CEA启动子驱动的HSV-TK/CD双自杀基因治疗人肺癌细胞的动物实验研究
|
摘要
目的:研究CEA启动子驱动的HSV-TK/CD双自杀基因系统在裸鼠体内的抑瘤作用及安全性。
方法:使用普通RT-PCR验证SPC-A-1、SPC-A-1/TK+CD及SPC-A-1/pIRES-EGFP细胞的基因表达情况,然后建立裸鼠肺癌模型并进行分组:随机选用30只裸鼠,平均分为6组进行实验,分别为空白对照组、PBS对照组、空载体对照组、GCV治疗组、5-FC治疗组及双药治疗组。当肿瘤平均直径约为5mm时,开始治疗实验。PBS、GCV及5-FC经腹腔分别注入相应裸鼠体内,治疗5周后通过肿瘤平均体积、重量及生长抑制率评估抑瘤作用,进一步采用TUNEL法及透射电镜分析肿瘤细胞的凋亡情况,并通过常规病理切片HE染色观察心、肝、肾组织的病理改变。
结果:普通RT-PCR证实SPC-A-1、SPC-A-1/TK+CD及SPC-A-1/pIRES-EGFP细胞皆为CEA阳性细胞,外源性双自杀基因HSV-TK/CD仅在SPC-A-1/TK+CD细胞中表达;在化疗前药GCV和(或)5-FC的作用下,双自杀基因HSV-TK/CD能对CEA表达阳性的肺癌细胞皮下移植瘤产生显著的抑制作用,通过TUNEL凋亡染色检测及电镜观察,提示HSV-TK/CD双自杀基因系统主要通过诱导肿瘤细胞凋亡从而发挥抑瘤作用,光镜下对裸鼠各器官进行观察,未发现明显的毒副作用。
结论:CEA启动子驱动的HSV-TK/CD双自杀基因,在化疗前体药物GCV和(或)5-FC的作用下,对裸鼠体内CEA阳性的肺癌移植瘤具有明显的抑制作用,能诱导肿瘤细胞发生凋亡,但对裸鼠的重要器官无明显毒副作用。
Objective: To investigate the treatment efficiency of the double suicide gene therapy system on lung carcinoma and the security in vivo studies.
Method: Use the method of reverse transcription PCR to confirm the expression of gene in SPC-A-1,SPC-A-1/TK+CD and SPC-A-1/pIRES-EGFP cells.The total of 30 mice were randomly divided into 6 groups then established the model of human lung carcinoma xenografts, including blank control group, PBS control group, empty vector control group, GCV treatment group ,5-FC treatment group, combined treatment group..After tumors reached 5mm in diameter,the study began.Nude mice in Groups were given peritoneal injection of PBS、GCV、5-FC, respectively. After 5 weeks, the antitumor efficacy was evaluated by tumor mean volume, weight and inhibition rate .Moreover,we evaluated cell apoptosis by TUNEL and transmission electron microscope(TEM),and used routine pathologic examination(H.E)to observe the tissue of heart, liver, kidney.
Result:The reverse transcription PCR proved SPC-A-1,SPC-A-1/TK+CD and SPC-A-1/pIRES-EGFP cells are CEA positive cells. exogenous double suicide gene HSV-TK/CD are only expressed by SPC-A-1/TK+CD cells, which combined with prodrug GCV and (or) 5-FC can significantly inhibite CEA positive lung carcinoma xenografts. Cell apoptosis were evaluated by TUNEL technique and transmission electron microscope (TEM),suggesting the anti-tumor effect of HSV-TK/CD double suicide gene system is through leading tumor cells to apoptosis. No obvious side effects are found in the tissue of various organs in nude mice by routine pathologic examination.
Conclusion: To investigate the security and the treatment efficiency of the double suicide gene therapy system in a mouse xenografts model of lung carcinoma,we confirmed the HSV-TK/CD double suicide gene combined with prodrug GCV and (or) 5-FC can significantly inhibite CEA positive lung carcinoma cells through inducing targeted cells to apoptosis. Meanwhile, there are no significant side effects in other organs of nude mice.
方法:使用普通RT-PCR验证SPC-A-1、SPC-A-1/TK+CD及SPC-A-1/pIRES-EGFP细胞的基因表达情况,然后建立裸鼠肺癌模型并进行分组:随机选用30只裸鼠,平均分为6组进行实验,分别为空白对照组、PBS对照组、空载体对照组、GCV治疗组、5-FC治疗组及双药治疗组。当肿瘤平均直径约为5mm时,开始治疗实验。PBS、GCV及5-FC经腹腔分别注入相应裸鼠体内,治疗5周后通过肿瘤平均体积、重量及生长抑制率评估抑瘤作用,进一步采用TUNEL法及透射电镜分析肿瘤细胞的凋亡情况,并通过常规病理切片HE染色观察心、肝、肾组织的病理改变。
结果:普通RT-PCR证实SPC-A-1、SPC-A-1/TK+CD及SPC-A-1/pIRES-EGFP细胞皆为CEA阳性细胞,外源性双自杀基因HSV-TK/CD仅在SPC-A-1/TK+CD细胞中表达;在化疗前药GCV和(或)5-FC的作用下,双自杀基因HSV-TK/CD能对CEA表达阳性的肺癌细胞皮下移植瘤产生显著的抑制作用,通过TUNEL凋亡染色检测及电镜观察,提示HSV-TK/CD双自杀基因系统主要通过诱导肿瘤细胞凋亡从而发挥抑瘤作用,光镜下对裸鼠各器官进行观察,未发现明显的毒副作用。
结论:CEA启动子驱动的HSV-TK/CD双自杀基因,在化疗前体药物GCV和(或)5-FC的作用下,对裸鼠体内CEA阳性的肺癌移植瘤具有明显的抑制作用,能诱导肿瘤细胞发生凋亡,但对裸鼠的重要器官无明显毒副作用。
Objective: To investigate the treatment efficiency of the double suicide gene therapy system on lung carcinoma and the security in vivo studies.
Method: Use the method of reverse transcription PCR to confirm the expression of gene in SPC-A-1,SPC-A-1/TK+CD and SPC-A-1/pIRES-EGFP cells.The total of 30 mice were randomly divided into 6 groups then established the model of human lung carcinoma xenografts, including blank control group, PBS control group, empty vector control group, GCV treatment group ,5-FC treatment group, combined treatment group..After tumors reached 5mm in diameter,the study began.Nude mice in Groups were given peritoneal injection of PBS、GCV、5-FC, respectively. After 5 weeks, the antitumor efficacy was evaluated by tumor mean volume, weight and inhibition rate .Moreover,we evaluated cell apoptosis by TUNEL and transmission electron microscope(TEM),and used routine pathologic examination(H.E)to observe the tissue of heart, liver, kidney.
Result:The reverse transcription PCR proved SPC-A-1,SPC-A-1/TK+CD and SPC-A-1/pIRES-EGFP cells are CEA positive cells. exogenous double suicide gene HSV-TK/CD are only expressed by SPC-A-1/TK+CD cells, which combined with prodrug GCV and (or) 5-FC can significantly inhibite CEA positive lung carcinoma xenografts. Cell apoptosis were evaluated by TUNEL technique and transmission electron microscope (TEM),suggesting the anti-tumor effect of HSV-TK/CD double suicide gene system is through leading tumor cells to apoptosis. No obvious side effects are found in the tissue of various organs in nude mice by routine pathologic examination.
Conclusion: To investigate the security and the treatment efficiency of the double suicide gene therapy system in a mouse xenografts model of lung carcinoma,we confirmed the HSV-TK/CD double suicide gene combined with prodrug GCV and (or) 5-FC can significantly inhibite CEA positive lung carcinoma cells through inducing targeted cells to apoptosis. Meanwhile, there are no significant side effects in other organs of nude mice.
引文
1. Ahmedin Jemal,DVM,PhD,et al.Global Cancer Statistics,CA Cancer J Clin 2011, 61:000-000.
2. Tina Wang, BA1; Rebecca A. Nelson, PhD2. Five-Year Lung Cancer Survival. Cancer 2010;116:1518–25.
3. http://www.austrianova.com
4. Rainov NG.A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther .2000V11N17:2389-401 .
5. Differential ganciclovir-mediated cytotoxicity and bystander killing in human colon carcinoma cell lines expressing herpes simplex virus thymidine kinase. Boucher PD, Ruch RJ, Shewach DS. Hum Gene Ther. 1998 Apr 10;9(6):801-14.
6. In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus. Ichikawa T, Tamiya T,et al. Cancer Gene Ther. 2000 Jan;7(1):74-82.
7. Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Rogulski KR;Kim JH;Kim SH. Hum Gene Ther .1997V8N1:73-85.
8. Efficacy of recombinant adenovirus-mediated double suicide gene therapy in human keloid fibroblasts.Xu B;Liu ZZ;Zhu GY.Clin Exp Dermatol.2008V33N3: 322-8.
9. Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells.Hamel W;Magnelli L;Chiarugi VP.Cancer Res.1996V56N12:2697 -702.
10. High-malignancy orthotopic nude mouse model of human prostate cancer LNCaP. Wang X;An Z;Geller J. Prostate .1999V39N3:182-6.
11. Optimal amount of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy against hepatocellular carcinoma by M1 macrophage activation. Tsuchiyama T;Nakamoto Y;Sakai Y. Cancer Sci .2008V99N10:2075-82 .
12. Experimental study on intraperitoneal sequential MTX/5-FU therapy for peritoneal seeding in comparison with intravenous administration. Maruyama M;Takamatsu S;Sugano N. Gan To Kagaku Ryoho .1997V24N14:2131-6
13. A Good Practice Guide to the Administrationof Substances and Removal of Blood,including Routes and Volumes. Karl-Heinz Diehl,Robin Hull,et al. JOURNAL OF APPLIED TOXICOLOGY.21,15–23(2001).
14. Oncolytic gene therapy combined with double suicide genes for human bile duct cancer in nude mouse models. Kojima Y;Honda K;Hamada H. J Surg Res.2009V157N1: e63-70 .
15. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo. Uckert W;Kammertons T;Haack K;Hum Gene Ther .1998V9N6:855-65.
16. Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model. Moriuchi S;Wolfe D;Tamura M;Gene Ther.2002V9N9:584-91.
17. Human neural stem cells transduced with IFN-beta and cytosine deaminase genes intensify bystander effect in experimental glioma. Ito S;Natsume A;Shimato S. Cancer Gene Ther .2010V17N5:299-306 .
18. Clinical-grade preparation of human natural regulatory T-cells encoding the thymidine kinase suicide gene as a safety gene. Guillot-Delost M;Cherai M;Hamel Y. J Gene Med .2008V10N8:834-46 .
19. A novel mechanism of synergistic cytotoxicity with 5-fluorocytosine and ganciclovir in double suicide gene therapy. Boucher PD, Im MM, Freytag SO, Shewach DS. Cancer Res. 2006 Mar 15;66(6):3230-7.
20. Kanyama H, Tomita N, Yamano T, et al. Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy. Cancer Res. 2001 Jan 1;61(1):14-8.
21. An apoptosis-inducing gene therapy for pancreatic cancer with a combination of 55-kDa tumor necrosis factor (TNF) receptor gene transfection and mutein TNF administration. Sato T;Yamauchi N;Sasaki H. Cancer Res .1998V58N8:1677-83 .
22. Apoptotic cell death induced by local brain hyperthermia in a rat glioma model. Uesugi S;Yamashita K;Nakashima K. Acta Neuropathol .1998V96N4:351-6.
23. Identifying and quantifying apoptosis: navigating technical pitfalls. Garrity MM;Burgart LJ;Riehle DL. Mod Pathol .2003V16N4:389-94 .
24. Nonviral vectors with a biosurfactant MEL-A promote gene transfection into solid tumors in the mouse abdominal cavity. Inoh Y;Furuno T;Hirashima N. Biol Pharm Bull .2009V32N1:126-8 .
25. Gene therapy for high-grade glioma. Iwami K;Natsume A;Wakabayashi T. Neurol Med Chir (Tokyo) .2010V50N9:727-36 .
26. Gene therapy for gastric diseases. Fumoto S;Nishi J;Nakamura J. Curr Gene Ther .2008V8N3:187-200 .
27. Targeted chemotherapy for head and neck cancer with a chimeric oncolytic adenovirus coding for bifunctional suicide protein FCU1. Dias JD;Liikanen I;Guse K. Clin Cancer Res .2010V16N9:2540-9 .
28. Combination gene therapy using multidrug resistance (MDR1) gene shRNA and herpes simplex virus-thymidine kinase. Park SY ; Lee W ; Lee J. Cancer Lett .2008V261N2:205-14 .
29. Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy. Xie Y;Gilbert JD;Kim JH. Clin Cancer Res .1999V5N12:4224-32 .
30. Gene therapy safety issues come to fore.Fox JL.Nat Biotechnol.1999V17N12:1153 .
1. Ahmedin Jemal,DVM,PhD,et al.Global Cancer Statistics,CA Cancer J Clin 2011, 61:000-000.
2. Five-Year Lung Cancer Survival.Tina Wang;Rebecca A,et al. Cancer 2010;116:1518 -25.
3. http://www.austrianova.com
4. A phaseⅢclinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme.Rainov NG,et al.Hum Gene Ther. 2000V11N17:2389-401 .
5. In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus. Ichikawa T, Tamiya T,et al. Cancer Gene Ther. 2000 Jan;7(1):74-82.
6. Design, synthesis and enzymatic activity of highly selective human mitochondrial thymidine kinase inhibitors. Manfredini S;Baraldi PG,et al. Bioorg Med Chem Lett. 2001V11N10:1329-32 .
7. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Karle P;Renner M;Salmons B.Cancer Gene Ther .2001V8N3:220-30
8. Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Bilsland AE;Anderson CJ;Fletcher-Monaghan AJ. Oncogene .2003V22N3:370-80 .
9. Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity. Kawamura K;Tasaki K;Hamada H. Cancer Gene Ther .2000V7N4:637-43 .
10. The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells. Huang Q;Liu XZ;Kang CS. Cancer Gene Ther .2010V17N3:192-202.
11. Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Schwarzenberger P;Lei D;Freeman SM,et al.Am J Respir Cell Mol Biol .1998V19N2:333-7 .
12. Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models. Zheng FQ;Xu Y;Yang RJ.Acta Pharmacol Sin .2009V30N5:617-27.
13. Do there exist synergistic antitumor effects by coexpression of herpes simplex virus thymidine kinase with cytokine genes on human gastric cancer cell line SGC7901? Zhang JH;Wan MX;Yuan JY. World J Gastroenterol .2004V10N1:147-51.
14. The involvement of nuclear factor-kappa B in cyclooxygenase-2 overexpression in murine colon cancer cells transduced with herpes simplex virus thymidine kinase gene. Konson A;Mahajna JA;Danon A. Cancer Gene Ther .2006V13N12:1093-104 .
15. Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer. Makinen K;Loimas S;Wahlfors J. J Gene Med .2000V2N5:361-7 .
16. A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. Shand N, Weber F, Mariani L, et al. Hum Gene Ther. 1999 Sep 20;10(14):2325-35.
17. Radiosensitization of human glioma cells in vitro and in vivo with acyclovir and mutant HSV-TK75 expressed from adenovirus. Rosenberg E;Hawkins W;Holmes M. Int J Radiat Oncol Biol Phys .2002V52N3:831-6 .
18. Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Black ME;Kokoris MS;Sabo P. Cancer Res .2001V61N7:3022-6 .
19. Cytogenetic genotoxicity of anti-herpes purine nucleoside analogues in CHO cells expressing the thymidine kinase gene of herpes simplex virus type 1: comparison of ganciclovir,penciclovir and acyclovir.Thust R;Tomicic M;Klocking R,et al. 2000V15N2: 177-84 .
20. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Mullen CA, Kilstrup M, Blaese RM. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):33-7.
21. In vivo replication-deficient adenovirus vector-mediated transduction of the cytosine deaminase gene sensitizes glioma cells to 5-fluorocytosine. Dong Y;Wen P;Manome Y. Hum Gene Ther .1996V7N6:713-20 .
22. Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy. Kanyama H;Tomita N;Yamano T. Cancer Res .2001V61N1:14-8 .
23. Enzyme/prodrug gene therapy approach for breast cancer using a recombinant adenovirus expressing Escherichia coli cytosine deaminase. Li Z;Shanmugam N;Katayose D. Cancer Gene Ther .1997V4N2:113-7
24. Combined cytosine deaminase expression, 5-fluorocytosine exposure, and radiotherapy increases cytotoxicity to cholangiocarcinoma cells. Pederson LC;Vickers SM;Buchsbaum DJ. J Gastrointest Surg .1998V2N3:283-91 .
25. Regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver. Ohwada A;Hirschowitz EA;Crystal RG. Hum Gene Ther .1996V7N13:1567-76 .
26. Adenovirus mediated cytosine deaminase gene transduction and 5-fluorocytosine therapy sensitizes mouse prostate cancer cells to irradiation. Anello R;Cohen S;Atkinson G. J Urol .2000V164N6:2173-7 .
27. Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis.Liu SC;Minton NP;Giaccia AJ.Gene Ther.2002V9N4: 291-6 .
28. Superiority of yeast over bacterial cytosine deaminase for enzyme/prodrug gene therapy in colon cancer xenografts. Kievit E;Bershad E;Ng E.Cancer Res.1999; 59:1417-1421.
29. Cytochrome P450 reductase dependent inhibition of cytochrome P450 2B1 activity: Implications for gene directed enzyme prodrug therapy. Lengler J;Omann M;Duvier D. Biochem Pharmacol .2006V72N7:893-901 .
30. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Karle P;Renner M;Salmons B.Cancer Gene Ther .2001V8N3:220-30.
31. Enhanced bystander cytotoxicity of P450 gene-directed enzyme prodrug therapy by expression of the antiapoptotic factor p35. Schwartz PS;Chen CS;Waxman DJ. Cancer Res .2002V62N23:6928-37.
32. Identification of cytochrome P450s in human glioma cell line. Vasquez HG;Strobel H. Int J Oncol .1998V12N6:1291-4 .
33. Sensitization of human breast cancer cells to cyclophosphamide and ifosfamide by transfer of a liver cytochrome P450 gene.Chen L;Waxman DJ;Chen D.Cancer Res. 1996V56N6: 1331-40 .
34. Colorectal cancer-specific cytochrome P450 2W1:intracellular localization, glycosylation, and catalytic activity. Gomez A;Nekvindova J;Travica S.Mol Pharmacol. 2010V78N6: 1004-11.
35. P450-dependent enzymes as targets for prostate cancer therapy. De Coster R;Wouters W;Bruynseels J. J Steroid Biochem Mol Biol.1996V56N1-6 Spec No:133-43 .
36. Injection of encapsulated cells producing an ifosfamide-activating cytochrome P450 for targeted chemotherapy to pancreatic tumors. Muller P;Jesnowski R;Karle P. Ann N Y Acad Sci .1999V880N:337-51 .
37. Diffusible cytotoxic metabolites contribute to the in vitro bystander effect associated with the cyclophosphamide/cytochrome P450 2B1 cancer gene therapy paradigm. Wei MX;Tamiya T;Rhee RJ. Clin Cancer Res .1995V1N10:1171-7 .
38. Technology evaluation: MetXia-P450, Oxford Biomedica. Hunt S. Curr Opin Mol Ther .2001V3N6:595-8 .
39. Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer. Gunzburg WH;Salmons B. Acta Biochim Pol .2005V52N3:601-7 .
40. http://www.austrianova.com
41. Virus-directed enzyme prodrug therapy using CB1954. Grove JI;Searle PF;Weedon SJ. Anticancer Drug Des .1999V14N6:461-72 .
42. Virus directed enzyme prodrug therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954. McNeish IA;Green NK;Gilligan MG. Gene Ther .1998V5N8:1061-9.
43. Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase/ CB1954 is enhanced by high-level coexpression of heat shock protein 70. Djeha HA;Todryk SM;Pelech S. Cancer Gene Ther .2005V12N6:560-71 .
44. Late expression of nitroreductase in an oncolytic adenovirus sensitizes colon cancer cells to the prodrug CB1954. Lukashev AN;Fuerer C;Chen MJ. Hum Gene Ther.2005V16N12:1473-83 .
45. Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB1954. Chung-Faye G;Palmer D;Anderson D. Clin Cancer Res .2001V7N9:2662-8 .
46. Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. Palmer DH;Mautner V;Mirza D. J Clin Oncol.2004V22N9: 1546-52.
47. Nitroreductase: a prodrug-activating enzyme for cancer gene therapy. Searle PF;Chen MJ;Hu L. Clin Exp Pharmacol Physiol .2004V31N11:811-6.
48. A phaseⅠ/Ⅱclinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984]. Patel P;Young JG;Mautner V. Mol Ther .2009V17N7:1292-9.
49. Bystander or no bystander for gene directed enzyme prodrug therapy. Dachs GU;Hunt MA;Syddall S. Molecules .2009V14N11:4517-45 .
50. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Moolten FL. Cancer Res. 1986 Oct;46(10):5276-81.
51. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Ram Z, Culver KW,et al. Cancer Res. 1993 Jan 1;53(1):83-8.
52. Gene-directed enzyme prodrug therapy with a mustard prodrug/carboxypeptidase G2 combination. Marais R;Spooner RA;Light Y.Cancer Res.1996V56N20:4735-42.
53. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Culver KW, Ram Z, et al.Science.1992 Jun 12;256(5063): 1550-2.
54. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Mesnil M;Piccoli C;Tiraby G. Proc Natl Acad Sci U S A .1996V93N5:1831-5.
55. Bystander effect in glioblastoma cells with a predominant cytoplasmic localization of connexin43. Cottin S;Ghani K;Caruso M.Cancer Gene Ther. 2008V15N12:823-31.
56. Bystander tumoricidal effect and gap junctional communication in lung cancer cell lines. Imaizumi K;Hasegawa Y;Kawabe T. Am J Respir Cell Mol Biol.1998V18N2: 205-12.
57. The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified. Freeman SM, Abboud CN, et al.Cancer Res. 1993 Nov 1;53(21): 5274-83.
58. Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Hamel W;Magnelli L;Chiarugi VP.Cancer Res. 1996 Jun 15;56(12): 2697-702.
59. Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma.Kuriyama S,Nakatani T,et al. Hepatology.1995 Dec;22(6): 1838-46.
60. Cytochrome P450 gene-directed enzyme prodrug therapy (GDEPT) for cancer. Chen L;Waxman DJ. Curr Pharm Des .2002V8N15:1405-16.
61. Tentative novel mechanism of the bystander effect in glioma gene therapy with HSV-TK/GCV system. Bai S,Du L,Liu W.Biochem Biophys Res Commun. 1999V259N2: 455-9
62. Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors.Barba D,Hardin J,Proc Natl Acad Sci U S A.1994 May 10;91(10): 4348-52.
63. AV.TK-mediated killing of subcutaneous tumors in situ results in effective immunization against established secondary intracranial tumor deposits. Okada T;Shah M;Higginbotham JN. Gene Ther .2001V8N17:1315-22 .
64. Purified herpes simplex thymidine kinase retroviral particles. II. Influence of clinical parameters and bystander killing mechanisms. Kruse CA,Lamb C,et al.Cancer Gene Ther .2000V7N1:118-27 .
65. Enhancement of tumor killing using a combination of tumor immunization and HSV-tk suicide gene therapy. Ramesh R, Munshi A,et al. Int J Cancer. 1999 Jan 29;80(3):380-6.
66. Differential ganciclovir-mediated cytotoxicity and bystander killing in human colon carcinoma cell lines expressing herpes simplex virus thymidine kinase. Boucher PD, Ruch RJ,et al. Hum Gene Ther. 1998 Apr 10;9(6):801-14.
67. Hepatic intra-arterial delivery of a retroviral vector expressing the cytosine deaminase gene, controlled by the CEA promoter and intraperitoneal treatmentwith 5-fluorocytosine suppresses growth of colorectal liver metastases. Humphreys MJ, Ghaneh P,et al. Gene Ther. 2001 Aug;8(16):1241-7.
68. Genetically modified CD34+ cells exert a cytotoxic bystander effect on human endothelial and cancer cells. Arafat WO, Casado E,et al. Clin Cancer Res. 2000 Nov;6(11):4442-8.
69. Protection of herpes simplex virus thymidine kinase-transduced cells from ganciclovir-mediated cytotoxicity by bystander cells: the Good Samaritan effect. Wygoda MR, Wilson MR,et al. Cancer Res. 1997 May 1;57(9):1699-703.
70. Evaluation of the bystander effect in experimental brain tumors bearing herpes simplex virus-thymidine kinase gene by serial magnetic resonance imaging. Namba H, Iwadate Y,et al. Hum Gene Ther. 1996 Oct 1;7(15):1847-52.
71. A "distant" bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Kianmanesh AR, Perrin H,et al. Hum Gene Ther. 1997 Oct 10;8(15):1733-5.
72. An HSVtk-mediated local and distant antitumor bystander effect in tumors of head and neck origin in athymic mice. Bi W,Kim YG,et al. Cancer Gene Ther. 1997 Jul-Aug;4(4):246-52.
73. Suicide gene therapy for plasma cell tumors. Dilber MS, Abedi MR,et al. Blood. 1996 Sep 15;88(6):2192-200.
74. Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Rogulski KR,Kim JH,et al.Hum Gene Ther. 1997 Jan 1;8(1):73-85.
75. A novel mechanism of synergistic cytotoxicity with 5-fluorocytosine and ganciclovir in double suicide gene therapy. Boucher PD, Im MM,et al. Cancer Res. 2006 Mar 15;66(6):3230-7.
76. Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine. Adachi Y, Tamiya T,et al. Hum Gene Ther. 2000 Jan 1;11(1): 77-89.
77. Combination of the bioreductive drug tirapazamine with the chemotherapeutic prodrug cyclophosphamide for P450/P450-reductase-based cancer gene therapy. Jounaidi Y, Waxman DJ,et al. Cancer Res. 2000 Jul 15;60(14):3761-9.
78. Dlx5 induces expression of COL1A1 promoter contained in a retrovirus vector. Tadic T;Erceg I,et al. Croat Med J .2001V42N4:436-9.
79. Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma.Than SS,Kataoka K,et al. Oncol Rep .2011VN:
80. Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector. Yagi H,Ogura T,et al. J Gene Med .2011VN:
81. Rapid and sensitive lentivirus vector-based conditional gene expression assay to monitor and quantify cell fusion activity. Goncalves MA,Janssen JM,et al. PLoS One.2010V5N6:e10954.
82. A herpes simplex virus vector system for expression of complex cellular cDNA libraries. Wolfe D,Craft AM,et al. J Virol .2010V84N14:7360-8.
83. Muscle Damage Following Delivery of Naked Plasmid DNA into Skeletal Muscles is Batch-Dependent. Wooddell CI,Subbotin VM,et al. Hum Gene Ther .2010VN:
84. Novel cationic lipids based on malonic acid amides backbone: transfection efficacy and cell toxicity properties. Heinze M;Brezesinski G,et al. Bioconjug Chem .2010V21N4:696-708.
85. Cationic polymer optimization for efficient gene delivery. Sun X,Zhang N,et al. Mini Rev Med Chem .2010V10N2:108-25 .
86. Targeted drug and gene delivery systems for lung cancer therapy.Sundaram S,Trivedi R,et al. Clin Cancer Res .2009V15N23:7299-308.
87. Nanoparticles for gene delivery: a brief patent review. Xu G,Zhang N,et al.Recent Pat Drug Deliv Formul .2009V3N2:125-36
88. Targeted gene transfer to hepatocellular carcinoma cells in vitro using a novel monoclonal antibody-based gene delivery system. Mohr L, Schauer JI,et al. Hepatology. 1999 Jan;29(1): 82-9.
89. Design of a bifunctional fusion protein for ovarian cancer drug delivery: single-chain anti-CA125 core-streptavidin fusion protein. Wang WW, Das D,et al. Eur J Pharm Biopharm. 2007 Mar;65(3):398-405. Epub 2006 Dec 27.
90. Effect of cell media on polymer coated superparamagnetic iron oxide nanoparticles (SPIONs): colloidal stability, cytotoxicity, and cellular uptake studies. Petri-Fink A, Steitz B,et al. Eur J Pharm Biopharm. 2008 Jan;68(1): 129-37.Epub 2007 Jul 13.
91. Myocardial delivery of colloid nanoparticles using ultrasound-targeted microbubble destruction. Vancraeynest D, Havaux X,et al. Eur Heart J. 2006 Jan;27(2):237-45. Epub 2005 Sep 15.
92. Transcription factor co-repressors in cancer biology: roles and targeting. Battaglia S, Maguire O,et al. Int J Cancer. 2010 Jun 1;126(11):2511-9. Review.
93. Immortalization by large T-antigen of the adult epididymal duct epithelium. Kirchhoff C;Araki Y,et al. Mol Cell Endocrinol .2004V216N1-2:83-94
94. Association of age-related macular degeneration with polymorphisms in vascular endothelial growth factor and its receptor. Galan A,Ferlin A,et al. Ophthalmology.2010V117N9:1769-74.
95. TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression. Asakura K,Uchida H,et al. Mol Cancer Res .2004V2N6:339-47.
96. Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells. Chen CY,Hsu YL,et al. Food Chem Toxicol .2008V46N7:2476-84.
2. Tina Wang, BA1; Rebecca A. Nelson, PhD2. Five-Year Lung Cancer Survival. Cancer 2010;116:1518–25.
3. http://www.austrianova.com
4. Rainov NG.A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther .2000V11N17:2389-401 .
5. Differential ganciclovir-mediated cytotoxicity and bystander killing in human colon carcinoma cell lines expressing herpes simplex virus thymidine kinase. Boucher PD, Ruch RJ, Shewach DS. Hum Gene Ther. 1998 Apr 10;9(6):801-14.
6. In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus. Ichikawa T, Tamiya T,et al. Cancer Gene Ther. 2000 Jan;7(1):74-82.
7. Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Rogulski KR;Kim JH;Kim SH. Hum Gene Ther .1997V8N1:73-85.
8. Efficacy of recombinant adenovirus-mediated double suicide gene therapy in human keloid fibroblasts.Xu B;Liu ZZ;Zhu GY.Clin Exp Dermatol.2008V33N3: 322-8.
9. Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells.Hamel W;Magnelli L;Chiarugi VP.Cancer Res.1996V56N12:2697 -702.
10. High-malignancy orthotopic nude mouse model of human prostate cancer LNCaP. Wang X;An Z;Geller J. Prostate .1999V39N3:182-6.
11. Optimal amount of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy against hepatocellular carcinoma by M1 macrophage activation. Tsuchiyama T;Nakamoto Y;Sakai Y. Cancer Sci .2008V99N10:2075-82 .
12. Experimental study on intraperitoneal sequential MTX/5-FU therapy for peritoneal seeding in comparison with intravenous administration. Maruyama M;Takamatsu S;Sugano N. Gan To Kagaku Ryoho .1997V24N14:2131-6
13. A Good Practice Guide to the Administrationof Substances and Removal of Blood,including Routes and Volumes. Karl-Heinz Diehl,Robin Hull,et al. JOURNAL OF APPLIED TOXICOLOGY.21,15–23(2001).
14. Oncolytic gene therapy combined with double suicide genes for human bile duct cancer in nude mouse models. Kojima Y;Honda K;Hamada H. J Surg Res.2009V157N1: e63-70 .
15. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo. Uckert W;Kammertons T;Haack K;Hum Gene Ther .1998V9N6:855-65.
16. Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model. Moriuchi S;Wolfe D;Tamura M;Gene Ther.2002V9N9:584-91.
17. Human neural stem cells transduced with IFN-beta and cytosine deaminase genes intensify bystander effect in experimental glioma. Ito S;Natsume A;Shimato S. Cancer Gene Ther .2010V17N5:299-306 .
18. Clinical-grade preparation of human natural regulatory T-cells encoding the thymidine kinase suicide gene as a safety gene. Guillot-Delost M;Cherai M;Hamel Y. J Gene Med .2008V10N8:834-46 .
19. A novel mechanism of synergistic cytotoxicity with 5-fluorocytosine and ganciclovir in double suicide gene therapy. Boucher PD, Im MM, Freytag SO, Shewach DS. Cancer Res. 2006 Mar 15;66(6):3230-7.
20. Kanyama H, Tomita N, Yamano T, et al. Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy. Cancer Res. 2001 Jan 1;61(1):14-8.
21. An apoptosis-inducing gene therapy for pancreatic cancer with a combination of 55-kDa tumor necrosis factor (TNF) receptor gene transfection and mutein TNF administration. Sato T;Yamauchi N;Sasaki H. Cancer Res .1998V58N8:1677-83 .
22. Apoptotic cell death induced by local brain hyperthermia in a rat glioma model. Uesugi S;Yamashita K;Nakashima K. Acta Neuropathol .1998V96N4:351-6.
23. Identifying and quantifying apoptosis: navigating technical pitfalls. Garrity MM;Burgart LJ;Riehle DL. Mod Pathol .2003V16N4:389-94 .
24. Nonviral vectors with a biosurfactant MEL-A promote gene transfection into solid tumors in the mouse abdominal cavity. Inoh Y;Furuno T;Hirashima N. Biol Pharm Bull .2009V32N1:126-8 .
25. Gene therapy for high-grade glioma. Iwami K;Natsume A;Wakabayashi T. Neurol Med Chir (Tokyo) .2010V50N9:727-36 .
26. Gene therapy for gastric diseases. Fumoto S;Nishi J;Nakamura J. Curr Gene Ther .2008V8N3:187-200 .
27. Targeted chemotherapy for head and neck cancer with a chimeric oncolytic adenovirus coding for bifunctional suicide protein FCU1. Dias JD;Liikanen I;Guse K. Clin Cancer Res .2010V16N9:2540-9 .
28. Combination gene therapy using multidrug resistance (MDR1) gene shRNA and herpes simplex virus-thymidine kinase. Park SY ; Lee W ; Lee J. Cancer Lett .2008V261N2:205-14 .
29. Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy. Xie Y;Gilbert JD;Kim JH. Clin Cancer Res .1999V5N12:4224-32 .
30. Gene therapy safety issues come to fore.Fox JL.Nat Biotechnol.1999V17N12:1153 .
1. Ahmedin Jemal,DVM,PhD,et al.Global Cancer Statistics,CA Cancer J Clin 2011, 61:000-000.
2. Five-Year Lung Cancer Survival.Tina Wang;Rebecca A,et al. Cancer 2010;116:1518 -25.
3. http://www.austrianova.com
4. A phaseⅢclinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme.Rainov NG,et al.Hum Gene Ther. 2000V11N17:2389-401 .
5. In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus. Ichikawa T, Tamiya T,et al. Cancer Gene Ther. 2000 Jan;7(1):74-82.
6. Design, synthesis and enzymatic activity of highly selective human mitochondrial thymidine kinase inhibitors. Manfredini S;Baraldi PG,et al. Bioorg Med Chem Lett. 2001V11N10:1329-32 .
7. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Karle P;Renner M;Salmons B.Cancer Gene Ther .2001V8N3:220-30
8. Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Bilsland AE;Anderson CJ;Fletcher-Monaghan AJ. Oncogene .2003V22N3:370-80 .
9. Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity. Kawamura K;Tasaki K;Hamada H. Cancer Gene Ther .2000V7N4:637-43 .
10. The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells. Huang Q;Liu XZ;Kang CS. Cancer Gene Ther .2010V17N3:192-202.
11. Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Schwarzenberger P;Lei D;Freeman SM,et al.Am J Respir Cell Mol Biol .1998V19N2:333-7 .
12. Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models. Zheng FQ;Xu Y;Yang RJ.Acta Pharmacol Sin .2009V30N5:617-27.
13. Do there exist synergistic antitumor effects by coexpression of herpes simplex virus thymidine kinase with cytokine genes on human gastric cancer cell line SGC7901? Zhang JH;Wan MX;Yuan JY. World J Gastroenterol .2004V10N1:147-51.
14. The involvement of nuclear factor-kappa B in cyclooxygenase-2 overexpression in murine colon cancer cells transduced with herpes simplex virus thymidine kinase gene. Konson A;Mahajna JA;Danon A. Cancer Gene Ther .2006V13N12:1093-104 .
15. Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer. Makinen K;Loimas S;Wahlfors J. J Gene Med .2000V2N5:361-7 .
16. A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. Shand N, Weber F, Mariani L, et al. Hum Gene Ther. 1999 Sep 20;10(14):2325-35.
17. Radiosensitization of human glioma cells in vitro and in vivo with acyclovir and mutant HSV-TK75 expressed from adenovirus. Rosenberg E;Hawkins W;Holmes M. Int J Radiat Oncol Biol Phys .2002V52N3:831-6 .
18. Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Black ME;Kokoris MS;Sabo P. Cancer Res .2001V61N7:3022-6 .
19. Cytogenetic genotoxicity of anti-herpes purine nucleoside analogues in CHO cells expressing the thymidine kinase gene of herpes simplex virus type 1: comparison of ganciclovir,penciclovir and acyclovir.Thust R;Tomicic M;Klocking R,et al. 2000V15N2: 177-84 .
20. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Mullen CA, Kilstrup M, Blaese RM. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):33-7.
21. In vivo replication-deficient adenovirus vector-mediated transduction of the cytosine deaminase gene sensitizes glioma cells to 5-fluorocytosine. Dong Y;Wen P;Manome Y. Hum Gene Ther .1996V7N6:713-20 .
22. Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy. Kanyama H;Tomita N;Yamano T. Cancer Res .2001V61N1:14-8 .
23. Enzyme/prodrug gene therapy approach for breast cancer using a recombinant adenovirus expressing Escherichia coli cytosine deaminase. Li Z;Shanmugam N;Katayose D. Cancer Gene Ther .1997V4N2:113-7
24. Combined cytosine deaminase expression, 5-fluorocytosine exposure, and radiotherapy increases cytotoxicity to cholangiocarcinoma cells. Pederson LC;Vickers SM;Buchsbaum DJ. J Gastrointest Surg .1998V2N3:283-91 .
25. Regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver. Ohwada A;Hirschowitz EA;Crystal RG. Hum Gene Ther .1996V7N13:1567-76 .
26. Adenovirus mediated cytosine deaminase gene transduction and 5-fluorocytosine therapy sensitizes mouse prostate cancer cells to irradiation. Anello R;Cohen S;Atkinson G. J Urol .2000V164N6:2173-7 .
27. Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis.Liu SC;Minton NP;Giaccia AJ.Gene Ther.2002V9N4: 291-6 .
28. Superiority of yeast over bacterial cytosine deaminase for enzyme/prodrug gene therapy in colon cancer xenografts. Kievit E;Bershad E;Ng E.Cancer Res.1999; 59:1417-1421.
29. Cytochrome P450 reductase dependent inhibition of cytochrome P450 2B1 activity: Implications for gene directed enzyme prodrug therapy. Lengler J;Omann M;Duvier D. Biochem Pharmacol .2006V72N7:893-901 .
30. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Karle P;Renner M;Salmons B.Cancer Gene Ther .2001V8N3:220-30.
31. Enhanced bystander cytotoxicity of P450 gene-directed enzyme prodrug therapy by expression of the antiapoptotic factor p35. Schwartz PS;Chen CS;Waxman DJ. Cancer Res .2002V62N23:6928-37.
32. Identification of cytochrome P450s in human glioma cell line. Vasquez HG;Strobel H. Int J Oncol .1998V12N6:1291-4 .
33. Sensitization of human breast cancer cells to cyclophosphamide and ifosfamide by transfer of a liver cytochrome P450 gene.Chen L;Waxman DJ;Chen D.Cancer Res. 1996V56N6: 1331-40 .
34. Colorectal cancer-specific cytochrome P450 2W1:intracellular localization, glycosylation, and catalytic activity. Gomez A;Nekvindova J;Travica S.Mol Pharmacol. 2010V78N6: 1004-11.
35. P450-dependent enzymes as targets for prostate cancer therapy. De Coster R;Wouters W;Bruynseels J. J Steroid Biochem Mol Biol.1996V56N1-6 Spec No:133-43 .
36. Injection of encapsulated cells producing an ifosfamide-activating cytochrome P450 for targeted chemotherapy to pancreatic tumors. Muller P;Jesnowski R;Karle P. Ann N Y Acad Sci .1999V880N:337-51 .
37. Diffusible cytotoxic metabolites contribute to the in vitro bystander effect associated with the cyclophosphamide/cytochrome P450 2B1 cancer gene therapy paradigm. Wei MX;Tamiya T;Rhee RJ. Clin Cancer Res .1995V1N10:1171-7 .
38. Technology evaluation: MetXia-P450, Oxford Biomedica. Hunt S. Curr Opin Mol Ther .2001V3N6:595-8 .
39. Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer. Gunzburg WH;Salmons B. Acta Biochim Pol .2005V52N3:601-7 .
40. http://www.austrianova.com
41. Virus-directed enzyme prodrug therapy using CB1954. Grove JI;Searle PF;Weedon SJ. Anticancer Drug Des .1999V14N6:461-72 .
42. Virus directed enzyme prodrug therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954. McNeish IA;Green NK;Gilligan MG. Gene Ther .1998V5N8:1061-9.
43. Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase/ CB1954 is enhanced by high-level coexpression of heat shock protein 70. Djeha HA;Todryk SM;Pelech S. Cancer Gene Ther .2005V12N6:560-71 .
44. Late expression of nitroreductase in an oncolytic adenovirus sensitizes colon cancer cells to the prodrug CB1954. Lukashev AN;Fuerer C;Chen MJ. Hum Gene Ther.2005V16N12:1473-83 .
45. Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB1954. Chung-Faye G;Palmer D;Anderson D. Clin Cancer Res .2001V7N9:2662-8 .
46. Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. Palmer DH;Mautner V;Mirza D. J Clin Oncol.2004V22N9: 1546-52.
47. Nitroreductase: a prodrug-activating enzyme for cancer gene therapy. Searle PF;Chen MJ;Hu L. Clin Exp Pharmacol Physiol .2004V31N11:811-6.
48. A phaseⅠ/Ⅱclinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984]. Patel P;Young JG;Mautner V. Mol Ther .2009V17N7:1292-9.
49. Bystander or no bystander for gene directed enzyme prodrug therapy. Dachs GU;Hunt MA;Syddall S. Molecules .2009V14N11:4517-45 .
50. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Moolten FL. Cancer Res. 1986 Oct;46(10):5276-81.
51. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Ram Z, Culver KW,et al. Cancer Res. 1993 Jan 1;53(1):83-8.
52. Gene-directed enzyme prodrug therapy with a mustard prodrug/carboxypeptidase G2 combination. Marais R;Spooner RA;Light Y.Cancer Res.1996V56N20:4735-42.
53. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Culver KW, Ram Z, et al.Science.1992 Jun 12;256(5063): 1550-2.
54. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Mesnil M;Piccoli C;Tiraby G. Proc Natl Acad Sci U S A .1996V93N5:1831-5.
55. Bystander effect in glioblastoma cells with a predominant cytoplasmic localization of connexin43. Cottin S;Ghani K;Caruso M.Cancer Gene Ther. 2008V15N12:823-31.
56. Bystander tumoricidal effect and gap junctional communication in lung cancer cell lines. Imaizumi K;Hasegawa Y;Kawabe T. Am J Respir Cell Mol Biol.1998V18N2: 205-12.
57. The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified. Freeman SM, Abboud CN, et al.Cancer Res. 1993 Nov 1;53(21): 5274-83.
58. Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Hamel W;Magnelli L;Chiarugi VP.Cancer Res. 1996 Jun 15;56(12): 2697-702.
59. Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma.Kuriyama S,Nakatani T,et al. Hepatology.1995 Dec;22(6): 1838-46.
60. Cytochrome P450 gene-directed enzyme prodrug therapy (GDEPT) for cancer. Chen L;Waxman DJ. Curr Pharm Des .2002V8N15:1405-16.
61. Tentative novel mechanism of the bystander effect in glioma gene therapy with HSV-TK/GCV system. Bai S,Du L,Liu W.Biochem Biophys Res Commun. 1999V259N2: 455-9
62. Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors.Barba D,Hardin J,Proc Natl Acad Sci U S A.1994 May 10;91(10): 4348-52.
63. AV.TK-mediated killing of subcutaneous tumors in situ results in effective immunization against established secondary intracranial tumor deposits. Okada T;Shah M;Higginbotham JN. Gene Ther .2001V8N17:1315-22 .
64. Purified herpes simplex thymidine kinase retroviral particles. II. Influence of clinical parameters and bystander killing mechanisms. Kruse CA,Lamb C,et al.Cancer Gene Ther .2000V7N1:118-27 .
65. Enhancement of tumor killing using a combination of tumor immunization and HSV-tk suicide gene therapy. Ramesh R, Munshi A,et al. Int J Cancer. 1999 Jan 29;80(3):380-6.
66. Differential ganciclovir-mediated cytotoxicity and bystander killing in human colon carcinoma cell lines expressing herpes simplex virus thymidine kinase. Boucher PD, Ruch RJ,et al. Hum Gene Ther. 1998 Apr 10;9(6):801-14.
67. Hepatic intra-arterial delivery of a retroviral vector expressing the cytosine deaminase gene, controlled by the CEA promoter and intraperitoneal treatmentwith 5-fluorocytosine suppresses growth of colorectal liver metastases. Humphreys MJ, Ghaneh P,et al. Gene Ther. 2001 Aug;8(16):1241-7.
68. Genetically modified CD34+ cells exert a cytotoxic bystander effect on human endothelial and cancer cells. Arafat WO, Casado E,et al. Clin Cancer Res. 2000 Nov;6(11):4442-8.
69. Protection of herpes simplex virus thymidine kinase-transduced cells from ganciclovir-mediated cytotoxicity by bystander cells: the Good Samaritan effect. Wygoda MR, Wilson MR,et al. Cancer Res. 1997 May 1;57(9):1699-703.
70. Evaluation of the bystander effect in experimental brain tumors bearing herpes simplex virus-thymidine kinase gene by serial magnetic resonance imaging. Namba H, Iwadate Y,et al. Hum Gene Ther. 1996 Oct 1;7(15):1847-52.
71. A "distant" bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Kianmanesh AR, Perrin H,et al. Hum Gene Ther. 1997 Oct 10;8(15):1733-5.
72. An HSVtk-mediated local and distant antitumor bystander effect in tumors of head and neck origin in athymic mice. Bi W,Kim YG,et al. Cancer Gene Ther. 1997 Jul-Aug;4(4):246-52.
73. Suicide gene therapy for plasma cell tumors. Dilber MS, Abedi MR,et al. Blood. 1996 Sep 15;88(6):2192-200.
74. Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Rogulski KR,Kim JH,et al.Hum Gene Ther. 1997 Jan 1;8(1):73-85.
75. A novel mechanism of synergistic cytotoxicity with 5-fluorocytosine and ganciclovir in double suicide gene therapy. Boucher PD, Im MM,et al. Cancer Res. 2006 Mar 15;66(6):3230-7.
76. Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine. Adachi Y, Tamiya T,et al. Hum Gene Ther. 2000 Jan 1;11(1): 77-89.
77. Combination of the bioreductive drug tirapazamine with the chemotherapeutic prodrug cyclophosphamide for P450/P450-reductase-based cancer gene therapy. Jounaidi Y, Waxman DJ,et al. Cancer Res. 2000 Jul 15;60(14):3761-9.
78. Dlx5 induces expression of COL1A1 promoter contained in a retrovirus vector. Tadic T;Erceg I,et al. Croat Med J .2001V42N4:436-9.
79. Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma.Than SS,Kataoka K,et al. Oncol Rep .2011VN:
80. Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector. Yagi H,Ogura T,et al. J Gene Med .2011VN:
81. Rapid and sensitive lentivirus vector-based conditional gene expression assay to monitor and quantify cell fusion activity. Goncalves MA,Janssen JM,et al. PLoS One.2010V5N6:e10954.
82. A herpes simplex virus vector system for expression of complex cellular cDNA libraries. Wolfe D,Craft AM,et al. J Virol .2010V84N14:7360-8.
83. Muscle Damage Following Delivery of Naked Plasmid DNA into Skeletal Muscles is Batch-Dependent. Wooddell CI,Subbotin VM,et al. Hum Gene Ther .2010VN:
84. Novel cationic lipids based on malonic acid amides backbone: transfection efficacy and cell toxicity properties. Heinze M;Brezesinski G,et al. Bioconjug Chem .2010V21N4:696-708.
85. Cationic polymer optimization for efficient gene delivery. Sun X,Zhang N,et al. Mini Rev Med Chem .2010V10N2:108-25 .
86. Targeted drug and gene delivery systems for lung cancer therapy.Sundaram S,Trivedi R,et al. Clin Cancer Res .2009V15N23:7299-308.
87. Nanoparticles for gene delivery: a brief patent review. Xu G,Zhang N,et al.Recent Pat Drug Deliv Formul .2009V3N2:125-36
88. Targeted gene transfer to hepatocellular carcinoma cells in vitro using a novel monoclonal antibody-based gene delivery system. Mohr L, Schauer JI,et al. Hepatology. 1999 Jan;29(1): 82-9.
89. Design of a bifunctional fusion protein for ovarian cancer drug delivery: single-chain anti-CA125 core-streptavidin fusion protein. Wang WW, Das D,et al. Eur J Pharm Biopharm. 2007 Mar;65(3):398-405. Epub 2006 Dec 27.
90. Effect of cell media on polymer coated superparamagnetic iron oxide nanoparticles (SPIONs): colloidal stability, cytotoxicity, and cellular uptake studies. Petri-Fink A, Steitz B,et al. Eur J Pharm Biopharm. 2008 Jan;68(1): 129-37.Epub 2007 Jul 13.
91. Myocardial delivery of colloid nanoparticles using ultrasound-targeted microbubble destruction. Vancraeynest D, Havaux X,et al. Eur Heart J. 2006 Jan;27(2):237-45. Epub 2005 Sep 15.
92. Transcription factor co-repressors in cancer biology: roles and targeting. Battaglia S, Maguire O,et al. Int J Cancer. 2010 Jun 1;126(11):2511-9. Review.
93. Immortalization by large T-antigen of the adult epididymal duct epithelium. Kirchhoff C;Araki Y,et al. Mol Cell Endocrinol .2004V216N1-2:83-94
94. Association of age-related macular degeneration with polymorphisms in vascular endothelial growth factor and its receptor. Galan A,Ferlin A,et al. Ophthalmology.2010V117N9:1769-74.
95. TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression. Asakura K,Uchida H,et al. Mol Cancer Res .2004V2N6:339-47.
96. Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells. Chen CY,Hsu YL,et al. Food Chem Toxicol .2008V46N7:2476-84.