重组复制缺陷型腺病毒介导的人IL-24/MDA-7基因治疗胰腺癌的体内外实验研究
|
摘要
目的:1.构建携带IL-24基因片段的重组复制缺陷型腺病毒Ad-IL-24,为探讨治疗胰腺癌的方法提供实验基础。2.观察重组腺病毒介导的IL-24基因对人胰腺癌细胞patu8988生长的抑制作用,探讨IL-24抑制胰腺肿瘤生长的机理。3.研究重组腺病毒介导的IL-24基因对小鼠髓系树突状细胞成熟活化的影响,探讨IL-24基因在肿瘤免疫治疗中的作用。4.观察重组腺病毒介导的IL-24基因对裸鼠体内胰腺肿瘤生长的抑制作用,探讨IL-24对胰腺癌的治疗潜力。
方法:从Genbank中查得IL-24基因cDNA全长序列,选择5’端转录起始位点附近长621bp的基因序列为目的基因片段,设计特异性克隆引物。从人外周血单个核细胞(PBMC)中提取总RNA,以总RNA为模板用逆转录聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR )扩增IL-24基因片段。将经基因测序证实为正确的基因片段反向克隆到重组腺病毒载体AdEasy系统中的穿梭质粒pAdTrack-CMV的多克隆位点(multiple cloning site,MCS ),构建携带IL-24基因片段的重组穿梭质粒pAdTrack-CMV-IL-24;再将pAdTrack-CMV-IL-24与重组腺病毒载体AdEasy系统中的骨架质粒pAdEasy-1在大肠杆菌DH5a内进行同源重组,经293细胞包装生成携带IL-24基因片段的重组腺病毒Ad-IL-24,同时构建空病毒Ad-GFP。通过在荧光显微镜下观察发绿色荧光数检测绿色荧光蛋白(green fluorescence protein,GFP)的表达,测定Ad-IL-24和Ad-GFP的滴度。用感染复数(multiplicities of infection,MOI)为100的Ad-IL-24感染人胰腺癌细胞株patu8988,用Western blot、ELISA检测细胞培养液中IL-24的蛋白表达;用MTT法、流式细胞术(FCM)分别检测Ad-IL-24对人胰腺癌细胞株patu8988生长情况的影响。采用小鼠髓系树突状细胞(BMDCs)开展研究,从小鼠骨髓中获取和培养未成熟树突状细胞(dendritic cells,DC),通过FCM、ELISA法检测DC经IL-24转染后表型和功能状态的变化,研究IL-24促进DC成熟活化的作用。裸鼠成瘤实验,观察人胰腺癌patu8988细胞的成瘤情况及IL-24对裸鼠体内胰腺肿瘤的治疗作用;通过免疫组化检测肿瘤组织中微血管密度MVD、VEGF、MMP-2的表达。
结果:1.成功的从人外周血单个核细胞(PBMC)中提取并扩增出621bp的IL-24基因片段,经DNA测序证实该基因片段序列与Genbank中IL-24基因cDNA序列5’端转录起始位点附近621bp的基因序列完全一致。2.成功地构建出携带IL-24基因片段的重组腺病毒Ad-IL-24,病毒滴度>5×1010pfu/ml。3.Ad-IL-24感染的patu8988细胞增殖能力降低,凋亡率明显升高。4.IL-24刺激BMDCs 48h后,细胞表现出成熟DCs的表型和功能特征,即共刺激分子CD40, CD80, CD86上调表达;并能有效拮抗负性调控因子IL-10下调DCs上CD40、CD80、CD86表达的作用,细胞培养液中IL-12、TNF-α的表达水平升高。5.瘤内注射Ad-IL-24后胰腺肿瘤瘤体生长减慢,肿瘤内微血管密度MVD、VEGF、MMP-2较对照组明显减少,荷瘤裸鼠的生存期明显延长。
结论:1.重组腺病毒介导的IL-24基因可明显抑制胰腺癌细胞的生长、促进胰腺癌细胞凋亡。2.重组腺病毒介导的IL-24基因可促进树突状细胞的活化及功能成熟。3.重组腺病毒介导的IL-24基因能抑制胰腺肿瘤血管生成,延长荷瘤裸鼠的生存期。
Objective:This study was conducted (1) to construct a recombinant adenoviral vector carrying IL-24 gene(Ad-IL-24);(2) to detect the change of the human pancreatic carcinoma cell patu8988 infected with Ad-IL-24 and elucidate the molecular mechanism of Ad-IL-24 in inhibiting the growth of pancreatic carcinoma(PC);(3)to analyze the variations of the surface phenotype and immuno-status of dendritic cells that they had been IL-24 gene modified;(4) to observe the growth of PC in vivo,and demonstrat the effect of Ad-IL-24 in treatment of PC.
Methods:Total RNA was extracted from PBMC, and then a 621bp fragment at the 5' end of human IL-24 cDNA was synthesized by reverse-transcription polymerase chain reaction (RT-PCR) and was reversely inserted into the multiclone site (MCS) of the shuttle plasmid pAdTrack-CMV,with the resultant plasmid and the backbone plasmid pAdEasy-l,the homologous recombination took place in the E.coli DH5a and the recombinant adenoviral plasmid carrying the IL-24 gene was constructed was generated. The adenoviruses(Ad-IL-24) were packaged and amplified in the HEK 293 ce1ls. Ad-IL-24 infected the human pancreatic carcinoma cell line patu8988. Then the production of IL-24 in the human pancreatic carcinoma patu8988 cells was detected with Western Blot Analysis,ELISA and FCM. According to Inaba’smethods,bone marrow-derived Dcs were induced. The surface molecules of DCs are tested by FCM. Following the Ad-IL-24-infected cells was subcutaneously inoculated in nude mice, and injected intratumorally into pre-existing tumors.After four weeks,the tumor tissue was detected with IHC and RT-PCR.
Results:The recombinant adenovirus vector carrying IL-24 was constructed Successfully,fluorescence the strong green fluorescence was microscopy. The viral titer was observed in HEK 293 cells under a fluorescence microscopy.The viral titer was 5×1010 pfu/ml. Compared with PBS or Ad-GFP-infected patu8988 cells, infection of patu8988 cells with Ad-IL-24 significantly reduced the growth of human pancreatic carcinoma patu8988 cells,and the tumor volume resulted in reduction in nude mice.In addition,direct intratumoral injection of Ad-IL-24 into pre-existing tumors significantly impaired the further expansion of the tumor mass and resulted in a reduction in tumor.Ad-IL-24 therapy resulted in a reduction in tumor vessel density.In vitro,Ad-IL-24 induce the phenotypic and functional maturation of DC. Beside these results, the growth rate of PC significantly reduced and the survivals prolonged in the Ad-IL-24-infected nude rate models
Conclusion:(1)The recombinant adenovirus with IL-24 can effectively inhibit cells growth and promote the apoptosis of human pancreatic carcinoma patu8988 cells. (2)Ad-IL-24 induce the phenotypic and functional maturation of DC.(3)Ad-IL-24 can effectively prolong survivals and attenuate angiogenesis of pancreatic carcinoma in vivo models and demonstrat a therapeutic potential for human pancreatic carcinoma.
方法:从Genbank中查得IL-24基因cDNA全长序列,选择5’端转录起始位点附近长621bp的基因序列为目的基因片段,设计特异性克隆引物。从人外周血单个核细胞(PBMC)中提取总RNA,以总RNA为模板用逆转录聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR )扩增IL-24基因片段。将经基因测序证实为正确的基因片段反向克隆到重组腺病毒载体AdEasy系统中的穿梭质粒pAdTrack-CMV的多克隆位点(multiple cloning site,MCS ),构建携带IL-24基因片段的重组穿梭质粒pAdTrack-CMV-IL-24;再将pAdTrack-CMV-IL-24与重组腺病毒载体AdEasy系统中的骨架质粒pAdEasy-1在大肠杆菌DH5a内进行同源重组,经293细胞包装生成携带IL-24基因片段的重组腺病毒Ad-IL-24,同时构建空病毒Ad-GFP。通过在荧光显微镜下观察发绿色荧光数检测绿色荧光蛋白(green fluorescence protein,GFP)的表达,测定Ad-IL-24和Ad-GFP的滴度。用感染复数(multiplicities of infection,MOI)为100的Ad-IL-24感染人胰腺癌细胞株patu8988,用Western blot、ELISA检测细胞培养液中IL-24的蛋白表达;用MTT法、流式细胞术(FCM)分别检测Ad-IL-24对人胰腺癌细胞株patu8988生长情况的影响。采用小鼠髓系树突状细胞(BMDCs)开展研究,从小鼠骨髓中获取和培养未成熟树突状细胞(dendritic cells,DC),通过FCM、ELISA法检测DC经IL-24转染后表型和功能状态的变化,研究IL-24促进DC成熟活化的作用。裸鼠成瘤实验,观察人胰腺癌patu8988细胞的成瘤情况及IL-24对裸鼠体内胰腺肿瘤的治疗作用;通过免疫组化检测肿瘤组织中微血管密度MVD、VEGF、MMP-2的表达。
结果:1.成功的从人外周血单个核细胞(PBMC)中提取并扩增出621bp的IL-24基因片段,经DNA测序证实该基因片段序列与Genbank中IL-24基因cDNA序列5’端转录起始位点附近621bp的基因序列完全一致。2.成功地构建出携带IL-24基因片段的重组腺病毒Ad-IL-24,病毒滴度>5×1010pfu/ml。3.Ad-IL-24感染的patu8988细胞增殖能力降低,凋亡率明显升高。4.IL-24刺激BMDCs 48h后,细胞表现出成熟DCs的表型和功能特征,即共刺激分子CD40, CD80, CD86上调表达;并能有效拮抗负性调控因子IL-10下调DCs上CD40、CD80、CD86表达的作用,细胞培养液中IL-12、TNF-α的表达水平升高。5.瘤内注射Ad-IL-24后胰腺肿瘤瘤体生长减慢,肿瘤内微血管密度MVD、VEGF、MMP-2较对照组明显减少,荷瘤裸鼠的生存期明显延长。
结论:1.重组腺病毒介导的IL-24基因可明显抑制胰腺癌细胞的生长、促进胰腺癌细胞凋亡。2.重组腺病毒介导的IL-24基因可促进树突状细胞的活化及功能成熟。3.重组腺病毒介导的IL-24基因能抑制胰腺肿瘤血管生成,延长荷瘤裸鼠的生存期。
Objective:This study was conducted (1) to construct a recombinant adenoviral vector carrying IL-24 gene(Ad-IL-24);(2) to detect the change of the human pancreatic carcinoma cell patu8988 infected with Ad-IL-24 and elucidate the molecular mechanism of Ad-IL-24 in inhibiting the growth of pancreatic carcinoma(PC);(3)to analyze the variations of the surface phenotype and immuno-status of dendritic cells that they had been IL-24 gene modified;(4) to observe the growth of PC in vivo,and demonstrat the effect of Ad-IL-24 in treatment of PC.
Methods:Total RNA was extracted from PBMC, and then a 621bp fragment at the 5' end of human IL-24 cDNA was synthesized by reverse-transcription polymerase chain reaction (RT-PCR) and was reversely inserted into the multiclone site (MCS) of the shuttle plasmid pAdTrack-CMV,with the resultant plasmid and the backbone plasmid pAdEasy-l,the homologous recombination took place in the E.coli DH5a and the recombinant adenoviral plasmid carrying the IL-24 gene was constructed was generated. The adenoviruses(Ad-IL-24) were packaged and amplified in the HEK 293 ce1ls. Ad-IL-24 infected the human pancreatic carcinoma cell line patu8988. Then the production of IL-24 in the human pancreatic carcinoma patu8988 cells was detected with Western Blot Analysis,ELISA and FCM. According to Inaba’smethods,bone marrow-derived Dcs were induced. The surface molecules of DCs are tested by FCM. Following the Ad-IL-24-infected cells was subcutaneously inoculated in nude mice, and injected intratumorally into pre-existing tumors.After four weeks,the tumor tissue was detected with IHC and RT-PCR.
Results:The recombinant adenovirus vector carrying IL-24 was constructed Successfully,fluorescence the strong green fluorescence was microscopy. The viral titer was observed in HEK 293 cells under a fluorescence microscopy.The viral titer was 5×1010 pfu/ml. Compared with PBS or Ad-GFP-infected patu8988 cells, infection of patu8988 cells with Ad-IL-24 significantly reduced the growth of human pancreatic carcinoma patu8988 cells,and the tumor volume resulted in reduction in nude mice.In addition,direct intratumoral injection of Ad-IL-24 into pre-existing tumors significantly impaired the further expansion of the tumor mass and resulted in a reduction in tumor.Ad-IL-24 therapy resulted in a reduction in tumor vessel density.In vitro,Ad-IL-24 induce the phenotypic and functional maturation of DC. Beside these results, the growth rate of PC significantly reduced and the survivals prolonged in the Ad-IL-24-infected nude rate models
Conclusion:(1)The recombinant adenovirus with IL-24 can effectively inhibit cells growth and promote the apoptosis of human pancreatic carcinoma patu8988 cells. (2)Ad-IL-24 induce the phenotypic and functional maturation of DC.(3)Ad-IL-24 can effectively prolong survivals and attenuate angiogenesis of pancreatic carcinoma in vivo models and demonstrat a therapeutic potential for human pancreatic carcinoma.
引文
1. Arslan S, Erol MK, Bozkurt E, et al. Effect of beta-blocker therapy on left atrial function in patients with heart failure: comparison of metoprolol succinate with carvedilol. Int J Cardiovasc Imaging. 2007;23(5):549-555.
2. Jujo Y, Koshiba K, Suzuki R, et al. Histopathological changes due to transurethural microwave thermotherapy associated with androgen deprivation therapy in patients with localized prostate cancer. Nippon Hinyokika Gakkai Zasshi. 2006;97(3):575-582.
3. Jason Y, Bert IR, Micheal S, et a1. Gene transfer into synovial cells by intraarticular administration of plasmid DNA. Hum Gene Ther,1995,6:603-610.
4. Morgan ,R.A.&Anderson,F.A.Annu Rev Biochem. 1993,62,191-217。
5. Evans CH,Ghivizzani SC,Oligino TA,et a1.Future of adenoviruses in the gene therapy of arthritis.Arthritis Res,2001,3:142-146.
6. Work LM, Reynolds PN, Baker AH. Improved gene delivery to human saphenous vein cells and tissue using a peptide-modified adenoviral vector.Genet Vaccines Ther. 2004,2(1):14.
7. Bekker PJ,Holloway D,Nakanishi A, et al.The effect of a single dose of osteo- protegerin in postmenopausal woman. J Bone Miner Res,2001, 16:348-360.
8. Liu Y,Ehtesham M,Samoto K,et al.In situ adenoviral interleukin 12 gene transfer confers potent and long-lasting cytotoxic immunity in glioma [J].Cancer Gene Ther,2002,9(1):9-15.
9. Su ZZ,Lebedeva IV,Gopalkrishnan RV,et al. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells[J]. Proc Natl Acad Sci USA,2001,98(18):10332-10337.
10. Liu BR, Hu LH, Guan JM, et al.A study on the apoptosis of gastric carcinoma cells induced by arsenic trioxide combined with Ad-IkappaBalphaM. Zhonghua Nei Ke Za Zhi. 2007;46(7):569-572.
11. Liang Z, Wu J, Huang J,et al.Bioactivity and stability analysis of endostatin purified from fermentation supernatant of 293 cells transfected with Ad/rhEndo. Protein Expr Purif. 2007;56(2):205-211.
12. Masko Kamiyama,Yasushi Ichilawa,Talashi Ishikawa,et al.VEGFreceptor antisense therapy inhibits angiogenesis and peritonel dissemination of human gastric cancer innude mice.Cancer Gene THERAPY.2002;9:197-201.
13. Schiedner G, Morral N, Parks RJ, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet 1998; 18:180-188.
14. Wang X, Ye Z, Zhong J,et al.Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis and cycling arrest and reduction of angiogenesis. Cancer Biother Radiopharm. 2007;22(1):56-63.
15. Dent P, Yacoub A, Grant S, et al.MDA-7/IL-24 regulates proliferation, invasion and tumor cell radiosensitivity: a new cancer therapy? J Cell Biochem. 2005;95(4):712-719.
16. Jiang H, Lin J J, Su Z Z, et al. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene, 1995, 11(12): 2477-2486.
17. Sabat R, Wallace E, Endesfelder S, et al.IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets. 2007;11:601-612.
18. Lebedeva IV, Su ZZ, Chang Y, et al. The cancer growth suppressing gene mda-7 induces apoptosiss electively in human melanoma cells. Oncogene, 2002, 21:708-718.
19. Caudell EG, Mumm JB, Poindexter N, et al. The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibit simmuno- stimulatory activity and is designated IL-24. J Immunol, 2002, 168(12): 6041-6046.
20. Wang X, Ye Z, Zhong J,et al.Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis and cycling arrest and reduction of angiogenesis. Cancer Biother Radiopharm. 2007;22(1):56-63.
21. Mhashilkar AM, Stewart AL, Sieger K, et al. MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells. Mol Ther, 2003, 8(2): 207-219.
22. Ramesh R, Ito I, Gopalan B, et al. Ectopic production of mda-7/IL-24 inhibits invasion and migration of human lung cance cells. Mol Ther, 2004, 9(4): 510-518.
23. Shi H, Wei LL, Yuan CF, et al. Melanoma differentiation-associated gene-7/interleukin
24 inhibits invasion and migration of human cervical cancer cells in vitro. Saudi Med J. 2007;28(11):1671-1675.
24. Ramesh R, Mhashilkar AM, Tanaka F, et al. Melanoma differentiation-associated gene7/Interleukin(IL)-24 is a novel ligand that regulates angiogenesis via the IL-22receptor. Cancer Res, 2003, 63(16): 5105-5113.
25.施明,王福生,刘明旭,等.重组腺病毒介导的人野生型p53, GM-CSF和B7-1基因增强原代肝癌细胞的免疫原性.中国免疫学杂志.2002;18(11) 769-771.
26. Soderqvist H, Imereh G, Kihlmark M, et al. Intracelleular distri bution of an integral nuclear pore membrane protein fused to green fluorescent protein:location of a targeting domain.Eur J Biochem. 1997;250:808-813.
27. Fu XF, He YL.Green fluorescent protein gene transfection mediated by recombinant adenovirus vector to rat bone marrow mesenchymal stem cells. Nan Fang Yi Ke Da Xue Xue Bao. 2007;27(10):1517-1520.
28. Cao XX, Mohuiddin I, Chada S, et al. Adenoviral transfer of mda-7 leads to BAX up-regulation and apoptosis in mesothelioma cells, and is abrogated by over-expression of BCL-XL. Mol Med, 2002, 8 (12): 869-876.
29. Lebedeva V, Sarkar D, Su ZZ, et al. Bcl-2 and Bcl-x(L) differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24.Oncogene, 2003, 22(54): 8758-8773.
30. Krumbiegel D, Zepp F, Meyer CU. Combined Toll-like receptor agonists synergistically increase production of inflammatory cytokines in human neonatal dendritic cells. Hum Immunol. 2007;68(10):813-822.
31. Grayson MH, Cheung D, Rohlfing MM, et al.Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med. 2007;204(11):2759-2769.
32. Banchereau J, Francine B, Christophe C, et al. Immunbiology of dendritic cells. Annu Rev Immunol. 2000;18:767-811.
33. Banchereau J and Steinman R. Dendritic cells and the control of immunity. Nature. 1998;392:245-252.
34. Brossart P, Zobywalski A, Grunebach F,inhibitory effects et al. Tumor necrosis factor a and CD40 ligand antagonize the of interleukin 10 on T-cell stimulatory capacity of dendritic cells. Cancer Research.2000;60:4485-4492.
35. Inaba K, Inaba M. Romani N, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med.1992;176:1693-1702.
36. Basak S K, Harui A, Stolina M, et al.Increased dendriticcell number and function following continuous in vivo infusion of granulocyte macrophage-colony-stimulating factor and inter-leukin-4[J].Blood, 2002 , 99 ( 8 ) : 2869-2879.
37. Sedlik C,Orbach D, Veron P, et al.A critical role for syk protein tyrosine kinase in Fc receptor-mediated antigen pre-sentation and induction of dendritic cell maturation[J]. J Immunol, 2003,170(2) :846-852.
38. Enk AH, Angeloni VL, Udey MC, et al. Inhibition of Langerhans cell antigen-presenting function by IL-10. J Immuno1.1993;151:2390-2398.
39. Enk AH, Jonuleit H, Saloga J, et al. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer. 1997;73:309-316.
40. Zhong L, Granelli-Piperno A, Choi Y, et al. Recombinant adenovirus is an efficient and non-perturbing genetic vector for human dendritic cells. Eur J Immunol.1999;29(3):964-972.
41. Gahn B, Siller-Lopez F, Pirooz AD, et al. Adenoviral gene transfer into dendritic cells effciently amplifies the immune response to LMP2A antigen: a potential treatment strategy for Epstein-Barr virus--positive Hodgkin's lymphoma.Int J Cancer. 2001;93(5):706-713.
42. Steinbrink K, Wolfl M, Jonuleit H, et al. Induction of tolerance by IL-10-treated dendritic cells.J Immunol. 1997;159(10):4772-4780.
43. Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G Regulatory activity of autocrine IL-10 on dendritic cell functions.J Immunol.2001;166(7):4312-4318.
44. Chade S, Nemunaitis J, Tong A, et al. A phase I dose-escalation study of Ad.mad-7(INGN 241) in patients with advanced carcinoma. Cancer Gene Ther 2001;8:3233-3241.
45. Caudell EG,Mumm JB,Poindexter N,et al.The protein product of the tumor suppressor gene, melanoma differentiation- associated gene 7,exhibits immunostimulatory activity and is designated IL-24.J Immunol.2002;168(12):6041-6046.
46. Su ZZ, Madireddi T, Lin JJ, et al. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice [J]. Med Sci, 1998; 95 ( 24 ): 14400-14405.
47. Seaki T, Mhashilkar A, Chada, S, et al. Tumor-suppression effects by adenovirus-mediated mda-7 gene traPBSfer in non-small-cell lung cancer cells in vitro. Gene therapy.2000; 7:2051-2057.
48. Greenblatt MS, Bebbett WP, Hollstein M, et al. MutatioPBS in the P53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research, 1994(54):4855-4878.
49. Helm GA,Alden TD,Beres EJ,et al.Use of bone morphogenetic protein-9 gene theraphy to induce to induce spinal arthrodesis in the rodent.J Neurosurg 2000,92:191-196.
50. Fang J, Shing Y, Wiederschain D, et al. Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci U S A.2000;97(8): 3884-3889.
51. Itoh T, Tanioka M, Yoshida H, et al. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice, Cancer Res. 1998;58(5):1048-1051.
52. Foldman J, Shing Y. Angiogenesis. J Biot Chen, 1992, 267:10931-10934.
53. Semenza GL.Angiogenesis in ischemic and neoplastic disorders. Annu Rev Med. 2003;54:17–28.
54. Meihua Z. Difference of Microvessel DePBSity and CD34 Expression between Carcinoma and Normal Mucosa. Otolaryngology–Head and Neck Surgery (Research Posters). 2003;8:166.
55. Marcus Schmitt1, Axel Horbach1, Ralf Kubitz, et al. Disruption of hepatocellular tight junctioPBS by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion. Journal of Hepatology. 2004; 41: 274–283.
56. HArald Sautho,Jing Hu, Cielo Maca, et al. Intratumoral spread of wild-type Adenovirus is limited after Local injection of human xenograft tumor: Virus persist and spreads systemically at late time points. 2003, 14:425-433.
57. Johnson M, Huyn S,Burton J,et al.Differential biodistribution of adenoviral vector in vivo asmonitored by biolum inescence in aging and quantitative polymerase chain reaction [J].Hum Gene Ther. 2006,17( 12):1262-1269.
58. Shi H, Wei LL, Yuan CF, et al.Melanoma differentiation-associated gene-7/interleukin
24 inhibits invasion and migration of human cervical cancer cells in vitro. Saudi Med J. 2007;28(11):1671-1675.
59. Gopalan B, Shanker M, Chada S, et al.MDA-7/IL-24 suppresses human ovarian carcinoma growth in vitro and in vivo. Mol Cancer. 2007;6:11.
60. Mumm JB, Ekmekcioglu S, Poindexter NJ, et al.Soluble human MDA-7/IL-24: characterization of the molecular form(s) inhibiting tumor growth and stimulating monocytes.J Interferon Cytokine Res.2006;26(12):877-886.
61. Zhao L, Dong A, Gu J,et al.The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer. Cancer Gene Ther. 2006;13(11):1011-1022.
1. Sabat R, Wallace E, Endesfelder S, et al.IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets. 2007;11(5):601-612.
2. Wolk K, Kunz S, Asadullah K, et al. Immune cells as source and targets of IL-10 family members. J Immunology, 2002, 168: 5397-5402.
3. Schaefer G, Venkataraman C, Schindler U. Cutting edge: FISP (IL-4-induced secreted protein), a novel cytokine-like molecule secreted by Th2 cells. J Immunology, 2001, 166(10): 5859-5863.
4. Sabat R, Wallace E, Endesfelder S, et al.IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets. 2007;11(5):601-612.
5. Zheng M, Bocangel D, Doneske B, et al.Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother. 2007;56(2):205-215.
6. Huang EY, Madireddi MT, Gopalkrishnan RV, et al. Genomic structure,chromosomal localization and expression profile of a novel melanoma differentiation associated(mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene, 2001, 20: 7051-7063.
7. Ellerhorst JA, Prieto VG, Ekmekcioglu S, et al. Loss of MDA-7 expression with progression of melanoma. J Clin Oncol, 2002, 20: 1069-1074.
8. Wang M, Tan Z, Zhang R, et al. Interleukin-24 (MDA-7/MOB-5) signals through two heterodimeric receptors,IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem., 2002, 277: 7341-7347.
9. Sauane M, Gopalkrishnan RV, Lebedeva I, et al. Mda-7/IL-24 induces apoptosis of diverse cancer cell lines through JAK/STAT-independent pathways.J Cell Physiol.2003 Aug; 196(2):334-345.
10. Sauane M, Lebedeva IV, Su ZZ, et al. Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretoryand nonsecretory pathways. Cancer Research 2004,64(9):2988-2993.
11. LebedevaⅣ, Su ZZ, Chang Y, et al. The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene, 2002, 21:708-718.
12. Saeki T,Mhashilkar A,Chada S,et al.Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Therapy, 2000, 7(23): 2051-2057.
13. Lebedeva IV, Sarkar D, Su ZZ, et al.Molecular target-based therapy of pancreatic cancer. Cancer Res. 2006;66(4):2403-2413.
14. Wang X, Ye Z, Zhong J,et al.Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis. Cancer Biother Radiopharm. 2007;22(1):56-63.
15. Zhao L, Dong A, Gu J,et al.The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer. Cancer Gene Ther. 2006;13(11):1011-1022.
16. Zheng M, Bocangel D, Doneske B, et al.Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother. 2007;56(2):205-215.
17. Sauane M, Gopalkrishnan RV, Sarkar D, et al. MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine. Cytokine Growth Factor Rev, 2003, 14(1):35-51.
18. Sauane G, Gopalkrishnan RV, Sarkar D, et al. MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine. Cytokine Growth Factor Rev, 2003, 14(1): 45-52.
19. Tong AW, Nemunaitis J, Su D, et al. Intratumoral injection of INGN241, a nonreplicating adenovector expressing the melanoma differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol. Ther, 2005, 11(1): 160-172.
20. Pataer A, Chada S, Hunt KK, et al. Adenoviral melanoma differentiation- associated gene 7 induces apoptosis in lung cancer cells. J Thorac Cardiovasc Surg, 2003, 125( 6) 1328-1335.
21. Saeki T, Mhashilkar A, Swanson X, et al. Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene. 2002,21:4558-4566.
22. Ramesh R, Mhashilkar AM, Tanaka F, et al. Melanoma differentiation-associated gene 7/lnterleukin-24 is a novel ligand that regulates angiogenesis via the 1L-22 receptor.Cancer Res, 2003, 63( 16):5105-5113.
23. Su ZZ, Lebedeva IV, Sarkar D, et al. Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene, 2003, 22(8): 1164-1180.
24. Su Z, LebedevaⅣ,Gopalkrishnan RV, et al.A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci USA, 2001, 98; 10332-10337.
25. Sarkar D, Su ZZ, Lebedeva IV, et al.IL-24 mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of gene by means of p38MAPK.Proc Natl Acad Sci USA, 2002, 99: 10054-10059.
26. Pataer A,Vorburger SA,Barber GN,et al.Adenoviral transfer of the melanoma differentiation-associated gene induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase. Cancer Res. 2002, 62: 2239-2243.
27. Caudell EG, Mumm JB, Poindexter N, et al. The protein product of the tumor suppressor gene,melanoma differentiation-associated gene 7,exhibits immuno stimulatory activity and is designated IL-24.J Immunol, 2002, 168: 6041-6046.
28. Mhashilkar AM, Schrock RD, Hindi M, et al. Melanoma differentiation associated gene-7 (mda-7):a novel anti-tumor gene for cancer gene therapy. Mol Med., 2001, 7:271-282.
29. Shi H, Wei LL, Yuan CF, et al.Melanoma differentiation-associated gene-7/interleukin
24 inhibits invasion and migration of human cervical cancer cells in vitro. Saudi Med J. 2007;28(11):1671-1675.
30. Dent P, Yacoub A, Grant S, et al.MDA-7/IL-24 regulates proliferation, invasion and tumor cell radiosensitivity: a new cancer therapy? J Cell Biochem. 2005;95(4):712-719.
2. Jujo Y, Koshiba K, Suzuki R, et al. Histopathological changes due to transurethural microwave thermotherapy associated with androgen deprivation therapy in patients with localized prostate cancer. Nippon Hinyokika Gakkai Zasshi. 2006;97(3):575-582.
3. Jason Y, Bert IR, Micheal S, et a1. Gene transfer into synovial cells by intraarticular administration of plasmid DNA. Hum Gene Ther,1995,6:603-610.
4. Morgan ,R.A.&Anderson,F.A.Annu Rev Biochem. 1993,62,191-217。
5. Evans CH,Ghivizzani SC,Oligino TA,et a1.Future of adenoviruses in the gene therapy of arthritis.Arthritis Res,2001,3:142-146.
6. Work LM, Reynolds PN, Baker AH. Improved gene delivery to human saphenous vein cells and tissue using a peptide-modified adenoviral vector.Genet Vaccines Ther. 2004,2(1):14.
7. Bekker PJ,Holloway D,Nakanishi A, et al.The effect of a single dose of osteo- protegerin in postmenopausal woman. J Bone Miner Res,2001, 16:348-360.
8. Liu Y,Ehtesham M,Samoto K,et al.In situ adenoviral interleukin 12 gene transfer confers potent and long-lasting cytotoxic immunity in glioma [J].Cancer Gene Ther,2002,9(1):9-15.
9. Su ZZ,Lebedeva IV,Gopalkrishnan RV,et al. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells[J]. Proc Natl Acad Sci USA,2001,98(18):10332-10337.
10. Liu BR, Hu LH, Guan JM, et al.A study on the apoptosis of gastric carcinoma cells induced by arsenic trioxide combined with Ad-IkappaBalphaM. Zhonghua Nei Ke Za Zhi. 2007;46(7):569-572.
11. Liang Z, Wu J, Huang J,et al.Bioactivity and stability analysis of endostatin purified from fermentation supernatant of 293 cells transfected with Ad/rhEndo. Protein Expr Purif. 2007;56(2):205-211.
12. Masko Kamiyama,Yasushi Ichilawa,Talashi Ishikawa,et al.VEGFreceptor antisense therapy inhibits angiogenesis and peritonel dissemination of human gastric cancer innude mice.Cancer Gene THERAPY.2002;9:197-201.
13. Schiedner G, Morral N, Parks RJ, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet 1998; 18:180-188.
14. Wang X, Ye Z, Zhong J,et al.Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis and cycling arrest and reduction of angiogenesis. Cancer Biother Radiopharm. 2007;22(1):56-63.
15. Dent P, Yacoub A, Grant S, et al.MDA-7/IL-24 regulates proliferation, invasion and tumor cell radiosensitivity: a new cancer therapy? J Cell Biochem. 2005;95(4):712-719.
16. Jiang H, Lin J J, Su Z Z, et al. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene, 1995, 11(12): 2477-2486.
17. Sabat R, Wallace E, Endesfelder S, et al.IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets. 2007;11:601-612.
18. Lebedeva IV, Su ZZ, Chang Y, et al. The cancer growth suppressing gene mda-7 induces apoptosiss electively in human melanoma cells. Oncogene, 2002, 21:708-718.
19. Caudell EG, Mumm JB, Poindexter N, et al. The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibit simmuno- stimulatory activity and is designated IL-24. J Immunol, 2002, 168(12): 6041-6046.
20. Wang X, Ye Z, Zhong J,et al.Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis and cycling arrest and reduction of angiogenesis. Cancer Biother Radiopharm. 2007;22(1):56-63.
21. Mhashilkar AM, Stewart AL, Sieger K, et al. MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells. Mol Ther, 2003, 8(2): 207-219.
22. Ramesh R, Ito I, Gopalan B, et al. Ectopic production of mda-7/IL-24 inhibits invasion and migration of human lung cance cells. Mol Ther, 2004, 9(4): 510-518.
23. Shi H, Wei LL, Yuan CF, et al. Melanoma differentiation-associated gene-7/interleukin
24 inhibits invasion and migration of human cervical cancer cells in vitro. Saudi Med J. 2007;28(11):1671-1675.
24. Ramesh R, Mhashilkar AM, Tanaka F, et al. Melanoma differentiation-associated gene7/Interleukin(IL)-24 is a novel ligand that regulates angiogenesis via the IL-22receptor. Cancer Res, 2003, 63(16): 5105-5113.
25.施明,王福生,刘明旭,等.重组腺病毒介导的人野生型p53, GM-CSF和B7-1基因增强原代肝癌细胞的免疫原性.中国免疫学杂志.2002;18(11) 769-771.
26. Soderqvist H, Imereh G, Kihlmark M, et al. Intracelleular distri bution of an integral nuclear pore membrane protein fused to green fluorescent protein:location of a targeting domain.Eur J Biochem. 1997;250:808-813.
27. Fu XF, He YL.Green fluorescent protein gene transfection mediated by recombinant adenovirus vector to rat bone marrow mesenchymal stem cells. Nan Fang Yi Ke Da Xue Xue Bao. 2007;27(10):1517-1520.
28. Cao XX, Mohuiddin I, Chada S, et al. Adenoviral transfer of mda-7 leads to BAX up-regulation and apoptosis in mesothelioma cells, and is abrogated by over-expression of BCL-XL. Mol Med, 2002, 8 (12): 869-876.
29. Lebedeva V, Sarkar D, Su ZZ, et al. Bcl-2 and Bcl-x(L) differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24.Oncogene, 2003, 22(54): 8758-8773.
30. Krumbiegel D, Zepp F, Meyer CU. Combined Toll-like receptor agonists synergistically increase production of inflammatory cytokines in human neonatal dendritic cells. Hum Immunol. 2007;68(10):813-822.
31. Grayson MH, Cheung D, Rohlfing MM, et al.Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med. 2007;204(11):2759-2769.
32. Banchereau J, Francine B, Christophe C, et al. Immunbiology of dendritic cells. Annu Rev Immunol. 2000;18:767-811.
33. Banchereau J and Steinman R. Dendritic cells and the control of immunity. Nature. 1998;392:245-252.
34. Brossart P, Zobywalski A, Grunebach F,inhibitory effects et al. Tumor necrosis factor a and CD40 ligand antagonize the of interleukin 10 on T-cell stimulatory capacity of dendritic cells. Cancer Research.2000;60:4485-4492.
35. Inaba K, Inaba M. Romani N, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med.1992;176:1693-1702.
36. Basak S K, Harui A, Stolina M, et al.Increased dendriticcell number and function following continuous in vivo infusion of granulocyte macrophage-colony-stimulating factor and inter-leukin-4[J].Blood, 2002 , 99 ( 8 ) : 2869-2879.
37. Sedlik C,Orbach D, Veron P, et al.A critical role for syk protein tyrosine kinase in Fc receptor-mediated antigen pre-sentation and induction of dendritic cell maturation[J]. J Immunol, 2003,170(2) :846-852.
38. Enk AH, Angeloni VL, Udey MC, et al. Inhibition of Langerhans cell antigen-presenting function by IL-10. J Immuno1.1993;151:2390-2398.
39. Enk AH, Jonuleit H, Saloga J, et al. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer. 1997;73:309-316.
40. Zhong L, Granelli-Piperno A, Choi Y, et al. Recombinant adenovirus is an efficient and non-perturbing genetic vector for human dendritic cells. Eur J Immunol.1999;29(3):964-972.
41. Gahn B, Siller-Lopez F, Pirooz AD, et al. Adenoviral gene transfer into dendritic cells effciently amplifies the immune response to LMP2A antigen: a potential treatment strategy for Epstein-Barr virus--positive Hodgkin's lymphoma.Int J Cancer. 2001;93(5):706-713.
42. Steinbrink K, Wolfl M, Jonuleit H, et al. Induction of tolerance by IL-10-treated dendritic cells.J Immunol. 1997;159(10):4772-4780.
43. Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G Regulatory activity of autocrine IL-10 on dendritic cell functions.J Immunol.2001;166(7):4312-4318.
44. Chade S, Nemunaitis J, Tong A, et al. A phase I dose-escalation study of Ad.mad-7(INGN 241) in patients with advanced carcinoma. Cancer Gene Ther 2001;8:3233-3241.
45. Caudell EG,Mumm JB,Poindexter N,et al.The protein product of the tumor suppressor gene, melanoma differentiation- associated gene 7,exhibits immunostimulatory activity and is designated IL-24.J Immunol.2002;168(12):6041-6046.
46. Su ZZ, Madireddi T, Lin JJ, et al. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice [J]. Med Sci, 1998; 95 ( 24 ): 14400-14405.
47. Seaki T, Mhashilkar A, Chada, S, et al. Tumor-suppression effects by adenovirus-mediated mda-7 gene traPBSfer in non-small-cell lung cancer cells in vitro. Gene therapy.2000; 7:2051-2057.
48. Greenblatt MS, Bebbett WP, Hollstein M, et al. MutatioPBS in the P53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research, 1994(54):4855-4878.
49. Helm GA,Alden TD,Beres EJ,et al.Use of bone morphogenetic protein-9 gene theraphy to induce to induce spinal arthrodesis in the rodent.J Neurosurg 2000,92:191-196.
50. Fang J, Shing Y, Wiederschain D, et al. Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci U S A.2000;97(8): 3884-3889.
51. Itoh T, Tanioka M, Yoshida H, et al. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice, Cancer Res. 1998;58(5):1048-1051.
52. Foldman J, Shing Y. Angiogenesis. J Biot Chen, 1992, 267:10931-10934.
53. Semenza GL.Angiogenesis in ischemic and neoplastic disorders. Annu Rev Med. 2003;54:17–28.
54. Meihua Z. Difference of Microvessel DePBSity and CD34 Expression between Carcinoma and Normal Mucosa. Otolaryngology–Head and Neck Surgery (Research Posters). 2003;8:166.
55. Marcus Schmitt1, Axel Horbach1, Ralf Kubitz, et al. Disruption of hepatocellular tight junctioPBS by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion. Journal of Hepatology. 2004; 41: 274–283.
56. HArald Sautho,Jing Hu, Cielo Maca, et al. Intratumoral spread of wild-type Adenovirus is limited after Local injection of human xenograft tumor: Virus persist and spreads systemically at late time points. 2003, 14:425-433.
57. Johnson M, Huyn S,Burton J,et al.Differential biodistribution of adenoviral vector in vivo asmonitored by biolum inescence in aging and quantitative polymerase chain reaction [J].Hum Gene Ther. 2006,17( 12):1262-1269.
58. Shi H, Wei LL, Yuan CF, et al.Melanoma differentiation-associated gene-7/interleukin
24 inhibits invasion and migration of human cervical cancer cells in vitro. Saudi Med J. 2007;28(11):1671-1675.
59. Gopalan B, Shanker M, Chada S, et al.MDA-7/IL-24 suppresses human ovarian carcinoma growth in vitro and in vivo. Mol Cancer. 2007;6:11.
60. Mumm JB, Ekmekcioglu S, Poindexter NJ, et al.Soluble human MDA-7/IL-24: characterization of the molecular form(s) inhibiting tumor growth and stimulating monocytes.J Interferon Cytokine Res.2006;26(12):877-886.
61. Zhao L, Dong A, Gu J,et al.The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer. Cancer Gene Ther. 2006;13(11):1011-1022.
1. Sabat R, Wallace E, Endesfelder S, et al.IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets. 2007;11(5):601-612.
2. Wolk K, Kunz S, Asadullah K, et al. Immune cells as source and targets of IL-10 family members. J Immunology, 2002, 168: 5397-5402.
3. Schaefer G, Venkataraman C, Schindler U. Cutting edge: FISP (IL-4-induced secreted protein), a novel cytokine-like molecule secreted by Th2 cells. J Immunology, 2001, 166(10): 5859-5863.
4. Sabat R, Wallace E, Endesfelder S, et al.IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets. 2007;11(5):601-612.
5. Zheng M, Bocangel D, Doneske B, et al.Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother. 2007;56(2):205-215.
6. Huang EY, Madireddi MT, Gopalkrishnan RV, et al. Genomic structure,chromosomal localization and expression profile of a novel melanoma differentiation associated(mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene, 2001, 20: 7051-7063.
7. Ellerhorst JA, Prieto VG, Ekmekcioglu S, et al. Loss of MDA-7 expression with progression of melanoma. J Clin Oncol, 2002, 20: 1069-1074.
8. Wang M, Tan Z, Zhang R, et al. Interleukin-24 (MDA-7/MOB-5) signals through two heterodimeric receptors,IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem., 2002, 277: 7341-7347.
9. Sauane M, Gopalkrishnan RV, Lebedeva I, et al. Mda-7/IL-24 induces apoptosis of diverse cancer cell lines through JAK/STAT-independent pathways.J Cell Physiol.2003 Aug; 196(2):334-345.
10. Sauane M, Lebedeva IV, Su ZZ, et al. Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretoryand nonsecretory pathways. Cancer Research 2004,64(9):2988-2993.
11. LebedevaⅣ, Su ZZ, Chang Y, et al. The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene, 2002, 21:708-718.
12. Saeki T,Mhashilkar A,Chada S,et al.Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Therapy, 2000, 7(23): 2051-2057.
13. Lebedeva IV, Sarkar D, Su ZZ, et al.Molecular target-based therapy of pancreatic cancer. Cancer Res. 2006;66(4):2403-2413.
14. Wang X, Ye Z, Zhong J,et al.Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis. Cancer Biother Radiopharm. 2007;22(1):56-63.
15. Zhao L, Dong A, Gu J,et al.The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer. Cancer Gene Ther. 2006;13(11):1011-1022.
16. Zheng M, Bocangel D, Doneske B, et al.Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother. 2007;56(2):205-215.
17. Sauane M, Gopalkrishnan RV, Sarkar D, et al. MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine. Cytokine Growth Factor Rev, 2003, 14(1):35-51.
18. Sauane G, Gopalkrishnan RV, Sarkar D, et al. MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine. Cytokine Growth Factor Rev, 2003, 14(1): 45-52.
19. Tong AW, Nemunaitis J, Su D, et al. Intratumoral injection of INGN241, a nonreplicating adenovector expressing the melanoma differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol. Ther, 2005, 11(1): 160-172.
20. Pataer A, Chada S, Hunt KK, et al. Adenoviral melanoma differentiation- associated gene 7 induces apoptosis in lung cancer cells. J Thorac Cardiovasc Surg, 2003, 125( 6) 1328-1335.
21. Saeki T, Mhashilkar A, Swanson X, et al. Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene. 2002,21:4558-4566.
22. Ramesh R, Mhashilkar AM, Tanaka F, et al. Melanoma differentiation-associated gene 7/lnterleukin-24 is a novel ligand that regulates angiogenesis via the 1L-22 receptor.Cancer Res, 2003, 63( 16):5105-5113.
23. Su ZZ, Lebedeva IV, Sarkar D, et al. Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene, 2003, 22(8): 1164-1180.
24. Su Z, LebedevaⅣ,Gopalkrishnan RV, et al.A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci USA, 2001, 98; 10332-10337.
25. Sarkar D, Su ZZ, Lebedeva IV, et al.IL-24 mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of gene by means of p38MAPK.Proc Natl Acad Sci USA, 2002, 99: 10054-10059.
26. Pataer A,Vorburger SA,Barber GN,et al.Adenoviral transfer of the melanoma differentiation-associated gene induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase. Cancer Res. 2002, 62: 2239-2243.
27. Caudell EG, Mumm JB, Poindexter N, et al. The protein product of the tumor suppressor gene,melanoma differentiation-associated gene 7,exhibits immuno stimulatory activity and is designated IL-24.J Immunol, 2002, 168: 6041-6046.
28. Mhashilkar AM, Schrock RD, Hindi M, et al. Melanoma differentiation associated gene-7 (mda-7):a novel anti-tumor gene for cancer gene therapy. Mol Med., 2001, 7:271-282.
29. Shi H, Wei LL, Yuan CF, et al.Melanoma differentiation-associated gene-7/interleukin
24 inhibits invasion and migration of human cervical cancer cells in vitro. Saudi Med J. 2007;28(11):1671-1675.
30. Dent P, Yacoub A, Grant S, et al.MDA-7/IL-24 regulates proliferation, invasion and tumor cell radiosensitivity: a new cancer therapy? J Cell Biochem. 2005;95(4):712-719.