Combination therapy of ionizing radiation and lipofectin-mediated cytosine deaminase/5-flurocytosine system for pancreatic cancer cell_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 SUN Sheng ^1,2 , SUN Chengyi ¹ , PAN Yaozhen ¹ , DENG Xiaoqiang ² , LI Hongwei ²

1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guizhou Medical University, Guiyang 550005, P. R. China;
2. Department of Hepatobiliary Surgery, Central Hospital of Luohe City, Luohe, Henan 462000, P. R. China;

Corresponding author：

SUN Sheng, Email: sunsheng212@hotmail.com

Keywords：

pancreatic neoplasm; ionizing radiation; cytosine-deaminase; 5-flurocytosine; gene therapy; radiosensitization

DOI：

10.7507/1007-9424.201912009

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the synergistic antitumor effects of ionizing radiation and the cytosine deaminase (CD)/5-flurocytosine (5-FC) system therapy in human pancreatic cancer cell.Methods The expression vector containing CD was transfected into the human pancreatic cancer cell line PC3. The clones were picked out after G418 selection. The CD gene integration and expression were confirmed by the RT-PCR. The cytotoxicity to the cells with or without CD and (or) ionizing radiation under the treatment with 5-FC was measured by the MTT assay. The clonogenic assay was used to investigate the radiosensitizing effect of 5-FC on the PC3 cells transfected or untransfected with CD gene.Results The CD gene was stably expressed in the PC3 cells transfected with CD gene. The cytotoxic effect of 5-FC was superior on the PC3 cells transfected than that of untransfected with CD gene (P<0.05) and which were enhanced in combination with the ionizing radiation (P<0.05). The CD/5-FC enhanced the radiosensitivity of PC3 cells transfected with CD gene (P<0.05). The change in the radiosensitivity was quantified by calculating the sensitization enhancement ratio (SER) at the clinically relevant dose of 2 Gy. The SER was 1.5 in the PC3 cells transfected with CD gene by giving ionizing radiation of 2 Gy.Conclusions CD/5-FC system is a potenial radiosensitizer in PC3 cells transfected with CD gene. Ionizing radiation and CD/5-FC system is more effective for killing effect of PC3 cells than ionizing radiation or CD/5-FC system alone.

Citation： SUN Sheng, SUN Chengyi, PAN Yaozhen, DENG Xiaoqiang, LI Hongwei. Combination therapy of ionizing radiation and lipofectin-mediated cytosine deaminase/5-flurocytosine system for pancreatic cancer cell. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(9): 1078-1083. doi: 10.7507/1007-9424.201912009 Copy

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14.	Abdelaziz M, Sherif L, ElKhiary M, et al. Targeted adenoviral vector demonstrates enhanced efficacy for in vivo gene therapy of uterine leiomyoma. Reprod Sci, 2016, 23(4): 464-474.
15.	Faneca H, Düzgüneş N, Pedroso de Lima MC. Suicide gene therapy for oral squamous cell carcinoma. Methods Mol Bio, 2019, 1895: 43-55.
16.	Jiang X, Yan Y, Hu M, et al. Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells. J Neurosurg, 2016, 2016(1): 129-136.
17.	Zhao Y, Yu B, Hu H, et al. New low molecular weight polycation-based nanoparticles for effective codelivery of pDNA and drug. ACS Appl Mater Interfaces, 2014, 6(20): 17911-17919.
18.	Gabel M, Kim JH, Kolozsvary A, et al. Selective in vivo radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells transduced with the E. coli cytosine deaminase (CD) gene. Int J Radiat Oncol Biol Phys, 1998, 41(4): 883-887.
19.	Tiberghien P. Use of suicide genes in gene therapy. J Leukoc Biol, 1994, 56(2): 203-209.
20.	Wei D, Hou J, Zheng K, et al. Suicide gene therapy against malignant gliomas by the local delivery of genetically engineered umbilical cord mesenchymal stem cells as cellular vehicles. Curr Gene Ther, 2019, 19(5): 330-341.
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22.	Lambin P, Nuyts S, Landuyt W, et al. The potential therapeutic gain of radiation-associated gene therapy with the suicide gene cytosine deaminase. Int J Radiat Biol, 2000, 76(3): 285-293.
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24.	Greco O, Marples B, Joiner MC, et al. How to overcome (and exploit) tumor hypoxia for targeted gene therapy. J Cell Physiol, 2003, 197(3): 312-325.
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27.	Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer, 2003, 3(5): 330-338.

1. 赵玉沛. 胰腺癌的放射治疗进展. 中华肝胆外科杂志, 2011, 17(11): 944-947.
2. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet, 2011, 378(9791): 607-620.
3. Tamura R, Mivoshi H, Yoshida K, et al. Recent progress in the research of suicide gene therapy for malignant glioma. Neurosurg Rev, 2019 Nov 28. doi: 10.1007/s10143-019-01203-3.
4. Duarte S, Carle G, Faneca H, et al. Suicide gene therapy in cancer: where do we stand now? Cancer Lett, 2012, 324(2): 160-170.
5. Piña MJ, Girotti A, Serrano S, et al. A double safety lock tumor-specific device for suicide gene therapy in breast cancer. Cancer Lett. 2019 Nov 29. pii: S0304-3835(19)30586-5.
6. Sun CH, Berg K, Hirschberg H. Photochemical internalization enhanced nonviral suicide gene therapy. Methods Mol Biol, 2019, 1895: 165-176.
7. Hsiao WC, Sung SY, Chung LWK, et al. Osteonectin promoter-mediated suicide gene therapy of prostate cancer. Methods Mol Biol, 2019, 1895: 27-42.
8. Kohli J, Campisi J, Demaria M. A novel suicide gene therapy for the treatment of p16Ink4a-overexpressing tumors. Oncotarget, 2017, 9(7): 7274-7281.
9. Hashemi M, Hadjighassem M, Zali A, et al. Tumoricidal effect of human olfactory ensheathing cell mediated suicide gene therapy in human glioblastoma cells. Mol Biol Rep, 2018, 45(6): 2263-2273.
10. Huber BE, Austin EA, Richards CA, et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA, 1994, 91(17): 8302-8306.
11. Navarro SA, Carrillo E, Griñán-Lisón C, et al. Cancer suicide gene therapy: a patent review. Expert Opin Ther Pat, 2016, 26(9): 1095-1104.
12. Prosperi D, Colombo M. Suicide gene therapy: a new frontier for cancer fighting. Curr Pharm Biotechnol, 2019, 20(1): 2-4.
13. Düzgüneş N. Origins of suicide gene therapy. Methods Mol Biol, 2019, 1895: 1-9.
14. Abdelaziz M, Sherif L, ElKhiary M, et al. Targeted adenoviral vector demonstrates enhanced efficacy for in vivo gene therapy of uterine leiomyoma. Reprod Sci, 2016, 23(4): 464-474.
15. Faneca H, Düzgüneş N, Pedroso de Lima MC. Suicide gene therapy for oral squamous cell carcinoma. Methods Mol Bio, 2019, 1895: 43-55.
16. Jiang X, Yan Y, Hu M, et al. Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells. J Neurosurg, 2016, 2016(1): 129-136.
17. Zhao Y, Yu B, Hu H, et al. New low molecular weight polycation-based nanoparticles for effective codelivery of pDNA and drug. ACS Appl Mater Interfaces, 2014, 6(20): 17911-17919.
18. Gabel M, Kim JH, Kolozsvary A, et al. Selective in vivo radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells transduced with the E. coli cytosine deaminase (CD) gene. Int J Radiat Oncol Biol Phys, 1998, 41(4): 883-887.
19. Tiberghien P. Use of suicide genes in gene therapy. J Leukoc Biol, 1994, 56(2): 203-209.
20. Wei D, Hou J, Zheng K, et al. Suicide gene therapy against malignant gliomas by the local delivery of genetically engineered umbilical cord mesenchymal stem cells as cellular vehicles. Curr Gene Ther, 2019, 19(5): 330-341.
21. Stackhouse MA, Pederson LC, Grizzle WE, et al. Fractionated radiation therapy in combination with adenoviral delivery of the cytosine deaminase gene and 5-fluorocytosine enhances cytotoxic and antitumor effects in human colorectal and cholangiocarcinoma models. Gene Ther, 2000, 7(12): 1019-1026.
22. Lambin P, Nuyts S, Landuyt W, et al. The potential therapeutic gain of radiation-associated gene therapy with the suicide gene cytosine deaminase. Int J Radiat Biol, 2000, 76(3): 285-293.
23. Koyama F, Sawada H, Hirao T, et al. Combined suicide gene therapy for human colon cancer cells using adenovirus-mediated transfer of Escherichia coli cytosine deaminase gene and Escherichia coli uracil phosphoribosyltransferase gene with 5-fluorocytosine. Cancer Gene Ther, 2000, 7(7): 1015-1022.
24. Greco O, Marples B, Joiner MC, et al. How to overcome (and exploit) tumor hypoxia for targeted gene therapy. J Cell Physiol, 2003, 197(3): 312-325.
25. Greco O, Marples B, Dachs GU, et al. Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. Gene Ther, 2002, 9(20): 1403-1411.
26. Gerace D, Martiniello-Wilks R, Habib R, et al. Ex vivo expansion of murine MSC impairs transcription factor-induced differentiation into pancreatic β-cells. Stem Cells Int, 2019, 2019: 1395301.
27. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer, 2003, 3(5): 330-338.

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Combination therapy of ionizing radiation and lipofectin-mediated cytosine deaminase/5-flurocytosine system for pancreatic cancer cell

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