重组腺病毒载体介导p16～（INK4A）和p14～（ARF）的基因导入对人胰腺癌细胞生长影响的研究
摘要
胰腺癌是一种高度恶性的肿瘤，其发生发展与多种基因异常有关，如p53、K-ras、p16~(INK4A)、DPC4／SMAD4、BRCA2等。由于胰腺癌手术切除率低，放、化疗的效果差，探讨新的有效的治疗方法已成为胰腺癌研究的重要方向。我们采用重组腺病毒载体将外源性ARF／INK4a基因导入人胰腺癌细胞系中进行实验性基因治疗。
采用Western blot方法检测我实验室现有7株胰腺癌细胞系的p14~(ARF)和p16~(INK4a)的表达，发现其中PC-4、PC-7、Panc-1和Maia-Paca2的p14~(ARF)和p16~(INK4a)蛋白表达缺失，我们选取PC-7、Panc-1和Maia-Paca2进行转基因实验。
1．利用Hela细胞的mRNA，经RT-PCR得到野生型p14~(ARF)和p16~(INK4a)的cDNA，利用AdEasy重组腺病毒系统，构建复制缺陷型的重组腺病毒质粒pAdp14和pAdp16，经腺病毒包装细胞293细胞的包装、扩增后，得到复制缺陷型腺病毒Adp14和Adp16，分别感染PC-7、Panc-1和Maia-Paca2细胞，经Western Blot和RT-PCR证实各株细胞中有外源性的p14~(ARF)和p16~(INK4a)表达。
2．将Adp14分别感染PC-7、Panc-1和Maia-Paca2细胞，发现有野生型p53的PC-7细胞和p53突变的Maia-Paca2细胞生长速率减慢，G2期细胞比例增加，软琼脂克隆形成率降低，Western blot显示RB蛋白有不同程度去磷酸化，PC-7细胞p53表达上调；而p53突变的Panc-1细胞则未发生上述改变。经TUNEL法和流式细胞术未发现凋亡细胞比例明显上升。提示p14~(ARF)可通过依赖及不依赖p53的途径抑制胰腺癌细胞生长。
3．将Adp16分别感染PC-7、Panc-1和Maia-Paca2细胞，发现这三株细胞的生长速度均减低，出现G1期或G2期细胞比例增加，细胞出现衰老表型，Western blot显示RB蛋白磷酸化程度降低，E2F1表达上调，Panc-1和Maia-Paca2细胞软琼脂克隆形成率降低，经TUNEL法和流式细胞术未发现凋亡细胞比例明显上升。说明p16~(INK4a)通过RB途径抑制胰腺癌细胞生长。
4．在有野生型p53的PC-7细胞中可见Adp14和Adp16细胞生长抑制效果相似，联合使用这两种腺病毒与单独使用某一种病毒相比未见明显优势，Western blot显示与Adp16组相似的蛋白水平变化，TUNEL法和流式细胞术未发现凋亡细胞比例明显上升。
The incidence of pancreatic cancer is increasing, so far neither an early diagnosis nor a therapeutic strategy for advanced lesions has been developed yet. It is an urgent mission for both the clinicians and the scientists who are challenging pancreatic cancer to find a breakthrough using new technologies. Recent progresses indicated that cancers are a group of diseases with accumulation of genetic alternations of oncogens and tumor suppressor genes. In pancreatic carcinoma, p53、K-ras、 p16INK4a、DPC4/SMAD4、BRCA2 have been considered as molecules that play key roles in tumourigenesis. In order to develop an effective therapeutic intervention for patients with pancreatic cancer, we studied the effects of gene therapy by adenovirus-mediated transfer of p14ARF and p16INK4a into human pancreatic cancer cells.
Western blot was used to determine the expression of p14ARF and p16INK4a in seven pancreatic carcinoma cell lines. Four cell lines were negative for both p14ARF and p16INK4a protein, and three of them (PC-7, Panc-1 and Maia-paca2) were used in our study of gene transfer.
1. By RT-PCR technique, the wild-type cDNAs of p14ARF and p16INK4a were cloned and amplified from Hela cell. The recombinant replication-deficient adenoviral vectors Adp14 and Adp14, which contain p14ARF and p16INK4a cDNA respectively, were constructed by AdEasy System and amplified in 293 packaging cells. The pancreatic cancer cells transfected with Adp14 and Adpl6 showed expression of p14ARF and p16INK4a, respectively.
2. PC-7 (p53+) and Maia-Paca2 (p53 mutant) transfected with Adp14 showed significant inhibition of cell growth and soft-agar colony formation as compared with control, G2 arrest by flow cytometry and dephosphorylation of RB protein by Western blot, but no obvious increase in apoptotic cells as detected by flow cytometry and TUNEL methods. In addition, PC-7 has elevated expression of p53 after treatment with Adp14. Panc-1, which also had mutant p53, did not show the same effects when transfected by Adp14. These results suggest that p14ARF can inhibit the growth of pancreatic cancer cells through p53 dependent as well as p53 independent pathways.
采用Western blot方法检测我实验室现有7株胰腺癌细胞系的p14~(ARF)和p16~(INK4a)的表达，发现其中PC-4、PC-7、Panc-1和Maia-Paca2的p14~(ARF)和p16~(INK4a)蛋白表达缺失，我们选取PC-7、Panc-1和Maia-Paca2进行转基因实验。
1．利用Hela细胞的mRNA，经RT-PCR得到野生型p14~(ARF)和p16~(INK4a)的cDNA，利用AdEasy重组腺病毒系统，构建复制缺陷型的重组腺病毒质粒pAdp14和pAdp16，经腺病毒包装细胞293细胞的包装、扩增后，得到复制缺陷型腺病毒Adp14和Adp16，分别感染PC-7、Panc-1和Maia-Paca2细胞，经Western Blot和RT-PCR证实各株细胞中有外源性的p14~(ARF)和p16~(INK4a)表达。
2．将Adp14分别感染PC-7、Panc-1和Maia-Paca2细胞，发现有野生型p53的PC-7细胞和p53突变的Maia-Paca2细胞生长速率减慢，G2期细胞比例增加，软琼脂克隆形成率降低，Western blot显示RB蛋白有不同程度去磷酸化，PC-7细胞p53表达上调；而p53突变的Panc-1细胞则未发生上述改变。经TUNEL法和流式细胞术未发现凋亡细胞比例明显上升。提示p14~(ARF)可通过依赖及不依赖p53的途径抑制胰腺癌细胞生长。
3．将Adp16分别感染PC-7、Panc-1和Maia-Paca2细胞，发现这三株细胞的生长速度均减低，出现G1期或G2期细胞比例增加，细胞出现衰老表型，Western blot显示RB蛋白磷酸化程度降低，E2F1表达上调，Panc-1和Maia-Paca2细胞软琼脂克隆形成率降低，经TUNEL法和流式细胞术未发现凋亡细胞比例明显上升。说明p16~(INK4a)通过RB途径抑制胰腺癌细胞生长。
4．在有野生型p53的PC-7细胞中可见Adp14和Adp16细胞生长抑制效果相似，联合使用这两种腺病毒与单独使用某一种病毒相比未见明显优势，Western blot显示与Adp16组相似的蛋白水平变化，TUNEL法和流式细胞术未发现凋亡细胞比例明显上升。
The incidence of pancreatic cancer is increasing, so far neither an early diagnosis nor a therapeutic strategy for advanced lesions has been developed yet. It is an urgent mission for both the clinicians and the scientists who are challenging pancreatic cancer to find a breakthrough using new technologies. Recent progresses indicated that cancers are a group of diseases with accumulation of genetic alternations of oncogens and tumor suppressor genes. In pancreatic carcinoma, p53、K-ras、 p16INK4a、DPC4/SMAD4、BRCA2 have been considered as molecules that play key roles in tumourigenesis. In order to develop an effective therapeutic intervention for patients with pancreatic cancer, we studied the effects of gene therapy by adenovirus-mediated transfer of p14ARF and p16INK4a into human pancreatic cancer cells.
Western blot was used to determine the expression of p14ARF and p16INK4a in seven pancreatic carcinoma cell lines. Four cell lines were negative for both p14ARF and p16INK4a protein, and three of them (PC-7, Panc-1 and Maia-paca2) were used in our study of gene transfer.
1. By RT-PCR technique, the wild-type cDNAs of p14ARF and p16INK4a were cloned and amplified from Hela cell. The recombinant replication-deficient adenoviral vectors Adp14 and Adp14, which contain p14ARF and p16INK4a cDNA respectively, were constructed by AdEasy System and amplified in 293 packaging cells. The pancreatic cancer cells transfected with Adp14 and Adpl6 showed expression of p14ARF and p16INK4a, respectively.
2. PC-7 (p53+) and Maia-Paca2 (p53 mutant) transfected with Adp14 showed significant inhibition of cell growth and soft-agar colony formation as compared with control, G2 arrest by flow cytometry and dephosphorylation of RB protein by Western blot, but no obvious increase in apoptotic cells as detected by flow cytometry and TUNEL methods. In addition, PC-7 has elevated expression of p53 after treatment with Adp14. Panc-1, which also had mutant p53, did not show the same effects when transfected by Adp14. These results suggest that p14ARF can inhibit the growth of pancreatic cancer cells through p53 dependent as well as p53 independent pathways.
引文
1. Friess H, Guo XZ, Nan BC, et al. Growth factors and cytokines in pancreatic carcinogenesis. Ann N Y Acad Sci. 1999, 880, 110-21.
2. Manu M, Buckels J, Bramhall S. Molecular technology and pancreatic cancer. British Journal of Surgery. 2000, 87, 840-53.
3. Sakorafas GH, Tsiotou AG, Tsiotos GG, et al. Molecular biology of pancreatic cancer: oncogenes, tumor suppressor genes, growth factors, and their receptors from a clinical perspective. Cancer Treat Rev 2000, 26, 29-52.
4. Lynda Chin JP, Ronald A and Depinho. The INK4a/ARF tumor suppressor: one gene-two products-two pathways. Trends in Biochemical Sciences. 1998, 23, 291-296.
5. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994, 68, 753-756.
6. Sherr CJ. The INK4a/ARF network in tumour suppression. Nature review in Mol Cell Biol. 2001, 2, 731-737.
7. Hrber DA. Splicing into senescence: the curious cases of p16 and p19ARF. Cell, 1997, 9, 555-558.
8. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993, 366, 704-707.
9. Jin X, Nguyen D, Zhang WW, Kyritsis AP, Roth JA. Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector. Cancer Res. 1995, 55, 3250-3253.
10. 8. S, Seth P, Cowan K. Effects of adenovirus-mediated p16INK4A expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer Cells. Oncogene. 1998, 16, 265-72.
11. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation andstabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.Cell. 1998, 92, 725-34.
12. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Htuban RH, Yeo CJ and Kern SE. Frequent somatic mutation and homozygous deletion of p16 (MTS1) gene in pancreatic adenocarcinoma. Nat. Genet. 1994, 8, 27-32.
13. Sunamura M, Yatsuoka T, Motoi F, Duda DG,Kimura M, Abe T, Yokoyam T, Inoue H, Oonuma M, Takeda K, and Matsuno S. Gene therapy for pancreatic cancer based on genetic characterization of the disease. J Hepatobiliary Pancreat Surg. 2002, 9,32-38.
14. Geroge, JS. Gene therapy progress and prospects: Adenovirus. Gene therapy, 2003, 23, 1135-1141.
15. Zhang WW. Development and application of adenoviral vector for gene therapy of cancer. Cancer Gene Therapy. 1999,2, 113-138.
16. Chen Jie, Liu Tonghua, Guo Xiuying, et al. Two New human exocrine pancreatic adenocarcinoma cell lines in vitro and in vivo. Chinese Medical Journal, 1990, 103, 369-375.
17. Ghaneh P, Greenhalf W, Humphreys M, Wilson D, Zumstein L, Lemoine NR, Neoptolemos JP. Adenovirus-mediated transfer of p53 and p16(INK4a) results in pancreatic cancer regression in vitro and in vivo. Gene Ther. 2001, 8, 199-208.
18. He TC, Zhou SB, Da Costa LT, Yu L, Kinzler KW, and Vogelstein B, A simplified system for generating recombinant adenoviruses. Proc. Natl. Acad. Sci. USA, 1998, 95, 2509-2514.
19. Werner F, Zolzer F, Streffer C, et al. p53 levels, cell cycle kinetics and radiosensitivity in two SV40 transformed Wi38VA13 fibroblast strains. Strahlenther Onkol. 2001, 177, 662-9.
20．鄂征，组织培养和分子细胞学技术技术，北京出版社，第二版，1997，157-158．
21．F．奥斯伯 等。精遍分子生物学实验指南。科学出版社，第一版，1998，332-338．22. T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promoters histone gene transcription. Genes Dev 2000, 14, 2298-313.
23. Sinha P, Hutter G, Kottgen E, et al. Increased expression of annexin I and thioredoxin detected by two-dimensional gel electrophoresis of drug resistant human stomach cancer cells. J Biochem Biophys Methods. 1998, 37, 105-116.
24. Alaiya AA, Oppermann M, Langridge J, et al. Identification of proteins in human prostate tumor material by two-dimensional gel electrophoresis and mass spectrometry.Cell Mol Life Sci. 2001, 58, 307-311.
25. Guo XX, Ying WT, Wan JH, et al. Proteomic characterization of early-stage differentiation of mouse embryonic stem cells into neural cells induced by all-trans retinoic acid in vitro. Electrophoresis. 2001, 22, 3067-75.
26. Zhan X and Desiderio DM. A reference map of a human pituitary adenoma proteome. Proteomics. 2003, 3, 1-15.
27. Person MD, Lo HH, Towndrow KM, Jia Z, Monks TJ, and Lau SS。Comparative Identification of Prostanoid Inducible Proteins by LC-ESI-MS/MS and MALDI-TOF Mass Spectrometry. Chem. Res. Toxicol. 2003, 16, 757-767.
28. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhofff I., Schmiegel W, Baylin SB, Kern SE, and Herman JG. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinoma. Cancer Res. 57, 3126-3130, 1997.
29. Geradts J, Wilentz RE, Roberts H .Immunohistochemical [corrected] detection of the alternate INK4a-encoded tumor suppressor protein p14(ARF) in archival human cancers and cell lines using commercial antibodies: correlation with p16(INK4a) expression. Mod Pathol. 2001, 14, 1162-1168.
30. Ghaneh P, Greenhalf W, Humphreys M, Wilson D, Zumstein L, Lemoine NR, Neoptolemos JP. Adenovirus-mediated transfer of p53 and p16(INK4a) results inpancreatic cancer regression in vitro and in vivo.Gene Ther. 2001, 8, 199-208.
31. Kobayashi S, Shirasawa H, Sashiyama H, Kawahira H, Kaneko K, Asano T, Ochiai T. P16IN-K4a expression adenovirus vector to suppress pancreas cancer cell proliferation. Clin Cancer Res. 1999, 5, 4182-4185.
32. Barton M, et al. Abnormalities of the rb1 and dcc turmor-suppressor geneuncommon in human pancreatic carcinoma. Mol Carcinogen 1995, 13: 61-69.
33. Steiner MS, Wang Y, Zhang Y, Zhang X, Lu Y. Oncogene. p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways. 2000, 19, 1297-1306.
34. Pearson A, et al. Factors limiting adenovirus-mediated transfer into human lung and pancreatic cancer cell lines. Clin Cancer Res 1999, 5, 4028-4213.
35. Yang CT, You L, Lin YC, Lin CL, Mccormick F, Jablons DM. A comparison analysis of anti-tumor efficacy of adenoviral gene replacement therapy (p14ARF and p16INK4A) in human mesothelioma cells Anticancer Res 2003, 23(1A), 33-38.
36. Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G. Regulation ofp16CDKN2 expression and its implications for cell immortalization and senescence.Mol Cell Biol. 1996, 16, 859-867.
37. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality.Cell. 1996, 85, 27-37.
38. Loughran O, Malliri A, Owens D, Gallimore PH, Stanley MA, Ozanne B, Frame MC, Parkinson EK. Association of CDKN2A/p16INK4A with human head and neck keratinocyte replicative senescence: relationship of dysfunction to immortality and neoplasia.Oncogene. 1996, 13, 561-568.
39. Modesitt SC, Ramirez P, Zu Z, Bodurka-Bevers D, Gershenson D, Wolf JK. In vitro and in vivo adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer. Clin Cancer Res. 2001, 7, 1765-1772.
40. Naruse I, Heike Y, Hama S, Mori M, Saijo N. High concentrations of recombinant adenovirus expressing p16 gene induces apoptosis in lung cancer celllines.Anticancer Res. 1998, 18, 4275-4282.
41. Schreiber M, Muller WJ, Singh G, Graham FL. Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21(WAF1/CIP1) and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity.Oncogene. 1999, 18, 1663-1676.
42. Kawabe S, Roth JA, Wilson DR, Meyn RE. Adenovirus-mediated p16INK4a gene expression radiosensitizes non-small cell lung cancer cells in a p53-dependent manner.Oncogene. 2000, 19, 5359-5366.
43. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993, 366, 701-704.
44. Shim J, Park Hs, Kim MJ, Park J, Park E, Cho SG, Eom S J, Lee Hw, Joe CO and Choi EJ. Rb protein down-regulates the stress-activated signals through inhibiting c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem, 2000, 275, 14107-14111.
45. Fuchs X, Adler V, Bushmann T, Yin Z, Wu X, Jones SN, and Ronai A. JNK targets p53 ubiquitination and degradation in nonstressed cells. Gene Dev, 1998, 12, 665-669
46. Weber HO, Samuel T, Rauch P. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins.. Sciences, 1992, 258, 424-429.
47. Weinberg RA. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell, 1995, 81, 323-330.
48. Yamasaki L.,et al. Tumor induction and tissue atrophy in mice lack E2F-1. Cell, 1996, 85, 537-548.
49. Fueyo J, et al. Over expression of E2F-1 in glioma triggers apoptosis and suppresses tumor growth in vitro and in vivo. Nature Med 1997, 3, 313-319.
50. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF and Sherr CJ,. Functional and physical interaction of ARF tumor suppressor with p53 and MDM2. Proc Natl Acad Sci U S A 1998, 95, 8292-8297.
51. Pomerantz J, Schreiber-Agus N, Liegeois N J, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 1998, 92: 713-723.
52. Lohrum MA, Ashcroft M, Kubbutat MH, Vousden KH. Contribution of two independent MDM2-binding domains in p14(ARF) to p53 stabilization. Curr Biol 2000, 10:539-5420
53. Weber HO, Samuel T, Rauch P, Funk JO. Human p14(ARF)-mediated cell cycle arrest strictly depends on intact p53 signaling pathways. Oncogene 2002, 21, 3207-3212.
54. Saadatmandi N, Tyler T, Huang Y, Haghighi A, Frost G, Borgstrom P, Gjerset RA. Growth suppression by a p14(ARF) exon lbeta adenovirus in human tumor cell lines of varying p53 and Rb status. Cancer Gene Ther 2002, 9, 830-839.
55. Yang CT, You L, Uematsu K, Yeh CC, McCormick F, Jablons DM. p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53.Cancer Res. 2001, 61, 5959-5963.
56. Yang CT, You L, Yeh CC, Chang JW, Zhang F, McCormick F, Jablons DM. Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells. J Natl Cancer Inst. 2000, 92, 636-641.
57. Deng X, Kim M, Vandier D, Jung YJ, Rikiyama T, Sgagias MK, Goldsmith M, Cowan KH.Recombinant adenovirus-mediated p14(ARF) overexpression sensitizes human breast cancer cells to cisplatin. Biochem Biophys Res Commun 2002, 296, 792-798.
58. Sandig V, Brand K, Herwig S, Lukas J, Bartek J and Strauss M. Adenovirally transferred p16INK4/CDKN2 and p53 gene cooperate to induce apoptotic tumor cell death. Nat Med. 1997, 3, 313-319.
59. Katayose D, Dudas J, Nguyen H, Srivastava S, Cowan KH and Seth P. Cytotoxic effects of adenovirus-mediated wild-type p53 protein expression in normal andturmor mammary epithelial cells. Clin Cancer Res. 1995, 1, 889-897.
60. Carnero A, Hudson JD, Price CM, Beach DH. p1 6INK4A and p19ARF act in overlapping pathways in cellular immortalization. Nat Cell Biol. 2000, 2, 148-155.
61. Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev. 2000, 14, 2358-2365.
62. Sanchez-Cespedes M, Reed AL, Buta M, Wu L, Westra WH, Herman JG, Yang SC, Jen J, Sidransky D. Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. Oncogene 1999, 18, 5843-5849.
63. Gazzeri S, Della Valle V, Chaussade L, Brambilla C, Larsen CJ, Brambilla E. The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer.Cancer Res. 1998, 58, 3926-3931.
64. Saadatmandi N, Tyler T, Huang Y, Haghighi A, Frost G, Borgstrom P, Gjerset RA. Growth suppression by a p14(ARF) exon lbeta adenovirus in human tumor cell lines of varying p53 and Rb status. Cancer Gene Ther. 2002, 9, 830-839.
65. Hemmati PG, Gillissen B, von Haefen C, Wendt J, Starck L, Guner D, Dorken B, Daniel PT. Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. Oncogene. 2002, 21, 3149-3161.
66. Eymin B, Leduc C, Coil JL, Brambilla E, Gazzeri S. p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene. 2003, 22, 1822-1835.
67. Datta A, Nag A, Raychaudhuri P. Differential regulation of E2F1, DP1, and the E2F1/DP1 complex by ARF. Mol Cell Biol. 2002, 22, 8398-8408.
68. Eymin B, Karayan L, Seite P, Brambilla C, Brambilla E, Larsen CJ, Gazzeri S. Human ARF binds E2F1 and inhibits its transcriptional activity.Oncogene. 2001, 1, 20, 1033-41.
69. Karayan L, Riou JF, Seite P, Migeon J, Cantereau A, Larsen CJ. Human ARF protein interacts with topoisomerase I and stimulates its activity. Oncogene. 2001, 20,836-848
70. Jackson MW, Lindstrom MS, Berberich SJ. MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation. J Biol Chem. 2001, 276, 25336-25341.
71. Bramson JI. Direct intratumor injection of an adenovirus expressing interleukin-12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12. Hum Gene Ther, 1996; 7; 1995-2002
72. Fisher KJ, et al. Recombinationat adenovirus deleted of all viral genes for gene therapy of cystic firbios. Virology, 1996, 217, 11-22
73. Glayman GL et al. Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J clin Oncol, 1998, 16, 2221-2232.
74. Sunamura M, Yatsyoka T, Motoi F, et al. Gene therapy for pancreatic cancer based on genetic characterization of the disease. J Hepatobiliary Pancreat Surg, 2002, 9, 32-38.
75. Kawakami Y, Hama S, Hiura M, Nogawa T, Chiba T, Yokoyama T, Takashima S, Tajiri H, Eguchi K, Nagai N, Shigemasa K, Ohama K, Kurisu K, Heike Y. Adenovirus-mediated p16 gene transfer changes the sensitivity to taxanes and Vinca alkaloids of human ovarian cancer cells. Anticancer Res. 2001 Jul-Aug; 21(4A): 2537-45.
76. Hama S, Heike Y, Naruse I, Takahashi M, Yoshioka H, Arita K, Kurisu K, Goldman CK, Curiel DT, Saijo N. Adenovirus-mediated p16 gene transfer prevents drug-induced cell death through G1 arrest in human glioma cells. Int J Cancer. 1998 Jul 3; 77(1): 47-54.
77. Grim J, D'Amico A, Frizelle S, Zhou J, Kratzke RA, Curiel DT. Adenovirus-mediated delivery of p16 to p16-deficient human bladder cancer cells confers chemoresistance to cisplatin and paclitaxel.Clin Cancer Res. 1997 Dec; 3(12 Pt 1): 2415-23.
78. Guo-Chang F, Chu-Tse W. Transfer of p14ARF gene in drug-resistant human breastcancer MCF-7/Adr cells inhibits proliferation and reduces doxorubicin resistance. Cancer Lett 2000; 158: 203-10.
79. Gao N, Hu Y, Luo J. Increased radiosensitivity of lung cancer cell lines related with the functionally replaced p14ARF gene. Zhonghua Yi Xue Za Zhi 2000; 80: 776-9.
80. Peebles KA, Duncan MW, Ruch R J, Malkinson AM. Proteomic analysis of a neoplastic mouse lung epithelial cell line whose tumorigenicity has been abrogated by transfection with the gap junction structural gene for connexin 43, Gjal. Carcinogenesis. 2003, 24, 651-657.
81. Yu LR, Zeng R, Shao XX, et al. Identification of differentially expressed proteins between human hepatoma and normal liver cell lines by two-dimensional electrophoresis and liquid chromatography-ion trap mass spectrometry. Electrophoresis 2000, 21, 3058-3068.
82. Mazurek S, Grimm H, Oehmke M, Weisse G, Teigelkamp S, Eigenbrodt E. Tumor M2-PK and glutaminolytic enzymes in the metabolic shift of tumor cells. Anticancer Res. 2000, 20, 5151-5154.
83. Eigenbrodt E, Reinacher M, Scheefers-Borchel U, Scheefers H, Friis R. Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. Crit Rev Oncog. 1992, 3, 91-115.
84. Mazurek S, Eigenbrodt E. The tumor metabolome. Anticancer Res. 2003, 23, 1149-54.
85. Mazurek S, Grimm H, Boschek CB, Vaupel P, Eigenbrodt E. Pyruvate kinase type M2: a crossroad in the tumor metabolome. Br J Nutr. 2002, 87 Suppl, S23-29.
86. Cerwenka H, Aigner R, Bacher H, Werkgartner G, el-Shabrawi A, Quehenberger F, Mischinger HJ. TUM2-PK (pyruvate kinase type tumor M2), CA19-9 and CEA in patients with benign, malignant and metastasizing pancreatic lesions. Anticancer Res. 1999, 19, 849-851.
87. Schneider J, Neu K, Velcovsky HG, Morr H, Eigenbrodt E. Tumor M2-pyruvate kinase in the follow-up of inoperable lung cancer patients: a pilot study.Cancer Lett.2003, 193, 91-98.
88. Hoopmann M, Warm M, Mallmann P, Thomas A, Gohring UJ, Schondorf T. Tumor M2 pyruvate kinase--determination in breast cancer patients receiving trastuzumab therapy. Cancer Lett. 2002, 187, 223-228.
89. Nishihira J. Macrophage migration inhibitory factor (MIF): its essential role in the immune system and cell growth. J Interferon Cytokine Res. 2000, 20, 751-762.
90. Meyer-Siegler KL, Bellino MA, Tannenbaum M. Macrophage migration inhibitory factor evaluation compared with prostate specific antigen as a biomarker in patients with prostate carcinoma. Cancer. 2002, 94, 144~1456
91. Bando H, Matsumoto G, Bando M, Muta M, Ogawa T, Funata N, Nishihira J, Koike M, Toi M. Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res. 2002, 93, 389-396.
92. Campa M J, Wang MZ, Howard B, Fitzgerald MC, Patz EF Protein expression profiling identifies macrophage migration inhibitory factor and cyclophilin a as potential molecular targets in non-small cell lung cancer. Cancer Res. 2003, 63, 1652-1656.
93. Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes F J, Roger T, Calandra T, Kapumiotu A, Grell M, Finkelmeier D, Brunner H, and Bernhagen J. Nature. 2000, 408, 211-216.
94. Roger T, David J, Clauser MP and Bemhagen J. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature. 2001, 414, 920-924.
95. Hudson JD, Shoaibi MA, Maestro R, Camero A, Hannon GJ, Beach DH. A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med. 1999, 190, 1375-1382.
96. Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss R, Moll U, Muller W, Bucala R. The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci U S A. 2003, 100, 9354-9359.
97. Sun B, Nishihira J, Suzuki M, Fukushima N, Ishibashi T, Kondo M, Sato Y, Todo S. Induction of macrophage migration inhibitory factor by lysophosphatidic acid: Relevance to tumor growth and angiogenesis. Int J Mol Med. 2003, 12, 633-641.
98. Ren Y, Tsui HT, Poon RT, Ng IO, Li Z, Chen Y, Jiang G, Lau C, Yu WC, Bacher M, Fan ST. Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. Int J Cancer. 2003, 107, 22-29.
99. Sasaki Y, Kasuya K, Nishihira J, Magami Y, Tsuchida A, Aoki T, Koyanagi Y. Suppression of tumor growth through introduction of an antisense plasmid of macrophage migration inhibitory factor. Int J Mol Med. 2002, 10, 579-583.
100. Nishihira J, Ishibashi T, Fukushima T, Sun B, Sato Y, Todo S. Macrophage migration inhibitory factor (MIF): Its potential role in tumor growth and tumor-associated angiogenesis. Ann N Y Acad Sci. 2003, 995, 171-182.
1. Weinberg RA. The retinoblastpma gene and cell cycle control. Ce11,1995,81, 323-330.
2. Dyson N. The regulation of E2F by pRB-family proteins. Gene Dev.1998, 12, 2245-2262.
3. Serrano M, Harmon GJ and Beach DA. A new regulatory motif in cell cycle control??causing specific inhibition of cyclinD/CDK4. Nature, 1993, 366, 704-707.
4. Sherr CJ. Cancer cell cycle. Science, 1996, 274, 1672-1677.
5. Hickman E and Helin K. The p53 Tumor Suppressor Protein. Biotech Genet Engine Rew. 2000, 17, 179-211.
6. Giaccia AJ and Kastan MB. The complexity of p53 modulation:emerging patterns from diverging signals. Gene Dev. 1998, 12, 2973-2983.
7. Sionov RV and Haupt T. The cellular response to p53: the decision between life and death. Oncegene, 1999, 18, 6145-6157.
8. Bates S and Vousden KH. Mechanism of p53-mediated apoptosis. Cell,1999, 55, 28-37.
9. Momand J, Wu HH and Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein. Gene. 2000, 245, 15-29.
10. Zhang Y and Xiong Y. Control of p53 ubiquitination and nuclear export by MDM2 and ARF. Cell Growth Differ, 2001, 12, 175-186.
11. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, and Bar-Sagi D. Nuclear Arf sequesters Mdm2 and activates p53. Nature Cell Boil, 1999, 1, 20-26.
12. Honda R and Yasuda H. Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO, 1999, 18, 22-27.
13. Lianos S,Clark PA, Rowe J and Peters G. Stablization of p53 by p14ARF without recolation of MDM2 to the nucleolus. Nature Cell Biol. 2001, 3,445-452.
14. Quelle DE, Zindy F, Ashmum RA and Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelatede protein capable of inducing cell cycle arrest. Cell. 1995, 83, 991-1000.
15. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH.A cell cycle regulator involved in genesis of many tumor types. Science. 2994, 264, 436-440.
16. Ruas M and Peters G. The p16~(INK4a)/CDKN2A tumor suppressor and its relatives. Biochem Biophys Acta Rev Cancer. 1998, 1378, F115-F177.
17. Nevins JR. Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell Growth Differ. 1998, 9, 585-593.
18. Zheng L and Lee WH. The Retinoblastoma gene: a prototypic and multifunctional tumor suppressor. Experimental Cell Research. 2001, 264, 2-18.
19. Roussel MF. The INK4 family of cell cycle inhibitors in cancer. Oncoge. 1999, 18, 5311-5317.
20. Lukas J, Peterson BO, Holm K, Bartek J and Helin K. Deregulated expression of E2F family members induces S-phase entry and overcome p16~(INK4a)-mediated growth suppression. Mol Cell Biol. 1996, 16, 1047-1057.
21. DeGregori J, Leone G, Miron A, Jakoi L and Nevins JR. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA. 1997, 93, 7245-7250.
22. Muller H, Bracken AP, Vemell R, Moroni MC, Christians F, Grassilli E, Prosperini E, Vigo E, Oliner JD, Helin K. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev.2001, 15, 267-285.
23. Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA. E2f3 is critical for normal cellular proliferation. Genes Dev. 2000, 14, 690-703.
24. Ziebold U, Reza T, Caron A and Lees JA. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 2001, 15, 386-391.
25. Lissy NA, Davis PK, Irwin M, Kaelin WG and Dowdy SF. A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature, 2000, 642-645.
26. Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin WG Jr. Roles for p53 homologue p73 in E2F-1 induced apoptosis. Nature. 2000, 407, 645-648.
27. Yamasaki L, Bronson R, Williams BO, Dyson NJ, Harlow E, Jacks T. Loss of E2F1 reduces tumorigenesis and extends lifespan of Rb~(+/-) mice. Nature Genet. 1998, 18,360-364.
28. Pan H, Yin C, Dyson NJ, Harlow E, Yamasaki L, Van Dyke T. Key roles for E2F-1 in signaling p53-dependent apoptosis and cell division. Mol Cell. 1998, 2, 283-292.
29. Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell. 1998, 293-304.
30. Lipinski MM and Jacks T. The retinoblastoma fene family in differentiation and development. Oncogene. 1999, 18, 7873-7882.
31. Lukas J, Parry D, Aagaard L, Mann D J, Bartkova J, Strauss M, Peters G, Bartek J.Rb-dependent cell cycle inhibition by p 16~(INK4a) tumor suppressor. Nature. 1995, 375, 503-506.
32. Koh J, Enders GH, Dyblacht BD and Harlow E. Tumor-derived p16 alles encoding proteins defective in cell cycle inhibition. Nature. 1995, 375, 506-510.
33. Medema RH, Herrera RE, Lain F and Weinberg RA. Growth suppression by p16r~(INK4a) requires functional retinoblatoma protein. Proc Natl Acad Sci USA. 1995, 92, 6289-6293.
34. Sherr CJ and Robert JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999, 13, 1501-1512.
35. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A and Berns A. Loss of Cdkn2a(p16INK4a) confers susceptibility to metastatic melanoma in mice. Nature. 2001, 413, 84-86.
36. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Homer JW, DePinho RA. Loss of p16INK4a with retention of p19ARF predisposes to tumourgenesis in mice. Nature. 2001, 413, 86-91.
37. Latres E, Malumbres M, Sotillo R, Martin J, Ortega S, Martin-Caballero J, Flores JM, Cordon-Cardo C, Barbacid M. Limited overlapping roles of p15~(INK4b) and p18~(INK4c) cell cycle inhibitors in proliferation and tumourgenesis. EMBO J. 2000, 19, 3496-3506.
38. Herman JG, Jen J, Merio A and Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4b. Cancer Res. 1996, 56, 722-727.
39. Zindy F, den Besten W, Chen B, Rehg JE, Latres E, Barbacid M, Pollard JW, Sherr C J, Cohen PE, Roussel MF. Control of spermatogenesis in mice by the cyclin-D-dependent kinase inhibitors p18~(INK4c) and p19~(INK4d). Mol Cell Biol. 2001, 21, 3244-3255.
40. Zindy F, Cunningham JJ, Sherr CJ, Jogal S, Smeyne RJ, Roussel MF. postnatal neuronal proliferation in mice lacking Ink4d and Kipl inhibitors of cyclin-dependent kinase. Proc Natl Acad Sci USA. 1999, 96, 13462-13467.
41. Franklin DS, Godfery VL,O'Brien DA, Deng C and Xiong Y. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol. 2000, 20, 6147-6158.
42. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppressor and cell mortality. Cell. 1996, 85, 27-37.
43. Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ. Tumor suppression at mouse INK4a locus mediated by the alternative reading frame product p19~(ARF). Cell. 1997, 91,649-659.
44. Zhang S, Ramsay ES and Mock BA. Cdkn2a, the cyclin-dependent kinase inhibitor gene encoding p16INK4a and p19ARF, is a candidate for the plasmacytoma susceptibility locus. Proc Natl Acda Sci USA. 1998, 2429-2434.
45. Eischen CM, Weber JD, Riussel MF, Sherr CJ and Cleveland JL. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 1999, 13, 2658-2669.
46. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M.Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 1999, 13, 2678-2690.
47. Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR, Lowe SW. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance bydisabling p53. Genes Dev. 1999, 13, 2670-7.
48. Carnero A, Hudson JD, Price CM, Beach DH. p16INK4A and p19ARF act in overlapping pathways in cellular immortalization. Nat Cell Biol. 2000, 2,148-55.
49. Chin L, Pomerantz J, Polsky D, Jacobson M, Cohen C, Cordon-Cardo C, Homer JW 2nd, DePinho RA. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 1997, 1, 2822-34.
50. Sherr CJ and DePinho RA. Cellular senescence: mitotic clock or culture shock. Cell. 2001, 102, 407-410.
51. Wright WE and Shay JW. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr Opin Genet. Dev. 2001, 11, 98-103.
52. Sage J, et al. Target disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev. 2000, 14, 3037-3050.
53. Dannenberg JH, van Rossum A, Schujiff L and te Riele H. Ablation of the retinoblastoma protein gene family deregulates G1 control causing immrtalization and increased cell turnover under growth-restricting conditions. Genes Dev. 2000, 14, 2051-3064.
54. Peeper DS, Dannenberg JH, Dourma S, te Riele H and Bernard R. Escape from premature senescence is not sufficient for oncogeneic transformation by Ras. Nature Cell Biol. 2001, 3 198-203.
55. Randle DH, Zindy F, Sherr CJ, Roussel MF. Differential effects of p19(Arf) and p16(Ink4a) loss on senescence of murine bone marrow-derived preB cells and macrophages. Proc Natl Acad Sci U S A. 2001, 98, 9654-9.
56. Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998, 396,: 84-8
57. Brenner AJ, Stampfer MR, Aldaz CM. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene. 1998, 17, 199-205.
58. Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW, Wright WE. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions.Genes Dev. 2001, 15, 398-403.
59. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 1998, 12, 2424-33.
60. de Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ, Lowe SW. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 1998, 12, 2434-42
61. Palmero I, Pantoja C, Serrano M. p19ARF links the tumour suppressor p53 to Ras. Nature.1998, 395, 125-6
62. Radfar A, Unnikrishnan I, Lee HW, DePinho RA, Rosenberg N. p19(Arf) induces p53-dependent apoptosis during abelson virus-mediated pre-B cell transformation. Proc Natl Acad Sci U S A. 1998, 95, 13194-9
63. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997, 88, 593-602.
64. Pies S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, McMahon M, Oren M, McCormick F. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell. 2000, 103, 321-30
65. Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH. p14ARF links the tumour suppressors RB and p53. Nature. 1998, 395, 124-5.
66. Eymin H, Karayan L, Seite P, Brambilla C, Cramnilla E, Larsen CJ and Gazzeri S. Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene. 2001, 20, 1033-1041.
67. Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, Giangrande P, Wu L, Saavedra HI, Field SJ, Thompson MA, Yang H, Fujiwara Y, Greenberg ME, Orkin S, Smith C, Nevins JR. Myc requires distinct E2F actives to induce S phase andapoptosis. Mol Cell. 2001, 8, 105-113.
68. Khan SH, Moritsugu J, Wahl GM. Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Proc Natl Acad Sci U S A. 2000, 97, 3266-71
69. Kastan MB and Lim D. The many substrates and functions of ATM. Nature Rev Cell Biol. 2000, 1, 179-186.
70. Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, Moas M, Buschmann T, Ronai Z, Shiloh Y, Kastan MB, Katzir E, Oren M. ATM-dependent phosphorylation of Mdm2 on serine 395: role of p53 activation by DNA damage. Genes Dev. 2001, 15, 10567-1077.
71. Lin WC, Lin FT, and Nevins JR. Selective induction of E2F1 in response to DNA damage mediated by ATM dependent phosphorylation. Gene Dev. 2001, 15, 1833-1844.
72. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999, 13, 2678-90
73. Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999, 13, 2207-2217.
74. Jacobs JJ, Keblusek P, Robanus-Maandag E, Kristel P, Lingbeek M, Nederlof PM, van Welsem T, van de Vijver MJ, Koh EY, Daley GQ, van Lohuizen M. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet. 2000, 26, 291-9
75. Pantoja C and Serrano M. Murine fibroblasts lacking undergo senescence and are resistanct to transformation by oncogene Ras. Oncogene. 1999, 18, 4974-4982.
76. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 1998, 95, 8292-7
77. Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH, Peters G. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998, 17, 5001-14
78. Robertson KD and Jones PA. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Molecullar and Cellular Biology 1998; 18: 6457-6473.
79. Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev. 2000, 14, 2358-65
1. Shenk T. Adenovidae: The viruses and their replication in : Field Virology third edition. B. N. Fields et al. eds. Lippincot-Raven Publisher, Philadephia, 1996 2111-2148
2. Bergelson JM, Cunnunghan JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwita MS, Crowell RL, Finberg RW. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science. 1997, 275, 1320-1323.
3. Amberg N, Edlund K, Kidd AH, Wadell G. Adenovirus type 37 uses sialic acid as a cellular receptor. J virol, 2000, 74, 42-48.4. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR. Intergins avβ3 and avβ5 promote adenovirus internalization but not virus attachment. Cell. 1993, 75, 477-486.
5. Greber UF, Willetts M, Webster P, Helenius A. Stepwise dismantling of adenovirus 2 during entry into cells. Cell. 1993, 75, 477-489.
6. Graham FL, Prevec L. Manipulation of adenovirus vectors. In: Methods in Molecular Biology. Murray EJ, Clifton NJ eds. Humana Press Inc, NJ, USA, 1991, 109-128.
7. Arnalfitano A, Hauser MA, Hu H, Serra D, Begy CR, Chamberlain JS. Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted. J Virol. 1998, 72, 926-33.
8. Kochanek S. High-capacity adenoviral vectors for gene transfer and somatic gene therapy. Hum Gene Ther. 1999, 10, 2451-2459.
9. Russell WC. Update on adenovirus and its vectors. J Gen Virol. 2000, 81, 2573-2504.
10. Steinwaerder DS, Carlson CA, Lieber A. Generation of adenovirus vectors devoid of all viral genes by recombination between inverted repeats. J Virol. 1999, 73, 9303-13.
11. Reynolds PN, Feng M, Curiel DT. Chimeric viral vectors-the best of both world? Mol Med Tody. 1999, 5, 25-31.
12. Golubev DB, Zalkind SIa, Selivanov AA, Deriabina IS, Fokina AM, Zvereva EP. Comparative characteristics of histochemical and biochemical changes in tissue cultures infected by adenoviruses Biull Eksp Biol Med. 1967, 63, 44-8.
13. Todryk SM, Chong H, Vile RG, Pandha H, Lemoine NR. Can immunotherapy by gene transfer tip the balance against colorectal cancer?. Gut. 1998, 43, 445-449.
14. Bodey B, Bodey B Jr, siegel SE, Kaiser HE. Failure of cancer vaccines: The significant limitations of this approach to immunotherapy. Anticancer Res. 2000, 20, 2665-2676
15. Geutskens SB, van der Eb MM, Plomp AC, Jonges LE, Cramer SJ, Ensink NG, Kuppen PJ, Hoeben RC. Recombinant adenoviral vectors have adjuvant activity andstimulate T cell responses against tumor cells. Gene Ther. 2000, 7, 1410-6.
16. Ostrand-Rosenberg S, Thakur A, Clements V. Rejection of mouse sarcoma cells after transfection of MHC class II genes. J Immunol, 1990, 144, 4068-4071.
17. Putzer BM, Hitt M, Muller WJ, Emtage P, Gauldie J, Graham FL. Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression. Proc Natl Acad Sci U S A. 1997, 94, 10889-94
18. Nabel G J, Nabel EG, Yang ZY, Fox BA, Gao X, Huang L, Shu S, Gordon D, Chang AE. Director gene transfer with DNA-liposome complexes in melanoma: Expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci USA. 1993, 90, 11307-11311.
19. Gonzalez R, Atkins M, Schwarzenberger P, Lutzky J, Rublin J, Deisseroth A, Blum A, Glutheil, HutchinsL. Phase II trial of HLA-B7 plasmid DNA/lipid (Allovectin) immunotherapy in patients with metastatic melanoma. Proc Am Soc Clin Oncol. 2001, 20, Asb 1007.
20. Harris MP, Sutjipto S, Wills KN, Hancock W, Cornell D, Johnson DE, Gregory RJ, Shepard HM, Maneval DC. Adenovirus-mediated p53 gene transfer inhibits growths of human tumor cells expressing mutant p53 protein. Cancer Gene Ther. 1996, 3, 121-130.
21. Nishizaki M, Fujiwara T, Tanida T, Hizuta A, Nishimori H, Tokino T, Nakamura Y, Bouvet M, Roth JA, Tanaka N. Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect. Clin Cancer Res. 1999, 5, 1015-23.
22. Venook AP, Bergsland EK, Ring E, Nonaka-Wong S, Horowitz JA, Rybak ME, Warren RS. Gene therapy of colorectal liver metasrasis using recombinant adenovirus encoding wt p53 (SCH 58500) via hepatic artery infusion: A phase I study. Proc Am Soc Clin Oncol. 1998, 17, Abs 1661.
23. Cohen AM, Kemeny Ne, Kohne CH, Wils J, de Takats PG, Kerr DJ. Is intra-chemotherapy worthwhile in the treatment of patients with unresectable hepaticcolorectal cancer metastasis? Eur J Cancer. 1996, 321: 2195-2205.
24. Hao Z, Rowinsky EK, Smerzer LZ, Ochoa L, Hammond LA, Gamer A, Smith L, Parker, Merritt JA, Tolcher AW. A phase I and pharmacokinetics study of intravenous (IV) o53 gene therapy for with RPR//NGN-201 in patients with advanced cancer. Proc Am Soc Clin Oncol. 2001, 20, Abs 1045.
25. Nguyen DM, Spitz FR, Yen N, Cristain RJ, Roth JA. Gene therapy for lung cancer: Enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer. J Thorac Cardiovasc Surg. 1996, 112, 1372-1376.
26. Roth JA, Swisher SG, Meyn RE. p53 rumor suppressor gene therapy for cancer. Cancer Res, 2001, 61, 1796-1798.
27. Jiang GL, Huang S. Adenovirus expressing RIZ1 in tumor suppressor gene therapy of microsatellite-unstable colorectal cancers. Cancer Res. 2001, 61, 1796-8.
28. Xu G, McLeod HL. Strategies for enzyme/prodrug cancer therapy. Clin Cancer Res. 2001, 7, 3314-24.
29. Kuriyama S, Kikukawa M, Masui K, Okuda H, Nakatani T, Sakamoto T, Yoshiji H, Fukui H, Ikenaka K, Mullen CA, Tsujii T. Cytosine deaminase/5-fluorocytosine gene therapy can induced efficient anti-tumor effects and protective immunity in immunocompetent mice but not in athymic nude mice. Int J Cancer. 2001, 67, 1165-1173.
30. Link CJ, Levy JP, McCann LZ, Moorman DW. Gene therapy for colon cancer with the herpes simplex thymidine kinase gene. J Surr Oncol. 1997, 64, 289-294
31. Sandmire AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M, Hurskainen H, Tyynela K, Turunen M, Vanninen R, Lehtolainen P. Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses for adenoviruses. Hum Gene Ther. 2000, 11, 2197-2205.
32. Sung MW, Yeh HC, Thung SN, Schwartz ME, Mandeli JP, Chen SH, Woo SL. Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases fromcolorectal adenocarcinoma: results of a phase I clinical trial. Mol Ther. 2001, 4, 182-91.
33. Huber BE, Austin EA, Richard CA, Davis ST, Good SS. Metabolism of 5-flurocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: Singnificant antitumot effects when only small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA. 1994, 91, 8302-8306.
34. Chung-Faye GA, Chen M J, Green NK, Burton A, Anderson D, Mautner V, Searle PF, Kerr DJ. In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase. Gene Ther. 2001, 8: 1547-1554.
35. Topf N, Worgall S, Hackett NR, Crystal RG. Regional ‘pro-drug' gene therapy: intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinoma. Gene Ther. 1998, 5, 507-13.
36. Green NK, Youngs DJ, Neoptolemos JP, Friedlos F, Knox RJ, Springer CJ, Anlezark GM, Michael NP, Melton RG, Ford MJ, Young LS, Kerr DJ, Searle PF. Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5-(aziridin-l-yl)-2,4-dinitrobenzamide (CB1954) by retroviral transduction and expression of the E. coli nitroreductase gene. Cancer Gene Ther. 1997, 4, 229-38.
37. Palmer DH, Mautner V, Mirza D. Virus-directed enzyme prodrug therapy (VDEPT): Clinical trial with adenoviral nitroimidazole reductase (ad-ntr). Br J Cancer. 2002, 86, 530.
38. Biscoff JR, KimDH, Heise C, Hom S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 1996, 274, 373-376.
39. Rothmann T, Hengstermarm A, Whitaker NJ, Scheffner M, zur Hausen H. Replication ONYX-015, a potential anticancer adenovirus, si independent pf p53status in tumor cells. J Virol, 1998, 72, 9470-9478.
40. Ries S J, Brandts CH, Chung AS, Biederer CH, Hann BC, Lipner EM, McCormick F, Korn WM. Loss of p14ARF in tumor cell facilitates replication of the adenovirus mutant d1 1520(ONXY-015). Nat Med. 2000, 6, 1128-1133.
41. Habib NA, Sarraf CE, Mitry RR, Havlik R, Nicholls J, Kelly M, Vernon CC, Gueret-Wardle D, E1-Masry R, Salama H, Ahmed R, Michail N, Edward E, Jensen SL. E1B-deleted adenovirus (d11520) gene therapy for patients with primary and secondary liver tumors. Hum Gene Ther. 2001, 12, 219-26.
42. Habib NA, Sarraf CE, Mitry RR, Havlik R, Nicholls J, Kelly M, Vernon CC, Gueret-Wardle D, E1-Masry R, Salama H, Ahmed R, Michail N, Edward E, Jensen SL. E1B-deleted adenovirus (d11520) gene therapy for patients with primary and secondary liver tumors. Hum Gene Ther. 2001, 12, 219-26.
43. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Talmock IF, Romel L, Gore M, Ironside J, MacDougall TH, Heise C, Randlev B. A controlled trial of intratumoral ONXY-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patient with recurrent head and neck cancer. Nat/reed. 2000, 6, 879-885.
44. Komberg RD, Lroch Y. Chromatin-modifying and-remodeling complexes. Curr Opin Genet Dev. 1999, 9, 148-151.
45. Gaetano C, Catalano A, Palumbo R, Illi B, Orlando G, Ventoruzzo G, Serino F, Capogrossi MC. Transcriptionally active drugs improve adenovirus vector performance in vitro and in vivo. Gene Ther. 2000, 7, 1624-30.
2. Manu M, Buckels J, Bramhall S. Molecular technology and pancreatic cancer. British Journal of Surgery. 2000, 87, 840-53.
3. Sakorafas GH, Tsiotou AG, Tsiotos GG, et al. Molecular biology of pancreatic cancer: oncogenes, tumor suppressor genes, growth factors, and their receptors from a clinical perspective. Cancer Treat Rev 2000, 26, 29-52.
4. Lynda Chin JP, Ronald A and Depinho. The INK4a/ARF tumor suppressor: one gene-two products-two pathways. Trends in Biochemical Sciences. 1998, 23, 291-296.
5. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994, 68, 753-756.
6. Sherr CJ. The INK4a/ARF network in tumour suppression. Nature review in Mol Cell Biol. 2001, 2, 731-737.
7. Hrber DA. Splicing into senescence: the curious cases of p16 and p19ARF. Cell, 1997, 9, 555-558.
8. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993, 366, 704-707.
9. Jin X, Nguyen D, Zhang WW, Kyritsis AP, Roth JA. Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector. Cancer Res. 1995, 55, 3250-3253.
10. 8. S, Seth P, Cowan K. Effects of adenovirus-mediated p16INK4A expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer Cells. Oncogene. 1998, 16, 265-72.
11. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation andstabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.Cell. 1998, 92, 725-34.
12. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Htuban RH, Yeo CJ and Kern SE. Frequent somatic mutation and homozygous deletion of p16 (MTS1) gene in pancreatic adenocarcinoma. Nat. Genet. 1994, 8, 27-32.
13. Sunamura M, Yatsuoka T, Motoi F, Duda DG,Kimura M, Abe T, Yokoyam T, Inoue H, Oonuma M, Takeda K, and Matsuno S. Gene therapy for pancreatic cancer based on genetic characterization of the disease. J Hepatobiliary Pancreat Surg. 2002, 9,32-38.
14. Geroge, JS. Gene therapy progress and prospects: Adenovirus. Gene therapy, 2003, 23, 1135-1141.
15. Zhang WW. Development and application of adenoviral vector for gene therapy of cancer. Cancer Gene Therapy. 1999,2, 113-138.
16. Chen Jie, Liu Tonghua, Guo Xiuying, et al. Two New human exocrine pancreatic adenocarcinoma cell lines in vitro and in vivo. Chinese Medical Journal, 1990, 103, 369-375.
17. Ghaneh P, Greenhalf W, Humphreys M, Wilson D, Zumstein L, Lemoine NR, Neoptolemos JP. Adenovirus-mediated transfer of p53 and p16(INK4a) results in pancreatic cancer regression in vitro and in vivo. Gene Ther. 2001, 8, 199-208.
18. He TC, Zhou SB, Da Costa LT, Yu L, Kinzler KW, and Vogelstein B, A simplified system for generating recombinant adenoviruses. Proc. Natl. Acad. Sci. USA, 1998, 95, 2509-2514.
19. Werner F, Zolzer F, Streffer C, et al. p53 levels, cell cycle kinetics and radiosensitivity in two SV40 transformed Wi38VA13 fibroblast strains. Strahlenther Onkol. 2001, 177, 662-9.
20．鄂征，组织培养和分子细胞学技术技术，北京出版社，第二版，1997，157-158．
21．F．奥斯伯 等。精遍分子生物学实验指南。科学出版社，第一版，1998，332-338．22. T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promoters histone gene transcription. Genes Dev 2000, 14, 2298-313.
23. Sinha P, Hutter G, Kottgen E, et al. Increased expression of annexin I and thioredoxin detected by two-dimensional gel electrophoresis of drug resistant human stomach cancer cells. J Biochem Biophys Methods. 1998, 37, 105-116.
24. Alaiya AA, Oppermann M, Langridge J, et al. Identification of proteins in human prostate tumor material by two-dimensional gel electrophoresis and mass spectrometry.Cell Mol Life Sci. 2001, 58, 307-311.
25. Guo XX, Ying WT, Wan JH, et al. Proteomic characterization of early-stage differentiation of mouse embryonic stem cells into neural cells induced by all-trans retinoic acid in vitro. Electrophoresis. 2001, 22, 3067-75.
26. Zhan X and Desiderio DM. A reference map of a human pituitary adenoma proteome. Proteomics. 2003, 3, 1-15.
27. Person MD, Lo HH, Towndrow KM, Jia Z, Monks TJ, and Lau SS。Comparative Identification of Prostanoid Inducible Proteins by LC-ESI-MS/MS and MALDI-TOF Mass Spectrometry. Chem. Res. Toxicol. 2003, 16, 757-767.
28. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhofff I., Schmiegel W, Baylin SB, Kern SE, and Herman JG. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinoma. Cancer Res. 57, 3126-3130, 1997.
29. Geradts J, Wilentz RE, Roberts H .Immunohistochemical [corrected] detection of the alternate INK4a-encoded tumor suppressor protein p14(ARF) in archival human cancers and cell lines using commercial antibodies: correlation with p16(INK4a) expression. Mod Pathol. 2001, 14, 1162-1168.
30. Ghaneh P, Greenhalf W, Humphreys M, Wilson D, Zumstein L, Lemoine NR, Neoptolemos JP. Adenovirus-mediated transfer of p53 and p16(INK4a) results inpancreatic cancer regression in vitro and in vivo.Gene Ther. 2001, 8, 199-208.
31. Kobayashi S, Shirasawa H, Sashiyama H, Kawahira H, Kaneko K, Asano T, Ochiai T. P16IN-K4a expression adenovirus vector to suppress pancreas cancer cell proliferation. Clin Cancer Res. 1999, 5, 4182-4185.
32. Barton M, et al. Abnormalities of the rb1 and dcc turmor-suppressor geneuncommon in human pancreatic carcinoma. Mol Carcinogen 1995, 13: 61-69.
33. Steiner MS, Wang Y, Zhang Y, Zhang X, Lu Y. Oncogene. p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways. 2000, 19, 1297-1306.
34. Pearson A, et al. Factors limiting adenovirus-mediated transfer into human lung and pancreatic cancer cell lines. Clin Cancer Res 1999, 5, 4028-4213.
35. Yang CT, You L, Lin YC, Lin CL, Mccormick F, Jablons DM. A comparison analysis of anti-tumor efficacy of adenoviral gene replacement therapy (p14ARF and p16INK4A) in human mesothelioma cells Anticancer Res 2003, 23(1A), 33-38.
36. Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G. Regulation ofp16CDKN2 expression and its implications for cell immortalization and senescence.Mol Cell Biol. 1996, 16, 859-867.
37. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality.Cell. 1996, 85, 27-37.
38. Loughran O, Malliri A, Owens D, Gallimore PH, Stanley MA, Ozanne B, Frame MC, Parkinson EK. Association of CDKN2A/p16INK4A with human head and neck keratinocyte replicative senescence: relationship of dysfunction to immortality and neoplasia.Oncogene. 1996, 13, 561-568.
39. Modesitt SC, Ramirez P, Zu Z, Bodurka-Bevers D, Gershenson D, Wolf JK. In vitro and in vivo adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer. Clin Cancer Res. 2001, 7, 1765-1772.
40. Naruse I, Heike Y, Hama S, Mori M, Saijo N. High concentrations of recombinant adenovirus expressing p16 gene induces apoptosis in lung cancer celllines.Anticancer Res. 1998, 18, 4275-4282.
41. Schreiber M, Muller WJ, Singh G, Graham FL. Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21(WAF1/CIP1) and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity.Oncogene. 1999, 18, 1663-1676.
42. Kawabe S, Roth JA, Wilson DR, Meyn RE. Adenovirus-mediated p16INK4a gene expression radiosensitizes non-small cell lung cancer cells in a p53-dependent manner.Oncogene. 2000, 19, 5359-5366.
43. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993, 366, 701-704.
44. Shim J, Park Hs, Kim MJ, Park J, Park E, Cho SG, Eom S J, Lee Hw, Joe CO and Choi EJ. Rb protein down-regulates the stress-activated signals through inhibiting c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem, 2000, 275, 14107-14111.
45. Fuchs X, Adler V, Bushmann T, Yin Z, Wu X, Jones SN, and Ronai A. JNK targets p53 ubiquitination and degradation in nonstressed cells. Gene Dev, 1998, 12, 665-669
46. Weber HO, Samuel T, Rauch P. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins.. Sciences, 1992, 258, 424-429.
47. Weinberg RA. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell, 1995, 81, 323-330.
48. Yamasaki L.,et al. Tumor induction and tissue atrophy in mice lack E2F-1. Cell, 1996, 85, 537-548.
49. Fueyo J, et al. Over expression of E2F-1 in glioma triggers apoptosis and suppresses tumor growth in vitro and in vivo. Nature Med 1997, 3, 313-319.
50. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF and Sherr CJ,. Functional and physical interaction of ARF tumor suppressor with p53 and MDM2. Proc Natl Acad Sci U S A 1998, 95, 8292-8297.
51. Pomerantz J, Schreiber-Agus N, Liegeois N J, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 1998, 92: 713-723.
52. Lohrum MA, Ashcroft M, Kubbutat MH, Vousden KH. Contribution of two independent MDM2-binding domains in p14(ARF) to p53 stabilization. Curr Biol 2000, 10:539-5420
53. Weber HO, Samuel T, Rauch P, Funk JO. Human p14(ARF)-mediated cell cycle arrest strictly depends on intact p53 signaling pathways. Oncogene 2002, 21, 3207-3212.
54. Saadatmandi N, Tyler T, Huang Y, Haghighi A, Frost G, Borgstrom P, Gjerset RA. Growth suppression by a p14(ARF) exon lbeta adenovirus in human tumor cell lines of varying p53 and Rb status. Cancer Gene Ther 2002, 9, 830-839.
55. Yang CT, You L, Uematsu K, Yeh CC, McCormick F, Jablons DM. p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53.Cancer Res. 2001, 61, 5959-5963.
56. Yang CT, You L, Yeh CC, Chang JW, Zhang F, McCormick F, Jablons DM. Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells. J Natl Cancer Inst. 2000, 92, 636-641.
57. Deng X, Kim M, Vandier D, Jung YJ, Rikiyama T, Sgagias MK, Goldsmith M, Cowan KH.Recombinant adenovirus-mediated p14(ARF) overexpression sensitizes human breast cancer cells to cisplatin. Biochem Biophys Res Commun 2002, 296, 792-798.
58. Sandig V, Brand K, Herwig S, Lukas J, Bartek J and Strauss M. Adenovirally transferred p16INK4/CDKN2 and p53 gene cooperate to induce apoptotic tumor cell death. Nat Med. 1997, 3, 313-319.
59. Katayose D, Dudas J, Nguyen H, Srivastava S, Cowan KH and Seth P. Cytotoxic effects of adenovirus-mediated wild-type p53 protein expression in normal andturmor mammary epithelial cells. Clin Cancer Res. 1995, 1, 889-897.
60. Carnero A, Hudson JD, Price CM, Beach DH. p1 6INK4A and p19ARF act in overlapping pathways in cellular immortalization. Nat Cell Biol. 2000, 2, 148-155.
61. Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev. 2000, 14, 2358-2365.
62. Sanchez-Cespedes M, Reed AL, Buta M, Wu L, Westra WH, Herman JG, Yang SC, Jen J, Sidransky D. Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. Oncogene 1999, 18, 5843-5849.
63. Gazzeri S, Della Valle V, Chaussade L, Brambilla C, Larsen CJ, Brambilla E. The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer.Cancer Res. 1998, 58, 3926-3931.
64. Saadatmandi N, Tyler T, Huang Y, Haghighi A, Frost G, Borgstrom P, Gjerset RA. Growth suppression by a p14(ARF) exon lbeta adenovirus in human tumor cell lines of varying p53 and Rb status. Cancer Gene Ther. 2002, 9, 830-839.
65. Hemmati PG, Gillissen B, von Haefen C, Wendt J, Starck L, Guner D, Dorken B, Daniel PT. Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. Oncogene. 2002, 21, 3149-3161.
66. Eymin B, Leduc C, Coil JL, Brambilla E, Gazzeri S. p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene. 2003, 22, 1822-1835.
67. Datta A, Nag A, Raychaudhuri P. Differential regulation of E2F1, DP1, and the E2F1/DP1 complex by ARF. Mol Cell Biol. 2002, 22, 8398-8408.
68. Eymin B, Karayan L, Seite P, Brambilla C, Brambilla E, Larsen CJ, Gazzeri S. Human ARF binds E2F1 and inhibits its transcriptional activity.Oncogene. 2001, 1, 20, 1033-41.
69. Karayan L, Riou JF, Seite P, Migeon J, Cantereau A, Larsen CJ. Human ARF protein interacts with topoisomerase I and stimulates its activity. Oncogene. 2001, 20,836-848
70. Jackson MW, Lindstrom MS, Berberich SJ. MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation. J Biol Chem. 2001, 276, 25336-25341.
71. Bramson JI. Direct intratumor injection of an adenovirus expressing interleukin-12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12. Hum Gene Ther, 1996; 7; 1995-2002
72. Fisher KJ, et al. Recombinationat adenovirus deleted of all viral genes for gene therapy of cystic firbios. Virology, 1996, 217, 11-22
73. Glayman GL et al. Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J clin Oncol, 1998, 16, 2221-2232.
74. Sunamura M, Yatsyoka T, Motoi F, et al. Gene therapy for pancreatic cancer based on genetic characterization of the disease. J Hepatobiliary Pancreat Surg, 2002, 9, 32-38.
75. Kawakami Y, Hama S, Hiura M, Nogawa T, Chiba T, Yokoyama T, Takashima S, Tajiri H, Eguchi K, Nagai N, Shigemasa K, Ohama K, Kurisu K, Heike Y. Adenovirus-mediated p16 gene transfer changes the sensitivity to taxanes and Vinca alkaloids of human ovarian cancer cells. Anticancer Res. 2001 Jul-Aug; 21(4A): 2537-45.
76. Hama S, Heike Y, Naruse I, Takahashi M, Yoshioka H, Arita K, Kurisu K, Goldman CK, Curiel DT, Saijo N. Adenovirus-mediated p16 gene transfer prevents drug-induced cell death through G1 arrest in human glioma cells. Int J Cancer. 1998 Jul 3; 77(1): 47-54.
77. Grim J, D'Amico A, Frizelle S, Zhou J, Kratzke RA, Curiel DT. Adenovirus-mediated delivery of p16 to p16-deficient human bladder cancer cells confers chemoresistance to cisplatin and paclitaxel.Clin Cancer Res. 1997 Dec; 3(12 Pt 1): 2415-23.
78. Guo-Chang F, Chu-Tse W. Transfer of p14ARF gene in drug-resistant human breastcancer MCF-7/Adr cells inhibits proliferation and reduces doxorubicin resistance. Cancer Lett 2000; 158: 203-10.
79. Gao N, Hu Y, Luo J. Increased radiosensitivity of lung cancer cell lines related with the functionally replaced p14ARF gene. Zhonghua Yi Xue Za Zhi 2000; 80: 776-9.
80. Peebles KA, Duncan MW, Ruch R J, Malkinson AM. Proteomic analysis of a neoplastic mouse lung epithelial cell line whose tumorigenicity has been abrogated by transfection with the gap junction structural gene for connexin 43, Gjal. Carcinogenesis. 2003, 24, 651-657.
81. Yu LR, Zeng R, Shao XX, et al. Identification of differentially expressed proteins between human hepatoma and normal liver cell lines by two-dimensional electrophoresis and liquid chromatography-ion trap mass spectrometry. Electrophoresis 2000, 21, 3058-3068.
82. Mazurek S, Grimm H, Oehmke M, Weisse G, Teigelkamp S, Eigenbrodt E. Tumor M2-PK and glutaminolytic enzymes in the metabolic shift of tumor cells. Anticancer Res. 2000, 20, 5151-5154.
83. Eigenbrodt E, Reinacher M, Scheefers-Borchel U, Scheefers H, Friis R. Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. Crit Rev Oncog. 1992, 3, 91-115.
84. Mazurek S, Eigenbrodt E. The tumor metabolome. Anticancer Res. 2003, 23, 1149-54.
85. Mazurek S, Grimm H, Boschek CB, Vaupel P, Eigenbrodt E. Pyruvate kinase type M2: a crossroad in the tumor metabolome. Br J Nutr. 2002, 87 Suppl, S23-29.
86. Cerwenka H, Aigner R, Bacher H, Werkgartner G, el-Shabrawi A, Quehenberger F, Mischinger HJ. TUM2-PK (pyruvate kinase type tumor M2), CA19-9 and CEA in patients with benign, malignant and metastasizing pancreatic lesions. Anticancer Res. 1999, 19, 849-851.
87. Schneider J, Neu K, Velcovsky HG, Morr H, Eigenbrodt E. Tumor M2-pyruvate kinase in the follow-up of inoperable lung cancer patients: a pilot study.Cancer Lett.2003, 193, 91-98.
88. Hoopmann M, Warm M, Mallmann P, Thomas A, Gohring UJ, Schondorf T. Tumor M2 pyruvate kinase--determination in breast cancer patients receiving trastuzumab therapy. Cancer Lett. 2002, 187, 223-228.
89. Nishihira J. Macrophage migration inhibitory factor (MIF): its essential role in the immune system and cell growth. J Interferon Cytokine Res. 2000, 20, 751-762.
90. Meyer-Siegler KL, Bellino MA, Tannenbaum M. Macrophage migration inhibitory factor evaluation compared with prostate specific antigen as a biomarker in patients with prostate carcinoma. Cancer. 2002, 94, 144~1456
91. Bando H, Matsumoto G, Bando M, Muta M, Ogawa T, Funata N, Nishihira J, Koike M, Toi M. Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res. 2002, 93, 389-396.
92. Campa M J, Wang MZ, Howard B, Fitzgerald MC, Patz EF Protein expression profiling identifies macrophage migration inhibitory factor and cyclophilin a as potential molecular targets in non-small cell lung cancer. Cancer Res. 2003, 63, 1652-1656.
93. Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes F J, Roger T, Calandra T, Kapumiotu A, Grell M, Finkelmeier D, Brunner H, and Bernhagen J. Nature. 2000, 408, 211-216.
94. Roger T, David J, Clauser MP and Bemhagen J. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature. 2001, 414, 920-924.
95. Hudson JD, Shoaibi MA, Maestro R, Camero A, Hannon GJ, Beach DH. A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med. 1999, 190, 1375-1382.
96. Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss R, Moll U, Muller W, Bucala R. The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci U S A. 2003, 100, 9354-9359.
97. Sun B, Nishihira J, Suzuki M, Fukushima N, Ishibashi T, Kondo M, Sato Y, Todo S. Induction of macrophage migration inhibitory factor by lysophosphatidic acid: Relevance to tumor growth and angiogenesis. Int J Mol Med. 2003, 12, 633-641.
98. Ren Y, Tsui HT, Poon RT, Ng IO, Li Z, Chen Y, Jiang G, Lau C, Yu WC, Bacher M, Fan ST. Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. Int J Cancer. 2003, 107, 22-29.
99. Sasaki Y, Kasuya K, Nishihira J, Magami Y, Tsuchida A, Aoki T, Koyanagi Y. Suppression of tumor growth through introduction of an antisense plasmid of macrophage migration inhibitory factor. Int J Mol Med. 2002, 10, 579-583.
100. Nishihira J, Ishibashi T, Fukushima T, Sun B, Sato Y, Todo S. Macrophage migration inhibitory factor (MIF): Its potential role in tumor growth and tumor-associated angiogenesis. Ann N Y Acad Sci. 2003, 995, 171-182.
1. Weinberg RA. The retinoblastpma gene and cell cycle control. Ce11,1995,81, 323-330.
2. Dyson N. The regulation of E2F by pRB-family proteins. Gene Dev.1998, 12, 2245-2262.
3. Serrano M, Harmon GJ and Beach DA. A new regulatory motif in cell cycle control??causing specific inhibition of cyclinD/CDK4. Nature, 1993, 366, 704-707.
4. Sherr CJ. Cancer cell cycle. Science, 1996, 274, 1672-1677.
5. Hickman E and Helin K. The p53 Tumor Suppressor Protein. Biotech Genet Engine Rew. 2000, 17, 179-211.
6. Giaccia AJ and Kastan MB. The complexity of p53 modulation:emerging patterns from diverging signals. Gene Dev. 1998, 12, 2973-2983.
7. Sionov RV and Haupt T. The cellular response to p53: the decision between life and death. Oncegene, 1999, 18, 6145-6157.
8. Bates S and Vousden KH. Mechanism of p53-mediated apoptosis. Cell,1999, 55, 28-37.
9. Momand J, Wu HH and Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein. Gene. 2000, 245, 15-29.
10. Zhang Y and Xiong Y. Control of p53 ubiquitination and nuclear export by MDM2 and ARF. Cell Growth Differ, 2001, 12, 175-186.
11. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, and Bar-Sagi D. Nuclear Arf sequesters Mdm2 and activates p53. Nature Cell Boil, 1999, 1, 20-26.
12. Honda R and Yasuda H. Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO, 1999, 18, 22-27.
13. Lianos S,Clark PA, Rowe J and Peters G. Stablization of p53 by p14ARF without recolation of MDM2 to the nucleolus. Nature Cell Biol. 2001, 3,445-452.
14. Quelle DE, Zindy F, Ashmum RA and Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelatede protein capable of inducing cell cycle arrest. Cell. 1995, 83, 991-1000.
15. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH.A cell cycle regulator involved in genesis of many tumor types. Science. 2994, 264, 436-440.
16. Ruas M and Peters G. The p16~(INK4a)/CDKN2A tumor suppressor and its relatives. Biochem Biophys Acta Rev Cancer. 1998, 1378, F115-F177.
17. Nevins JR. Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell Growth Differ. 1998, 9, 585-593.
18. Zheng L and Lee WH. The Retinoblastoma gene: a prototypic and multifunctional tumor suppressor. Experimental Cell Research. 2001, 264, 2-18.
19. Roussel MF. The INK4 family of cell cycle inhibitors in cancer. Oncoge. 1999, 18, 5311-5317.
20. Lukas J, Peterson BO, Holm K, Bartek J and Helin K. Deregulated expression of E2F family members induces S-phase entry and overcome p16~(INK4a)-mediated growth suppression. Mol Cell Biol. 1996, 16, 1047-1057.
21. DeGregori J, Leone G, Miron A, Jakoi L and Nevins JR. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA. 1997, 93, 7245-7250.
22. Muller H, Bracken AP, Vemell R, Moroni MC, Christians F, Grassilli E, Prosperini E, Vigo E, Oliner JD, Helin K. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev.2001, 15, 267-285.
23. Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA. E2f3 is critical for normal cellular proliferation. Genes Dev. 2000, 14, 690-703.
24. Ziebold U, Reza T, Caron A and Lees JA. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 2001, 15, 386-391.
25. Lissy NA, Davis PK, Irwin M, Kaelin WG and Dowdy SF. A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature, 2000, 642-645.
26. Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin WG Jr. Roles for p53 homologue p73 in E2F-1 induced apoptosis. Nature. 2000, 407, 645-648.
27. Yamasaki L, Bronson R, Williams BO, Dyson NJ, Harlow E, Jacks T. Loss of E2F1 reduces tumorigenesis and extends lifespan of Rb~(+/-) mice. Nature Genet. 1998, 18,360-364.
28. Pan H, Yin C, Dyson NJ, Harlow E, Yamasaki L, Van Dyke T. Key roles for E2F-1 in signaling p53-dependent apoptosis and cell division. Mol Cell. 1998, 2, 283-292.
29. Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell. 1998, 293-304.
30. Lipinski MM and Jacks T. The retinoblastoma fene family in differentiation and development. Oncogene. 1999, 18, 7873-7882.
31. Lukas J, Parry D, Aagaard L, Mann D J, Bartkova J, Strauss M, Peters G, Bartek J.Rb-dependent cell cycle inhibition by p 16~(INK4a) tumor suppressor. Nature. 1995, 375, 503-506.
32. Koh J, Enders GH, Dyblacht BD and Harlow E. Tumor-derived p16 alles encoding proteins defective in cell cycle inhibition. Nature. 1995, 375, 506-510.
33. Medema RH, Herrera RE, Lain F and Weinberg RA. Growth suppression by p16r~(INK4a) requires functional retinoblatoma protein. Proc Natl Acad Sci USA. 1995, 92, 6289-6293.
34. Sherr CJ and Robert JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999, 13, 1501-1512.
35. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A and Berns A. Loss of Cdkn2a(p16INK4a) confers susceptibility to metastatic melanoma in mice. Nature. 2001, 413, 84-86.
36. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Homer JW, DePinho RA. Loss of p16INK4a with retention of p19ARF predisposes to tumourgenesis in mice. Nature. 2001, 413, 86-91.
37. Latres E, Malumbres M, Sotillo R, Martin J, Ortega S, Martin-Caballero J, Flores JM, Cordon-Cardo C, Barbacid M. Limited overlapping roles of p15~(INK4b) and p18~(INK4c) cell cycle inhibitors in proliferation and tumourgenesis. EMBO J. 2000, 19, 3496-3506.
38. Herman JG, Jen J, Merio A and Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4b. Cancer Res. 1996, 56, 722-727.
39. Zindy F, den Besten W, Chen B, Rehg JE, Latres E, Barbacid M, Pollard JW, Sherr C J, Cohen PE, Roussel MF. Control of spermatogenesis in mice by the cyclin-D-dependent kinase inhibitors p18~(INK4c) and p19~(INK4d). Mol Cell Biol. 2001, 21, 3244-3255.
40. Zindy F, Cunningham JJ, Sherr CJ, Jogal S, Smeyne RJ, Roussel MF. postnatal neuronal proliferation in mice lacking Ink4d and Kipl inhibitors of cyclin-dependent kinase. Proc Natl Acad Sci USA. 1999, 96, 13462-13467.
41. Franklin DS, Godfery VL,O'Brien DA, Deng C and Xiong Y. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol. 2000, 20, 6147-6158.
42. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppressor and cell mortality. Cell. 1996, 85, 27-37.
43. Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ. Tumor suppression at mouse INK4a locus mediated by the alternative reading frame product p19~(ARF). Cell. 1997, 91,649-659.
44. Zhang S, Ramsay ES and Mock BA. Cdkn2a, the cyclin-dependent kinase inhibitor gene encoding p16INK4a and p19ARF, is a candidate for the plasmacytoma susceptibility locus. Proc Natl Acda Sci USA. 1998, 2429-2434.
45. Eischen CM, Weber JD, Riussel MF, Sherr CJ and Cleveland JL. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 1999, 13, 2658-2669.
46. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M.Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 1999, 13, 2678-2690.
47. Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR, Lowe SW. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance bydisabling p53. Genes Dev. 1999, 13, 2670-7.
48. Carnero A, Hudson JD, Price CM, Beach DH. p16INK4A and p19ARF act in overlapping pathways in cellular immortalization. Nat Cell Biol. 2000, 2,148-55.
49. Chin L, Pomerantz J, Polsky D, Jacobson M, Cohen C, Cordon-Cardo C, Homer JW 2nd, DePinho RA. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 1997, 1, 2822-34.
50. Sherr CJ and DePinho RA. Cellular senescence: mitotic clock or culture shock. Cell. 2001, 102, 407-410.
51. Wright WE and Shay JW. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr Opin Genet. Dev. 2001, 11, 98-103.
52. Sage J, et al. Target disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev. 2000, 14, 3037-3050.
53. Dannenberg JH, van Rossum A, Schujiff L and te Riele H. Ablation of the retinoblastoma protein gene family deregulates G1 control causing immrtalization and increased cell turnover under growth-restricting conditions. Genes Dev. 2000, 14, 2051-3064.
54. Peeper DS, Dannenberg JH, Dourma S, te Riele H and Bernard R. Escape from premature senescence is not sufficient for oncogeneic transformation by Ras. Nature Cell Biol. 2001, 3 198-203.
55. Randle DH, Zindy F, Sherr CJ, Roussel MF. Differential effects of p19(Arf) and p16(Ink4a) loss on senescence of murine bone marrow-derived preB cells and macrophages. Proc Natl Acad Sci U S A. 2001, 98, 9654-9.
56. Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998, 396,: 84-8
57. Brenner AJ, Stampfer MR, Aldaz CM. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene. 1998, 17, 199-205.
58. Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW, Wright WE. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions.Genes Dev. 2001, 15, 398-403.
59. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 1998, 12, 2424-33.
60. de Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ, Lowe SW. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 1998, 12, 2434-42
61. Palmero I, Pantoja C, Serrano M. p19ARF links the tumour suppressor p53 to Ras. Nature.1998, 395, 125-6
62. Radfar A, Unnikrishnan I, Lee HW, DePinho RA, Rosenberg N. p19(Arf) induces p53-dependent apoptosis during abelson virus-mediated pre-B cell transformation. Proc Natl Acad Sci U S A. 1998, 95, 13194-9
63. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997, 88, 593-602.
64. Pies S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, McMahon M, Oren M, McCormick F. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell. 2000, 103, 321-30
65. Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH. p14ARF links the tumour suppressors RB and p53. Nature. 1998, 395, 124-5.
66. Eymin H, Karayan L, Seite P, Brambilla C, Cramnilla E, Larsen CJ and Gazzeri S. Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene. 2001, 20, 1033-1041.
67. Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, Giangrande P, Wu L, Saavedra HI, Field SJ, Thompson MA, Yang H, Fujiwara Y, Greenberg ME, Orkin S, Smith C, Nevins JR. Myc requires distinct E2F actives to induce S phase andapoptosis. Mol Cell. 2001, 8, 105-113.
68. Khan SH, Moritsugu J, Wahl GM. Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Proc Natl Acad Sci U S A. 2000, 97, 3266-71
69. Kastan MB and Lim D. The many substrates and functions of ATM. Nature Rev Cell Biol. 2000, 1, 179-186.
70. Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, Moas M, Buschmann T, Ronai Z, Shiloh Y, Kastan MB, Katzir E, Oren M. ATM-dependent phosphorylation of Mdm2 on serine 395: role of p53 activation by DNA damage. Genes Dev. 2001, 15, 10567-1077.
71. Lin WC, Lin FT, and Nevins JR. Selective induction of E2F1 in response to DNA damage mediated by ATM dependent phosphorylation. Gene Dev. 2001, 15, 1833-1844.
72. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999, 13, 2678-90
73. Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999, 13, 2207-2217.
74. Jacobs JJ, Keblusek P, Robanus-Maandag E, Kristel P, Lingbeek M, Nederlof PM, van Welsem T, van de Vijver MJ, Koh EY, Daley GQ, van Lohuizen M. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet. 2000, 26, 291-9
75. Pantoja C and Serrano M. Murine fibroblasts lacking undergo senescence and are resistanct to transformation by oncogene Ras. Oncogene. 1999, 18, 4974-4982.
76. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 1998, 95, 8292-7
77. Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH, Peters G. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998, 17, 5001-14
78. Robertson KD and Jones PA. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Molecullar and Cellular Biology 1998; 18: 6457-6473.
79. Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev. 2000, 14, 2358-65
1. Shenk T. Adenovidae: The viruses and their replication in : Field Virology third edition. B. N. Fields et al. eds. Lippincot-Raven Publisher, Philadephia, 1996 2111-2148
2. Bergelson JM, Cunnunghan JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwita MS, Crowell RL, Finberg RW. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science. 1997, 275, 1320-1323.
3. Amberg N, Edlund K, Kidd AH, Wadell G. Adenovirus type 37 uses sialic acid as a cellular receptor. J virol, 2000, 74, 42-48.4. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR. Intergins avβ3 and avβ5 promote adenovirus internalization but not virus attachment. Cell. 1993, 75, 477-486.
5. Greber UF, Willetts M, Webster P, Helenius A. Stepwise dismantling of adenovirus 2 during entry into cells. Cell. 1993, 75, 477-489.
6. Graham FL, Prevec L. Manipulation of adenovirus vectors. In: Methods in Molecular Biology. Murray EJ, Clifton NJ eds. Humana Press Inc, NJ, USA, 1991, 109-128.
7. Arnalfitano A, Hauser MA, Hu H, Serra D, Begy CR, Chamberlain JS. Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted. J Virol. 1998, 72, 926-33.
8. Kochanek S. High-capacity adenoviral vectors for gene transfer and somatic gene therapy. Hum Gene Ther. 1999, 10, 2451-2459.
9. Russell WC. Update on adenovirus and its vectors. J Gen Virol. 2000, 81, 2573-2504.
10. Steinwaerder DS, Carlson CA, Lieber A. Generation of adenovirus vectors devoid of all viral genes by recombination between inverted repeats. J Virol. 1999, 73, 9303-13.
11. Reynolds PN, Feng M, Curiel DT. Chimeric viral vectors-the best of both world? Mol Med Tody. 1999, 5, 25-31.
12. Golubev DB, Zalkind SIa, Selivanov AA, Deriabina IS, Fokina AM, Zvereva EP. Comparative characteristics of histochemical and biochemical changes in tissue cultures infected by adenoviruses Biull Eksp Biol Med. 1967, 63, 44-8.
13. Todryk SM, Chong H, Vile RG, Pandha H, Lemoine NR. Can immunotherapy by gene transfer tip the balance against colorectal cancer?. Gut. 1998, 43, 445-449.
14. Bodey B, Bodey B Jr, siegel SE, Kaiser HE. Failure of cancer vaccines: The significant limitations of this approach to immunotherapy. Anticancer Res. 2000, 20, 2665-2676
15. Geutskens SB, van der Eb MM, Plomp AC, Jonges LE, Cramer SJ, Ensink NG, Kuppen PJ, Hoeben RC. Recombinant adenoviral vectors have adjuvant activity andstimulate T cell responses against tumor cells. Gene Ther. 2000, 7, 1410-6.
16. Ostrand-Rosenberg S, Thakur A, Clements V. Rejection of mouse sarcoma cells after transfection of MHC class II genes. J Immunol, 1990, 144, 4068-4071.
17. Putzer BM, Hitt M, Muller WJ, Emtage P, Gauldie J, Graham FL. Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression. Proc Natl Acad Sci U S A. 1997, 94, 10889-94
18. Nabel G J, Nabel EG, Yang ZY, Fox BA, Gao X, Huang L, Shu S, Gordon D, Chang AE. Director gene transfer with DNA-liposome complexes in melanoma: Expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci USA. 1993, 90, 11307-11311.
19. Gonzalez R, Atkins M, Schwarzenberger P, Lutzky J, Rublin J, Deisseroth A, Blum A, Glutheil, HutchinsL. Phase II trial of HLA-B7 plasmid DNA/lipid (Allovectin) immunotherapy in patients with metastatic melanoma. Proc Am Soc Clin Oncol. 2001, 20, Asb 1007.
20. Harris MP, Sutjipto S, Wills KN, Hancock W, Cornell D, Johnson DE, Gregory RJ, Shepard HM, Maneval DC. Adenovirus-mediated p53 gene transfer inhibits growths of human tumor cells expressing mutant p53 protein. Cancer Gene Ther. 1996, 3, 121-130.
21. Nishizaki M, Fujiwara T, Tanida T, Hizuta A, Nishimori H, Tokino T, Nakamura Y, Bouvet M, Roth JA, Tanaka N. Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect. Clin Cancer Res. 1999, 5, 1015-23.
22. Venook AP, Bergsland EK, Ring E, Nonaka-Wong S, Horowitz JA, Rybak ME, Warren RS. Gene therapy of colorectal liver metasrasis using recombinant adenovirus encoding wt p53 (SCH 58500) via hepatic artery infusion: A phase I study. Proc Am Soc Clin Oncol. 1998, 17, Abs 1661.
23. Cohen AM, Kemeny Ne, Kohne CH, Wils J, de Takats PG, Kerr DJ. Is intra-chemotherapy worthwhile in the treatment of patients with unresectable hepaticcolorectal cancer metastasis? Eur J Cancer. 1996, 321: 2195-2205.
24. Hao Z, Rowinsky EK, Smerzer LZ, Ochoa L, Hammond LA, Gamer A, Smith L, Parker, Merritt JA, Tolcher AW. A phase I and pharmacokinetics study of intravenous (IV) o53 gene therapy for with RPR//NGN-201 in patients with advanced cancer. Proc Am Soc Clin Oncol. 2001, 20, Abs 1045.
25. Nguyen DM, Spitz FR, Yen N, Cristain RJ, Roth JA. Gene therapy for lung cancer: Enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer. J Thorac Cardiovasc Surg. 1996, 112, 1372-1376.
26. Roth JA, Swisher SG, Meyn RE. p53 rumor suppressor gene therapy for cancer. Cancer Res, 2001, 61, 1796-1798.
27. Jiang GL, Huang S. Adenovirus expressing RIZ1 in tumor suppressor gene therapy of microsatellite-unstable colorectal cancers. Cancer Res. 2001, 61, 1796-8.
28. Xu G, McLeod HL. Strategies for enzyme/prodrug cancer therapy. Clin Cancer Res. 2001, 7, 3314-24.
29. Kuriyama S, Kikukawa M, Masui K, Okuda H, Nakatani T, Sakamoto T, Yoshiji H, Fukui H, Ikenaka K, Mullen CA, Tsujii T. Cytosine deaminase/5-fluorocytosine gene therapy can induced efficient anti-tumor effects and protective immunity in immunocompetent mice but not in athymic nude mice. Int J Cancer. 2001, 67, 1165-1173.
30. Link CJ, Levy JP, McCann LZ, Moorman DW. Gene therapy for colon cancer with the herpes simplex thymidine kinase gene. J Surr Oncol. 1997, 64, 289-294
31. Sandmire AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M, Hurskainen H, Tyynela K, Turunen M, Vanninen R, Lehtolainen P. Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses for adenoviruses. Hum Gene Ther. 2000, 11, 2197-2205.
32. Sung MW, Yeh HC, Thung SN, Schwartz ME, Mandeli JP, Chen SH, Woo SL. Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases fromcolorectal adenocarcinoma: results of a phase I clinical trial. Mol Ther. 2001, 4, 182-91.
33. Huber BE, Austin EA, Richard CA, Davis ST, Good SS. Metabolism of 5-flurocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: Singnificant antitumot effects when only small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA. 1994, 91, 8302-8306.
34. Chung-Faye GA, Chen M J, Green NK, Burton A, Anderson D, Mautner V, Searle PF, Kerr DJ. In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase. Gene Ther. 2001, 8: 1547-1554.
35. Topf N, Worgall S, Hackett NR, Crystal RG. Regional ‘pro-drug' gene therapy: intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinoma. Gene Ther. 1998, 5, 507-13.
36. Green NK, Youngs DJ, Neoptolemos JP, Friedlos F, Knox RJ, Springer CJ, Anlezark GM, Michael NP, Melton RG, Ford MJ, Young LS, Kerr DJ, Searle PF. Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5-(aziridin-l-yl)-2,4-dinitrobenzamide (CB1954) by retroviral transduction and expression of the E. coli nitroreductase gene. Cancer Gene Ther. 1997, 4, 229-38.
37. Palmer DH, Mautner V, Mirza D. Virus-directed enzyme prodrug therapy (VDEPT): Clinical trial with adenoviral nitroimidazole reductase (ad-ntr). Br J Cancer. 2002, 86, 530.
38. Biscoff JR, KimDH, Heise C, Hom S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 1996, 274, 373-376.
39. Rothmann T, Hengstermarm A, Whitaker NJ, Scheffner M, zur Hausen H. Replication ONYX-015, a potential anticancer adenovirus, si independent pf p53status in tumor cells. J Virol, 1998, 72, 9470-9478.
40. Ries S J, Brandts CH, Chung AS, Biederer CH, Hann BC, Lipner EM, McCormick F, Korn WM. Loss of p14ARF in tumor cell facilitates replication of the adenovirus mutant d1 1520(ONXY-015). Nat Med. 2000, 6, 1128-1133.
41. Habib NA, Sarraf CE, Mitry RR, Havlik R, Nicholls J, Kelly M, Vernon CC, Gueret-Wardle D, E1-Masry R, Salama H, Ahmed R, Michail N, Edward E, Jensen SL. E1B-deleted adenovirus (d11520) gene therapy for patients with primary and secondary liver tumors. Hum Gene Ther. 2001, 12, 219-26.
42. Habib NA, Sarraf CE, Mitry RR, Havlik R, Nicholls J, Kelly M, Vernon CC, Gueret-Wardle D, E1-Masry R, Salama H, Ahmed R, Michail N, Edward E, Jensen SL. E1B-deleted adenovirus (d11520) gene therapy for patients with primary and secondary liver tumors. Hum Gene Ther. 2001, 12, 219-26.
43. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Talmock IF, Romel L, Gore M, Ironside J, MacDougall TH, Heise C, Randlev B. A controlled trial of intratumoral ONXY-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patient with recurrent head and neck cancer. Nat/reed. 2000, 6, 879-885.
44. Komberg RD, Lroch Y. Chromatin-modifying and-remodeling complexes. Curr Opin Genet Dev. 1999, 9, 148-151.
45. Gaetano C, Catalano A, Palumbo R, Illi B, Orlando G, Ventoruzzo G, Serino F, Capogrossi MC. Transcriptionally active drugs improve adenovirus vector performance in vitro and in vivo. Gene Ther. 2000, 7, 1624-30.