resistance each other. Notably, the replication and spread of each RRV in culture remained unaffected by pretransduction with the counterpart RRV. We further transduced cells with RRVs which individually possessed the prodrug activator genes yeast cytosine deaminase (CD) and herpes simplex virus thymidine kinase (TK) alone or in combination, and evaluated the cytotoxic effects of RRV-mediated gene therapy with CD and TK in the presence of the respective prodrugs, 5-fluorocytosine and ganciclovir. All combinations of the two prodrug activator genes produced synergistic cytocidal effects, but the combined effects of the different genes were significantly greater than those of the same genes when delivered by two different vectors. The present findings indicate the potential utility of dual-vector gene therapy using two different RRVs carrying different prodrug activator genes.

Citing Articles

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References

Liu T, Kirn D . Gene therapy progress and prospects cancer: oncolytic viruses. Gene Ther. 2008; 15(12):877-84. DOI: 10.1038/gt.2008.72. View

Russell S, Peng K, Bell J . Oncolytic virotherapy. Nat Biotechnol. 2012; 30(7):658-70. PMC: 3888062. DOI: 10.1038/nbt.2287. View

Moolten F . Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res. 1986; 46(10):5276-81. View

Tomicic M, Thust R, Kaina B . Ganciclovir-induced apoptosis in HSV-1 thymidine kinase expressing cells: critical role of DNA breaks, Bcl-2 decline and caspase-9 activation. Oncogene. 2002; 21(14):2141-53. DOI: 10.1038/sj.onc.1205280. View

Denner J . Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV) and the Koala Retrovirus (KoRV). Viruses. 2016; 8(12). PMC: 5192397. DOI: 10.3390/v8120336. View

Hiraoka K, Kimura T, Logg C, Tai C, Haga K, Lawson G . Therapeutic efficacy of replication-competent retrovirus vector-mediated suicide gene therapy in a multifocal colorectal cancer metastasis model. Cancer Res. 2007; 67(11):5345-53. PMC: 8207455. DOI: 10.1158/0008-5472.CAN-06-4673. View

Aghi M, Kramm C, Chou T, Breakefield X, Chiocca E . Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies. J Natl Cancer Inst. 1998; 90(5):370-80. DOI: 10.1093/jnci/90.5.370. View

Uckert W, Kammertons T, Haack K, Qin Z, Gebert J, Schendel D . Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo. Hum Gene Ther. 1998; 9(6):855-65. DOI: 10.1089/hum.1998.9.6-855. View

Portsmouth D, Hlavaty J, Renner M . Suicide genes for cancer therapy. Mol Aspects Med. 2007; 28(1):4-41. DOI: 10.1016/j.mam.2006.12.001. View

10.

Roth J, Cristiano R . Gene therapy for cancer: what have we done and where are we going?. J Natl Cancer Inst. 1997; 89(1):21-39. DOI: 10.1093/jnci/89.1.21. View

11.

Logg C, Baranick B, Lemp N, Kasahara N . Adaptive evolution of a tagged chimeric gammaretrovirus: identification of novel cis-acting elements that modulate splicing. J Mol Biol. 2007; 369(5):1214-29. PMC: 2938735. DOI: 10.1016/j.jmb.2007.04.026. View

12.

Springer C, Niculescu-Duvaz I . Prodrug-activating systems in suicide gene therapy. J Clin Invest. 2000; 105(9):1161-7. PMC: 315452. DOI: 10.1172/JCI10001. View

13.

Mullen C, Kilstrup M, Blaese R . Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Proc Natl Acad Sci U S A. 1992; 89(1):33-7. PMC: 48169. DOI: 10.1073/pnas.89.1.33. View

14.

Alfano N, Kolokotronis S, Tsangaras K, Roca A, Xu W, Eiden M . Episodic Diversifying Selection Shaped the Genomes of Gibbon Ape Leukemia Virus and Related Gammaretroviruses. J Virol. 2015; 90(4):1757-72. PMC: 4734002. DOI: 10.1128/JVI.02745-15. View

15.

Kawasaki Y, Tamamoto A, Takagi-Kimura M, Maeyama Y, Yamaoka N, Terada N . Replication-competent retrovirus vector-mediated prodrug activator gene therapy in experimental models of human malignant mesothelioma. Cancer Gene Ther. 2011; 18(8):571-8. PMC: 3159547. DOI: 10.1038/cgt.2011.25. View

16.

Liu M, Eiden M . The receptors for gibbon ape leukemia virus and amphotropic murine leukemia virus are not downregulated in productively infected cells. Retrovirology. 2011; 8:53. PMC: 3136417. DOI: 10.1186/1742-4690-8-53. View

17.

Miller A, Chen F . Retrovirus packaging cells based on 10A1 murine leukemia virus for production of vectors that use multiple receptors for cell entry. J Virol. 1996; 70(8):5564-71. PMC: 190516. DOI: 10.1128/JVI.70.8.5564-5571.1996. View

18.

Logg C, Tai C, Logg A, Anderson W, Kasahara N . A uniquely stable replication-competent retrovirus vector achieves efficient gene delivery in vitro and in solid tumors. Hum Gene Ther. 2001; 12(8):921-32. PMC: 8184367. DOI: 10.1089/104303401750195881. View

19.

Cloughesy T, Landolfi J, Hogan D, Bloomfield S, Carter B, Chen C . Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med. 2016; 8(341):341ra75. PMC: 6707068. DOI: 10.1126/scitranslmed.aad9784. View

20.

Nethe M, Berkhout B, van der Kuyl A . Retroviral superinfection resistance. Retrovirology. 2005; 2:52. PMC: 1224871. DOI: 10.1186/1742-4690-2-52. View