跳到主要內容

臺灣博碩士論文加值系統

(18.208.126.232) 您好!臺灣時間:2022/08/12 01:57
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:林佳穎
研究生(外文):Chia-Ying Lin
論文名稱:併用細胞生長抑制因子及化療藥物於腫瘤治療之研究
論文名稱(外文):Studies on Combination Treatment Using Cytostatic Agents and Chemotherapy Drugs for Cancer Therapy
指導教授:杜杰憲戴明泓
指導教授(外文):Chieh-Hsien TuMing-Hong Tai
學位類別:碩士
校院名稱:國立屏東科技大學
系所名稱:獸醫學系
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:69
中文關鍵詞:雞母珠
外文關鍵詞:ABR-ATAT-ABR-Aabrin
相關次數:
  • 被引用被引用:1
  • 點閱點閱:389
  • 評分評分:
  • 下載下載:115
  • 收藏至我的研究室書目清單書目收藏:0
摘要
傳統之腫瘤治療方式主要有外科手術,化學療法及放射線療法,但治癒率不高而且容易產生副作用及併發症;現今之腫瘤治療以合併治療的方式,比起單獨使用某一方式治療來得有效且可以減低副作用之產生。因此,我們利用一種不同於傳統之腫瘤治療藥物,並合併化療藥物,來進行腫瘤之治療研究,期能找到一種有效且低副作用之腫瘤治療方式。在本研究中,我們將台灣本土之雞母珠毒蛋白(abrin)的毒性A chain基因與愛滋病毒 (human immunodeficiency virus; HIV) 之TAT (transcription activator) 的蛋白傳送區 (protein transduction domain; PTD) 基因進行融合,於大腸桿菌表現與純化後,獲得到TAT-ABR-A 重組蛋白。另外,我們也以限制酶將TAT-ABR-A 之TAT切除,然後表現並純化得ABR-A。 經SDS-PAGE 與西方點漬分析後, 將TAT-ABR-A 或ABR-A等重組蛋白加入肺癌細胞 (Lewis lung carcinoma cell; LLC) 及內皮細胞 (bovine aortic endothelial cell; BAEC) 的培養液中。發現這些重組蛋白均能改變細胞形態,抑制細胞增生,甚至誘發細胞死亡。以Hoechst染色TAT-ABR-A或ABR-A處理之細胞發現細胞核呈現染色體萎縮 (chromosome condensation)或DNA斷裂(DNA fragmentation),部分細胞有分裂延遲的現象。流式細胞儀分析發現TAT-ABR-A處理明顯增加 sub-G0/G1期之細胞,並改變G0/G1與 S/G2M等細胞週期分布。以西方點漬分析也發現TAT-ABR-A較ABR-A顯著減少bcl-2,cdk-1,及cdk-2 的細胞表現量,由上列研究顯示 TAT-ABR-A 不僅會造成細胞凋亡(apoptosis) 而且會造成細胞分裂延遲。此外,這些結果亦證實TAT-ABR-A抑制細胞生長之能力約為ABR-A之5-10倍強。蛋白合成分析顯示TAT-ABR-A 與 ABR-A 抑制蛋白合成之能力相似。另外,抗氧化劑能緩解TAT-ABR-A 或 ABR-A對細胞增生之抑制作用,顯示兩者造成細胞死亡之機轉均與過氧化物產生有關。利用FITC (fluorescein isothiocyanate) 蛋白結合實驗發現TAT-ABR-A 之FITC 結合蛋白在加入培養液半小時內便能有效被細胞吸收,而加入ABR-A 之FITC 結合蛋白則未發現細胞內顯著螢光,証實TAT-ABR-A較ABR-A更能有效進入細胞。TAT-ABR-A能增加cisplatin 對LLC之生長抑制效應。我們利用動物實驗評估ABR-A,TAT-ABR-A,及化療藥物cisplatin對動物腫瘤模式之單獨或合併治療效果。 發現單獨注射TAT-ABR-A或ABR-A蛋白無法明顯減緩小鼠身上之腫瘤生長。然而,合併TAT-ABR-A 及cisplatin兩種藥物治療之小鼠的腫瘤較其他實驗組明顯縮小。小鼠體重變化指出注射TAT-ABR-A或ABR-A 蛋白未影響化療藥物cisplatin所造成之副作用。總結來說,我們利用基因工程技術生產出具功能性之毒性重組蛋白,並利用這些重組蛋白完成細胞訊息傳導與動物癌症抑制之研究。

Abstract
The major procedures for cancer therapy include surgery, chemotherapy and ionizing radiation therapy. However, none of these approaches were completely effective. Besides, they frequently caused severe side effects and serious complication during clinical application. Therefore, the development of combinatory therapy using chemotherapy drugs and novel anti-cancer agents is highly demanded, which would improve the therapeutic efficacy while minimizing undesired effects. In present study, we produced recombinant cytotoxic A chain of abrin (ABR-A) as well as its fusion form with cell-penetrating peptide TAT (TAT-ABR-A). After expression and purification, the molecular weight of recombinant ABR-A and TAT-ABR-A were determined at 32 and 34 kDa, respectively. ABR-A and TAT-ABR-A exhibited differential abilities in inhibiting the proliferation of Lewis lung carcinoma cells (LLC) and bovine aortic endothelial cell (BAEC). Nucleus staining indicated treatment of cells with TAT-ABR-A resulted in chromosome condensation, DNA fragmentation, and attenuated mitosis. Flow cytometry analysis revealed the TAT-ABR-A increased the number of cells in sub-G0/G1. TAT-ABR-A decreased the levels of bcl-2, cdk-1, and cdk-2 as revealed by western blot analysis. Together, these results indicated the potency of TAT-ABR-A in inhibiting cell proliferation is 5-10 folds higher than ABR-A. In rabbit reticulocyte translation system, the efficacy of TAT-ABR-A in inhibition of protein synthesis is similar to that of ABR-A. Furthermore, pretreatment with antioxidants such as superoxide dismutase- (SOD) or N-acetyl-L-cysteine (NAC) attenuated the cytotoxicity of TAT-ABR-A and ABR-A, indicating generation of reactive oxygen species participated in the cytotoxic mechanism of both proteins. By chemical conjugation with FITC (fluorescein 5-isothiocyanate), cellular uptake of TAT-ABR-A was detected within less than 30 min, whereas there was no significant uptake of ABR-A even after 16 h. These data indicated that fusion with TAT promoted the entry and increased the cytotoxicity of ABR-A. Subsequently, we analyzed the efficacy of cisplatin on LLC proliferation in the presence of TAT-ABR-A or ABR-A, and found that TAT-ABR-A significantly enhanced the cytotoxicity of cisplatin. The combinatory effect of TAT-ABR-A or ABR-A with cisplatin was evaluated in Lewis lung carcinoma grown in C57BL/6 mice, in which the tumors were grown to ~100 mm3 before treatment. Administration of TAT-ABR-A or ABR-A alone had no significant inhibitory effect on tumor growth. However, the combination therapy using TAT-ABR-A and cisplatin significantly reduced the tumor growth. Examination of body weight of tumor-bearing mice indicated that the injection of TAT-ABR-A or ABR-A did not aggravate the side effects of cisplatin. In summary, we demonstrated the feasibility of using genetic engineering techniques to produce biologically functional toxin, ABR-A. Furthermore, the efficacy of this recombinant toxin could be improved through fusion with cell-penetrating peptide. Above all, this improved toxin might be use TAT-ABR-A as adjuvant agents in conjunction with chemotherapy drugs to improve the therapeutic efficacy for treatment of cancer.

Index
Abstract………….…………………………………………………………………………………………………...I
摘要………………………………………………….…………………………………………………………………..…….IV
Acknowledgments…………………………………………………………………………………………….…..VI
Index……………………………………………………………………………………………………………………..…VIII
List of illustrations……………………………………………………………….……………..………………...X
List of tables…………………………………………………………………………………………………….……..XI
Introduction…………………………….…………………………………………………………………..…………..1
Literature review……………………………………………………………………………………………..……4
Endocytosis and Penetration…………………………………………….…………………….……4
Protein Transduction……………………………………………………………………….……….……4
TAT (transactivator of transcription)……….…………………………………..…..…..…....7
PTD (protein transduction domains)……………………………..……………………….…9
ABR-A (abrin subunit A chain)…………………………………………..…………….……..10
Apoptosis (programmed cell death)………………….……………………………….……12
Cancer therapy……………………………………..…………………………….………………………...14
Materials and methods………………………………………………………………………….…..……...15
Expression of TAT-ABR-A and ABR-A in Escherichia coli…….……18
Cell culture……………………………….…………………….………………………………….…….…….19
Proliferation assay………………………..……………………..………………………………….……19
Flow cytometry analysis……………………………………………..……………………….…….20
Hoechst 33258 nuclear staining…………………………………..…………………….……..20
Cell extract and western blot………………………………….…………………………….…...21
MTT assay.…………………………………………………………………..………………………….……..22
Measurement of in vitro protein synthesis inhibition………………….……...22
Fluorescein conjugation……………………………………………………………..……....…..…..23
Mouse studies……………………………………………………………………..………………….……..24
Results………..……………………………………………………………………………………………………..…….25
Construction of E. coli expression plasmids for production
of ABR-A and TAT-ABR-A…….………………………………………………….…..25
Expression and purification of ABR-A and TAT-ABR-A……….………. 25
TAT-ABR-A and ABR-A inhibited the proliferation of
Lewis lung carcinoma cells (LLC) and bovine artery
endothelial cells (BAEC)……………………………………..…………….…….………26
TAT promote entry of ABR-A into cells…………………………….……….……….. 27
TAT-ABR-A and ABR-A induced apoptosis and affected
cell cycle progression in LLC…………………….……………………..…………....27
Reactive oxygen species (ROS) participated in the cytotoxic mechanism of ABR-A and TAT-ABR-A……………………....……..….... 29
TAT-ABR-A and ABR-A inhibited protein synthesis……..…….…...…….30
Combinatory effect of TAT-ABR-A with cisplatin on
proliferation of LLC….…………………….……………………………………….…….…..30
In vivo tumor growth assessment……………….………..…………………………..…..….31
Evaluation of side-effects……………………………….……………………………………...….31
Discussion…………………………………………………………………………….…………………..……………32
Figures and legends………………………………………………………………………………………….. 35
References………….………………………………………………………………………………………..………...55

References
1. Fodstad, Q., Olsnes, S., and Pihl, A. Inhibitory effet of abrin and ricin on the growth of transplantable murine tumors and of abrin on human cancers in nude mice. Cancer Res., 37: 4559-4567, 1977.
2. Scheld, W. M. Drug delivery to the central nervous system: general principles and relevance to therapy for infections of the central nervous system. Rev. Infect. Dis., 11: 1669-1690, 1989.
3. Egleton, R. D. and Davis, T. P. Bioavailability and transport of peptides and peptide drugs into the brain. Peptides, 18: 1431-1439,1997.
4. Mukherjee, S. et al. Endocytosis. Phys. Rev., 77: 760-790, 1997.
5. Ho, A., Schwarze, S. R., Mermelstein, S. J., Waksman, G. and Dowdy F. Synthetic protein transduction domains: enhanced transduction potential in vitro and in vivo. Cancer Research, 61: 474-477, 2001.
6. Green, M., and Loewenstein, P. M. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell, 55: 1179-1188, 1988.
7. Frankel, A. D., and Pabo, C. O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell, 55: 1189-1193, 1988.
8. Vives, E., Brodin, P., and Leblus, B. A truncated tat basic domain rapidly translocates through the plasma membrane and accumulates in the nucleus. J Biol. Chem., 272: 16010-16017, 1997.
9. Nagahara, H., Vocero-Akbani, A. M., Snyder, E. L., Ho, A., Latham, D. G., Lissy, N. A., Becker-Hapak, M., Ezhevsky, S. A., and Dowdy, S. F. Transduction of full length tat fusion proteins into mammalian cells:p27kip1 mediates cell migration. Nat. Med., 4: 1449-1452, 1998.
10. Vocero-Akbani, A., Heyden, N.V., Lissy, N. A., Ratner, L., and Dowdy, S.F. Killing HIV infected cells by direct transduction of an HIV protease-activated caspase-3 protein. Nat. Med., 5: 29-33, 1999.
11. Gius, D., Ezhevsky, S. A., Becker-Hapak, M., Nagahara, H., Wei, M. C., and Dowdy, S. F. Transduced p16INK4a peptides inhibit hypo-phosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of cdk2 complexes in late G1. Cancer Res., 59: 2577-2580, 1999.
12. Schwarze, S. R., Ho, A., Vocero-Akbani, A., and Dowdy, S. F. In vivo protein transduction: delivery of biologically active protein into the mouse. Science, 285: 1569-1572, 1999.
13. Schwarze, S. R., Hruska, K. A., and Dowdy, S.F. Protein transduction: unrestricted delivery into all cells? Trends Cell Biol., 10: 290-295, 2000.
14. Hawiger, J. Noninvasive intracellular delivery of functional peptides and proteins. Curr. Opin. Chem. Biol., 3: 89-94, 1999.
15. Lindgren, M., Hallbrink, M., Prochiantz, A., and Langel U. Cell-penetrating peptides. Trends Pharmacol. Sci., 21: 99-103, 2000.
16. Ruben, S. et al. Structural and functional characterization of human immunodeficiency virus Tat protein. J. Virol., 63: 1-8, 1989.
17. Vogel, B. E. et al. A novel integrin specificity exemplified by binding of the ανβ5 integrin to the basic domain of the HIV Tat protein and vitronectin. J. Cell Biol.,121: 461-468, 1993.
18. Ensoli, B. et al. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J. Virol., 67: 277-287, 1993.
19. Derossi, D., Calvet, S., Trembleau, A., Brunissen, A., Chassaing, G. and Prochiantz, A. Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J. Biol. Chem., 271: 18188-18193, 1996.
20. Ezhevsky S. A., Nagahara, H., Vocero-Akbani, A.M., Gius, D.R., Wei, M.C. and Dowdy, S.F. Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb. Proc. Natl. Acad. Sci. U.S.A., 94, 10699, 1997.
21. Lissy, N. A. et al. TCR-antigen induced cell death (AID) occurs from a late G1 phase cell-cycle check point. Immunity, 8: 57-65, 1998.
22. Jeang, K. T., Xiao, H. and Rich, E. A. Multifaceted activities of the HIV-1 transactivator of transcription, Tat. J. Biol. Chem., 274: 28837-28840, 1999.
23. Vives, E., Granier, C., Prevot, P. and Leblue, B. Lett. Pept. Sci. 4: 429-436, 1997.
24. Pepinsky, R. B., Androphy, E.J., Corina, K., Brown, R. and Barsoum, J. Specific inhibition of a human papillomavirus E2 trans-activator by intracellular delivery of its repressor. DNA Cell Biol., 13: 1011-1019, 1994.
25. Fawell, S., Seery, J., Daikh, T., Moore, C., Chen, L. L., Pepinsky, B. and Barsoum, J. Tat-mediated delivery of heterologous protein into cells. Proc. Natl. Acad. Sci. USA., 91: 664-668, 1994.
26. Anderson, D. C., Nichols, E., Manger, R., Woodle, D., Barry, M. and Fritzberg, A. R. Tumor cell retention of antibody Fab fragments is enhanced by an attached HIV TAT protein-derived peptide. Biochem. Biophys. Res. Commun., 194: 876-884, 1993.
27. Kim, D. T., Mitchell, D. J., Brockstedt, D. G., Fong, L., Nolan, G. P., Fathman, C. G., Engelman, E. G. and Rothbard, J. B. Introduction of soluble proteins into the MHC class I pathway by conjugation to an HIV tat peptide. J. Immunol., 159: 1666-1668, 1997.
28. Derossi, D., chasseing, G. and Prochiantz, A. Trojan peptides: the penetratin system for intracellular delivery. Trends Cell Biol., 8:84-87, 1998.
29. Lin, Y.-Z., Yao, s., Veach, R. A., Torgerson, T. R. and Hawiger, J. Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J. Biol. Chem., 270: 14255-14258, 1995.
30. Pooga, M., Hallbrink, M., Zorko, M. and Langel, U. Cell penetration by transportan. FASEBJ, 12: 67-77, 1998.
31. Elliott, G. and O’Hare, P. Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell, 88: 223-233, 1997.
32. Wender, P. A., Mitchell, D. J., Pattabiraman, K., Pelkey, E. T., Steinman, L. and Rothbard J. B. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters. Proc. Natl. Acad. Sci. U.S.A., 97: 13003-13008, 2000.
33. Anderson, W. F. Human gene therapy. Nature, 392: 25-30, 1998.
34. Bar-Sagi, D. Mammalian cell microinjection assay. Meth. Enzymol., 255: 436-442, 1995.
35. Schwarze, S. R. and Dowdy, S. F. In vivo protein transduction: intracellular delivery of biologically active proteins, compounds and DNA. Trends Pharmacol. Sci., 21: 45-48, 2000.
36. Ford, K. G., Souberbielle, B. E., Darling, D. and Farzaneh, F. Protein transduction: an alternative to genetic intervention? Gene Ther., 8: 1-4, 2001.
37. Prochiantz, A. Messenger proteins: homeoproteins, TAT and others. Curr. Opin. Cell Biol., 12: 400-406, 2000.
38. Mann, D. A. and Frankel, A. D. Endocytosis and targeting of exogenous HIV-1 Tat protein. EMBO J., 10: 1733-1739, 1991.
39. Morris, M. C., Depollier, J., Mery, J., Heitz, F. and Divita, G. A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nature Biotechnology, 19: 1173-1176, 2001.
40. Lin, J. Y., Lee, T. C., Hu. S. T. and Tung, T. C. Isolation of four isotoxic proteins and one agglutinin from jequiriti bean (Abrus precatorius). Toxicon, 19: 41-51, 1981.
41. Lin, J. Y., Tserng, K. Y., Chen, C. C., Lin, L. T., and Tung, T. C. Abrin and ricin: new anti-tumour substances. Nature, 227: 292-293, 1970.
42. Olsnes, S. and Pihl, A. Isolation and properties of abrin: a toxic protein inhibiting protein synthesis. Evidence for different biological functions of its two constituent-peptide chains. Eur. J. Biochem., 35: 179-185, 1973.
43. Stripe, F., Barbieri, L., Battelli, M. G., Soria, M. and Lappi, D. A. Ribosome-inactivating proteins from plants: present status and future prospects. BioTechnology, 10: 405-412, 1992.
44. Nicolson, G. l., AND Blaustein, J. The interaction of Ricinus communis agglutinin with normal and tumor cell surfaces. Biochim. Biophys. Acta, 266: 543-547, 1972.
45. Wu, A M., Watkins, W. M., Chen, C. P., Song, S. C., Chow, L. P. and Lin, J. Y. Native and/or asialo-Tamm-Horsfall glycoproteins Sd(a+) are important receptors for Triticum vulgaris (wheat germ) agglutinin and for three toxic lectins (abrin-a, ricin and mistletoe toxic lectin-I). FEBS Lett., 371: 32-34, 1995.
46. Baenziger, J. U., and Fiete, D. Structural determinants of Ricinus communis agglutinin and toxin specificity for oligosaccharides. J. Biol. Chem., 254: 9795-9799, 1979.
47. Ma, X. Q., Wang, Y. P., and Wang, J. H. An X-ray analysis of the orthorhombic crystal form of trichosanthin at 5 angstrom. Sci. Sin. Ser., B30: 692-697, 1987.
48. Huang, Q., Liu, S., Tang, Y., Jin, S., and Wang, Y. Studies on crystal structures, active-centre geometry and depurinating mechanism of two ribosome-inactivating proteins. Biochem. J., 309: 285-298, 1995.
49. Endo, Y., Mitsui, K., Motizuki, M. and Tsurugi, K. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. The site and the characteristics of the modification in 28 S ribosomal RNA caused by the toxins. J. Biol. Chem., 262: 5908-5912, 1987.
50. Hung, C. H., Lee, M. C., Chen, J. K. and Lin, J. Y. Primary structure of three distinct isoabrins determined by cDNA sequencing. Conservation and significance. J. Mol. Biol., 229: 263-267, 1993a.
51. Hung, C. H., Lee, M. C., Chen, J. K. and Lin, J. Y. Cloning and expression of three abrin A-chains and their mutants derived by site-specific mutagenesis in Escherichia coli. Eur. J. Biochem., 219: 83-87, 1994.
52. Hudson, T. H. and Grillo, F. G. Brefeldin-A enhancement of ricin A-chain immunotoxins and blockade of intact ricin, modeccin, and abrin. J. Biol. Chem., 266: 18586-18592, 1991.
53. Lambert, J. M., Goldmacher, V. S., Collinson, A. R., Nadler, L. M. and Blattler, W. A. An immunotoxin prepared with blocked ricin: a natural plant toxin adapted for therapeutic use. Cancer Res., 51: 6236-6242, 1991.
54. Barbieri, L., Battelli, M. G. and Stripe, F. Ribosome-inactivating proteins from plants. Biochim. Biophys. Acta, 1154: 237-282, 1993.
55. Eiklid, K., Olsnes, S. and Pihl, A. Entry of lethal doses of abrin, ricin and modeccin into the cytosol of HeLa cells. Exp. Cell Res., 126: 321-326, 1980.
56. Sandvig, K. and Deurs, B. Toxin-induced cell lysis: protection by 3-methyladenine and cycloheximide. Exp. Cell Res., 200: 253-262, 1992.
57. Geier, A., Bar-shalom, I., Beery, R., Haimsohn, M., Hemi, R., Malik, Z., Lunenfeld, B., and Karasik, A. Induction of apoptosis in MDA-231 cells by protein synthesis inhibitors is suppressed by multiple agents. Cancer Invest., 14: 435-444, 1996.
58. Komatsu, N., Oda, T., and Muramatsu, T. Involvement of both caspase-like proteases and serine proteases in apoptotic cell death induced by ricin, modeccin, diphtheria toxin, and pseudomonas toxin. J. Biochem. (Tokyo), 124: 1038-1044, 1998.
59. Keppler-Hafkemeyer, A., Brinkmann, U., and Pastan, I. Role of caspases in immunotoxin-induced apoptosis of cancer cells. Biochemistry, 37: 16934-16942, 1998.
60. Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., Watson, J.D. Molecular Biology of the Cell. Third Edition. (1991).
61. Jacobson, M.D. , Weil, M. and Raff, M.C. Programmed cell death in animal development. Cell, 88: 347-354, 1997.
62. Nicholson, D.W., Ali, A. Thornberry, N.A., Vaillancourt, J.,Ding, C.K, Gallant, M., Gareau, Y., Griffin, P.R., Labelle, M., Lazebnik Y.A., Munday, N.A., Raju, M., Smulson, M.E., Yamin, T.T., Yu, V.L., and Miller, D.K. Identification and inhibition of the ICE/CED3 protease necessary for mammalian apoptosis. Nature, 376: 37-43, 1995.
63. Zamzami, N., Susin, A., Marchetti, P., Hirsch, T., Gomez-Monterrey, I., Castedo, M., and Kroemer, G. Mitochondrial control of nuclearapoptosis. J. Exp. Med., 183, 1533—1544, 1996.
64. Earnshaw, W. C., Martins, L. M., Kaufmann, S. H. MAMMALIAN CASPASES: Structure, Activation, Substrates, and Functions During Apoptosis. Annu. Rev. Biochem., 68: 383-424, 1999.
65. Steller, H. Mechanisms and genes of cellular suicide. Science, 267: 1445-1449, 1995.
66. Parrizas, M., Saltiel, A. R., and Leroith, D. Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. J. Biol. Chem., 272: 154-161, 1997.
67. Ivanov, V.N., and Ronai, Z. Down-regulation of tumor necrosis factor alpha expression by activating transcription factor 2 increases UVC-induced apoptosis of late-stage melanoma cells. J. Biol. Chem., 274: 14079-14089, 1999.
68. Zhuang, L., Wang, B., Shinder, G. A., Shivji, G. M., Mak, T. W., and Sauder, D. N. TNF receptor p55 plays a pivotal role in murine keratinocyte apoptosis induced by ultraviolet B irradiation. J. Immunol., 162: 1440-1447, 1999.
69. Green, D. R., and Reed, J. C. Mitochondria and apoptosis. Science, 281: 1309-1312, 1998.
70. Thormberry, N. A., and Lazebnik, Y. Caspases: enemies within. Science, 281: 1312-1316, 1998.
71. Buttke, T. M., and Sandstrom, P. A. Oxidative stress as a mediator of apoptosis. Immunol. Today, 15: 7-10, 1994.
72. Jacobson, M. D. Reactive oxygen species and programmed cell death. Trends. Biochem. Sci., 21: 83-86, 1996.
73. Karbowski, M., Kurono, C., Wozniak, M., Ostrowski, M., Teranishi, M., Soji, T., and Wakabayashi, T. Cycloheximide and 4-OH-TEMPO suppress chloramphenicol-induced apoptosis in RL-34 cells via the suppression of the formation of megamitochondria. Biochim. Biophys. Acta, 1449: 25-40, 1999.
74. Li, P. F., Dietz, R., and von Harsdorf, R. Superoxide induces apoptosis in cardiomyocytes, but proliferation and expression of transforming growth factor-beta1 in cardiac fibroblasts. FEBS Letters, 448: 206-210, 1999.
75. Ye, J., Wang, S., Leonard, S. S., Sun, Y., Butterworth, L., Antonini, J, Ding, M., Rojanasakul, Y., Vallyathan, V., Castranova, V., and Shi, X. Role of reactive oxygen species and p53 in chromium(VI)-induced apoptosis. J. Biol. Chem., 274: 34974-34980, 1999.
76. Bohler, T., Waiser, J., Hepburn, H., Gaedeke, J., Lehmann, C., Hambach, P., Budde, K., and Neumayer, H. H. TNF-alpha and IL-1alpha induce apoptosis in subconfluent rat mesangial cells. Evidence for the involvement of hydrogen peroxide and lipid peroxidation as second messengers. Cytokine, 12: 986-991, 2000.
77. Liu, H., Nishitoh, H., Ichijo, H., and Kyriakis, J. M. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol. Cell Biol., 20: 2198-2208, 2000.
78. Stein, G and Oystein, F. Treatment of micrometastases from Lewis lung carcinoma with abrin and cyclophosphamide, given singly and in combination. Int. J. Cancer, 23: 530-535, 1979.
79. Anderson, L. C., Shipp, M. A., Docherty, A. J. P., and Teicher, B. A. Combination therapy including gelatinase inhibitor and cytotoxic agent reduces local invasion and metastasis of murine Lewis lung carcinoma. Cancer Research, 56: 715-718, 1996.
80. Maucerl, H. J. et al. Combined effects of angiostatin and ionizing radiation in antitumor therapy. Nature, 394: 287-291, 1998
81. Van Moorsel, C. J. A., Pinedo, H. M., Veerman, G, Bergman, A. M., Kuiper, C. M., Vermorken, J. B., van der Vijgh, W. J. F. and Peters. G. J. Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines. British Journal of Cancer, 80: 981-990, 1999.
82. Klement, G., Baruchel, S., Rak, J., Man, S., Clark, K., Hicklin, D. J., Bohlen, P., and Kerbel, R. S. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest., 105: R15-R24, 2000.
83. Yao, L., Pike, S. E., Setsuda, J., Parekh, J., Gupta, G., Raffeld, M., Jaffe, E. S., and Tosato, G. Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12. Blood, 96: 1900-1905, 2000.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top