【网学提醒】：本文主要为网上学习者提供消化系统癌肿的自杀基因疗法，希望对需要消化系统癌肿的自杀基因疗法网友有所帮助，学习一下吧!
资料包括： 论文(13页11439字)
说明：
关键词： 消化系统肿瘤/治疗,自杀基因,基因疗法
Subject headings digestive system neoplasms/therapy; suicide gene; gene therapy
在恶性肿瘤的各种基因治疗中，自杀基因(suicide gene)/前药(prodrug)系统备受关注. 目前已在多种肿瘤进行大量临床前研究，有的已进入Ⅰ/Ⅱ期临床试验. 该疗法对消化系肿瘤的治疗作用，业已得到证明［1］. 不管哪一种自杀基因/前药系统，均需有下列3个成分：①能编码一种酶的自杀基因：该基因通常来源于病毒或真核细胞，其编码的酶能将无毒的前药转变为活性毒物，引起靶细胞死亡；在缺乏前药的条件下，该种基因的表达对机体无害；该基因编码的酶对基质(前药)应具有高度催化效能(高Kcat)［2］. ②基因转移载体(gene-transfer Vectors)：为了转移自杀基因至靶细胞，一般采用基因工程改造的逆转录病毒(retroviruses)、腺病毒(adenoviruses)和腺病毒相关性病毒(adenovirus-associated viruses)作为载体［3］. 也有人采用阳离子脂质体作为载体，发现其对内皮细胞有高度亲和力［4］. 基因转移的关键是其靶向性(targeting)［5］. 如将甲胎蛋白(AFP)启动子和清蛋白增强子(Alb)TRS连接自杀基因，则后者便仅于表达AFP的肝癌细胞中表达，而不影响正常肝细胞［6］. ③能被自杀基因编码的酶作用的前药(prodrug)：这种前药在自杀基因不存在时，对机体无毒或仅有微小毒性，而在自杀基因编码的酶特异性作用下，前药转化为活性药物，后者的细胞毒性较无活性的前药至少强100倍.
目录：
1 自杀基因/前药系统
2 作用机制
3 消化系肿瘤的治疗
4 问题和前景
参考文献：
1 Morris JC, Touraine R, Wildner O, Blaese RM. Suicide genes: gene therapy applications using enzyme/prodrug strategies. in: the development of human gene therapy. Cold Spring Harbor Laboratory Press. 1999:477-526
2 Connors TA. The choice of prodrugs for gene directed enzyme prodrug therapy of cancer. Gene Ther, 1995;2:702-709
3 Wilson JM. Vectors-shuttle vehicles gor gene therapy. Clin Exp Immunol, 1997;1:31-32
4 Fife K, Bower M, Cooper RG, Stewart L, Etheridge CJ, Coombel RC, Buluwela L. Endothelial cell transfection with cationic liposomes and herpes simplex-thymidine kinase mediated killing. Gene Ther, 1998;5:614-620
5 Dachs GU, Dougherty GJ, Stratford IJ, Chaplin DJ. Targeting gene therapy to cancer: a review. Oncol Res, 1997;9:313-325
6 Su H, Lu R, Chang JC, Kan YW. Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice. Proc Natl Acad Sci USA, 1997;94:13891-13896
7 Haynes P, Lambert TR, Mitchell ID. Comparative in vivo genotoxicity of antiviral nucleoside analogues; penciclovir, acyclovir, ganciclovir and xanthine analogue, caffeine, in the mouse bone marrow micronucleus assay. Mutat Res, 1996;369:65-74
8 Thurst R, Schacke M, Wutzler P. Cytogenic genetoxicity of the antiherpes virostatics in Chinese hamster V79-E cells. I. Purine nucleoside analogues. Antivi Res, 1996;31:105-113
9 Hakumaki JM, Poptani H, Paumalainen AM, Loimas S, Paljarvi LA, Yla-Herttuala S, Kauppinen RA. Quantilative 1H nuclear magnetic resonance diffusion spectroscopy of BT 4C rat glioma during thymidine kinase-mediated gene therapy in vivo: identification of apoptotic response. Cancer Res, 1998;58:3791-3799
10 Wei SJ, Chao Y, Hung YM, Lin WC, Yang DM, Shih YL, Chang LY. S-and G2 phase cell cycle arrests and apoptosis induced by ganciclovir in murine melanoma cells tranduced with herpes simplex virus thymidine kinase. Exp Cell Res, 1998;241:66-75
11 Boucher PD, Ruch RJ, Shewach DS. Differential ganciclovir-mediated cytotoxicity and bystander killing in human colon carcinoma cell lines expressing herpes simplex thymidine kinase. Hum Gene Ther, 1998;9:801-814
12 Haberkorn U, Khazaie K, Morr I, Altmann A, Muller M, VanKaick G. Ganciclovir uptake in human mammary carcinoma cells expressing herpes simplex virus thymidine kinase. Nucl Med Biol, 1998;25:367-373
13 Balzarini J, Degreve B, Andrei G, Neyts J, Sandvold M, Myhren F, de Clercq E. Superior cytostatic activity of the ganciclovir elaidic acid ester due to the prolonged introcellular retention of ganciclovior anabolites in herpes simplex virus type 1 thymidine kinase gene transfected liver cells. Gene Ther, 1998;5:419-426
14 Tong XW, Engehausen DG, Kaufman RH, Agoulnik I, Contant C, Freund CT, Oehler MK. Improvement of gene therapy for ovarian cancer by using acyclovir instead of ganciclovir in adenovirus mediated thymidine kinase gene therapy. Anticancer Res, 1998;18(2A):713-718
15 Grignet-Debrus C, Calberg-Bacq CM. Potential of vericella zoster virus thymidine kinase as a suicide gene in breast cancer cells. Gene Ther, 1997;4:560-569
16 Degreve B, Andrei G, Izquierdo M, Piette J, Morin K, Knaus EE, Wiebe LI. Vericella-zoster virus thymidine kinase gene and antiherpetic pyrimidine nucleoside analogues in a combined gene/chemotherapy treatment for cancer. Gene Ther, 1997;4:1107-1114
17 Rowley S, Lindauer M, Gebert JF, Haberkorn U, Oberdorfer F, Moebius U, Herfarth C. Cytosine deaminase gene as a potential tool for the genetic therapy of colorectal cancer. J Surg Oncol, 1996;61:42-48
18 Hoganson DK, Batra RK, Olsen JC, Boucher RC. Comparison of the effects of three different toxin genes and their levels of expression on cell growth and bystander effect in lung adenocarcinoma. Cancer Res, 1996;56:1315-1323
19 Dong Y, Wen P, Manome Y, Parr M, Hirshowitz A, Chen L, Hirschowitz EA. In vivo replication-deficient adenovirus vector-mediated transduction of the cytosine deaminase gene sensitizes glioma cells to 5-fluorocytosine. Hum Gene Ther, 1996;7:713-720
20 Rainov NG, Dobberstein K-U, Sena-Esteves M, Herrlinger U, Kramm CM, Philpot RM, Hilton J. New prodrug activation gene therapy for cancer using cytochrome P450 4B1 and 2-aminoanthracene/4-ipomeanol. Hum Gene Ther, 1998;9:1261-1273
21 Manome Y, Wen PY, Dong Y, Tanaka T, Mitchell BS, Kufe DW, Fine HA. Viral vector transduction of the human deoxycytidine kinase cDNA sensitizes glioma cells to the cytotoxic effects of cytosine arabinoside in vitro and in vivo. Nat Med, 1996;2:567-573
22 Tamiya T, Ono Y, Wei MX, Mroz PJ, Moolten FL, Chiocca EA. Escherichia coli gpt gene sensitizes rat glioma cells to killing by 6-thioxanthine or 6-thioguanine. Cancer Gene Ther, 1996;3:155-162
23 Ono Y, Ikeda K, Wei MX. Regression of experimental brain tumors with 6 -thioxanthine and Escherichia coli gpt gene therapy. Hum Gene Ther, 1997;8:2043-2055
24 Green NK, Young DJ, Neoptolemos JP, Friedlos F, Knox RJ, Springer CJ, Anlezark GM. Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5-(aziridin-1-yl)-2, 4-dinitrobenzamide(CB1954) by retroviral transduction and expression of the E. coli nitroreductase gene. Cancer Gene Ther, 1997;4:229-238
25 Bridgewater JA, Knox RJ, Pitts JD, Collins MK, Springer CJ. The bystander effect of the nitroreductase/CB1954 enzyme/prodrug system is due to a cellpermeable metabolite. Hum Gene Ther, 1997;8:709-717
26 Marais R, Spooner RA, Stribbling SM, Light Y, Martin J, Springer CJ. A cell surface tethered enzyme improves efficiency in gene-directed enzyme prodrug therapy. Nat Biotechnol, 1997;15:1373-1377
27 Danks MK, Morton CL, Pawlik CA, Potter PM. Overexpression of a rabbit liver carboxylesterase sensitizes human tumor cells to CPT-11. Cancer Res, 1998;58:20-22
28 Aghi M, Kramm CM, Chou TC, Breakefield XO, Chiocca EA. Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies. J Natl Cancer Inst, 1998;90:370-380
29 Uckert W, Kammertons T, Haack K, Qin Z, Gebert J, Schendel DJ, Blankenstein T. Double suicide gene(cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumors cell in vivo. Hum Gene Ther, 1998;9:855-866
30 Ishii-Morita H, Agbaria R, Mullen CA, Hirano H, Koeplin DA, Ram Z, Oldfield EH. Mechanism of “bystander effect" killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment. Gene Ther, 1997;4:244-255
31 Yang L, Chiang Y, Lenz HJ, Danenberg KD, Spears CP, Gordon EM, Anderson WF. Intercellular communication mediates the bystander effect during herpes simplex thymidine kinase/ganciclovir based gene therapy of human gastrointestinal tumor cells. Hum Gene Ther, 1998;9:719-728
32 Park JY, Elshami AA, Amin K, Rizk N, Kaiser LR, Alberda SM. Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy. Gene Ther, 1997;4:909-917
33 Kianmanesh AR, Perrin H, Panis Y, Fabre M, Nagy HJ, Houssin D, Klatzmann D. A“distant" bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Hum Gene Ther, 1997;8:1807-1814
34 Mullen CA, Anderson L, Woods K, Mishino M, Petropoulos D. Ganciclovir chemoablation of herpes thymidine kinase suicide gene-medified tumors produces tumors necrosis and induces systemic immune responses. Hum Gene Ther, 1998;9:2019-2030
35 Hall SJ, Sanford MA, Atkinson G, Chen SH. Induction of potent antitumor natural killer cell activity by herpes simplex virus-thymidine kinase and ganciclovir therapy in an orthotopic mouse model of prostate cancer. Cancer Res, 1998;58:3221-3225
36 Morinchi S, Oligino T, Krisky D, Marconi P, Fink D, Cohen J, Glorioso JC. Enhanced tumor cell killing in the presence of ganciclovir by herpes simplex virus type 1 vector-directed coexpression of human tumor necrosis factor-alpha and herpes simplex virus thymidine kinase. Cancer Res, 1998;58:5731-5737
37 Caruso M, Panis Y, Singh G, Houssin D, Salzmann JL, Klatzmann D. Regression of an established macroscopic liver tumor by in vivo retroviral-mediated transfer of a suicide gene. Proc Natl Acad Sci, 1993;90:7024-7028
38 Kwong YL, Chen SH, Kosai K, Finegold MJ, Woo SI. Adenoviral_mediated suicide gene therapy for hepatic metastases of breast. Cancer, 1996;3:339-344
39 Nagy H, Panis Y, Fabre M, Perrin H, Klatzmann D, Houssiin D. Are hepatoma a good target for suicide gene therapy An experimental study in rat using retroviral-mediated transfer of thymidine kinase gene. Surgery, 1998;123:19-24
40 Ueki T, Nakata K, Mawatari F, Tsuruta S, Ido A, Ishikawa H, Nakao K. Retrovirus-mediated gene therapy for human hepatocellular carcinoma tranplanted in athymic mice. Int J Mol Med, 1998;1:671-675
41 Mawatari F, Tsuruta S, Ido Ueki T, Nakao K, Kato Y, Tamaoki T. Retrovirus-mediated gene therapy for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by human alpha-fetoprotein enhancer directly linked to its promotor. Cancer Gene Res, 1998;5:301-306
42 Gerolami R, Cardoso J, Bralet MP, Cuenod CA, Clement O, Tran PL, Brechot C. Enhanced in vivo adenovirus-mediated gene transfer to rat hepatocarcinomas by selective administration into the hepatic artery. Gene Ther, 1998;5:896-904
43 Link CJ Jr, Levy JP, McCann LZ, Moorman DW. Gene therapy for colon cancer with the herpes simlex thymidine kinase gene. J Surg Oncol, 1997;64:289-294
44 Yang L, Hwang R, Chiang Y, Gordon EM, Anderson WF, Parekh D. Mechanism for ganciclovir resistance in gastrointestinal tumor cells transduced with a retroviral vector containing the herpes simplex virus thymidine kinase gene. Clin Cancer Res, 1998;4:731-741
45 McMaster RA, Saylors RL, Jones KE. Lack of bystander killing in herpes simplex virus thymidine kinase-transduced colon cell lines due to deficient connexin43 gap junction formation. Hum Gene Ther, 1998;9:2253-2261
46 Ohashi M, Kanai F, Tanaka T, Lan KH, Shiratori Y, Komatsu Y, Kawabe T. In vivo adenovirus-mediated prodrug gene therapy for carcinoembryonic antigen-prodrug pancreatic cancer. Jpn J Cancer Res, 1998;89:457-462
47 Rosenfeld ME, Vicker SM, Raben D, Wang M, Sampson L, Feng M, Jaffee E. Pancreatic carcinoma cell killing via adenoviral mediated delivery of the herpes simplex virus thymidine kinase gene. Ann Surg, 1997;225:609-618
48 Aoki K, Yoshida T, Matsumoto N, Ide H, Hosokawa K, Sugimura T, Terada M. Gene therapy for peritoneal dissemination of pancreatic cancer by liposome-mediated trandfer of herpes simplex virus thymidine kinase gene. Hum Gene Ther, 1997;8:1105-1113
49 Yoshida K, Kawami H, Yamaguchi Y, Kuniyasu H, Nishiyama M, Hirai T, Yanagihara K. Retrovirally transmitted gene therapy for gastric carcinoma using herpes simplex virus thymidine kinase gene. Cancer, 1995;75(6 Suppl):1467-1471
50 Tanaka T, Kanai F, Lan KH, Ohashi M, Shiratori Y, Yoshida Y, Hamada H. Adenovirus-mediated gene therapy of gastric carcinoma using cancer-specific gene expression in vivo. Biochem Biophys Res Commun, 1997;231:775-779
51 Klatzmann D, Valery CA, Bensimon G, Marro B, Boyer O, Mokhtari K, Diguet B. A phase Ⅰ/Ⅱ Study of herpes simplex virus type 1 thymidine kinase “suicide" gene therapy for recurrent glioblastoma. Hum Gene Ther, 1998;9:2595-2604
52 Sterman DH, Treat J, Litzky LA, Amin KM, Coonrod L, Molnar-Kimber K, Recio A. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase Ⅰ clinical trial in malignant mesothelioma. Hum Gene Ther, 1998;9:1083-1092
53 Qian C, Idoate M, Bilbao R, Sangro B, Bruna O, Vazquez J, Prieto J. Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. Hum Gene Ther, 1997;8:349-358
54 Van de Eb MM, Cramer SJ, Vergouwe Y, Schagen FH, van Krieken JH, van der Eb AJ, Rinkes IH. Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration. Gene Ther, 1998;5:451-458
