In Vivo Antitumor Activity of HSV tk/CD Combinative Gene Toward Human Cholangiocarcinoma Cells(QBC939)_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

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LI Meisheng ¹ , LIANG Lijian ² , HUANG Jiefu ³ , HU Wenjie ² , ZENG Zuojun. ²

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Keywords：

Cholangiocarcinoma Cytosine deaminase Thymidine kinase Gene therapy

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【Abstract】Objective To study the antitumor activity of HSVtk/CD combinative gene toward human cholangiocarcinoma in vivo. Methods Nude mouse models with transplanted subcutaneous cholangiocarcinoma were constructed and divided into 4 groups randomly, each group had 8 mice. Adenovirus solution free from suicide gene was injected in subcutaneous tumors of each mouse of control group. Adenovirus solution containing cytosine deaminase (CD), thymidine kinase (tk) and HSVtk/CD fusional gene were injected into single suicide gene either HSVtk or CD was transinfected into the tumor cells by injecting viras into subcutaneous tumor of mice of CD gene,tk gene and fused CD and tk gene group respectively. 24 hours after the injection, 5fluorocytosine (5FC) and ganciclovir (GCV) were injected introabdominally in each mouse. Growth of the tumors were monitored.Results Tumor growth of the genetransfection groups was suppressed in different degrees. Compared with the control group, the suppressing rates of the genetransfection groups were 41.2%, 55.7% and 70.0% respectively (P＜0.05). Histological examination showed good tumor growth in the control group, and tumor necrosis in the other 3 groups, particularly obvious in the group transfected with pAd(HSVtk/CD).Conclusion Combinative gene system has a b antitumor effect on cholangiocarcinoma in vivo. But it’s not powerful enough to eliminate tumor thoroughly because of insufficient “Bystander effect”.

Citation： LI Meisheng,LIANG Lijian,HUANG Jiefu,HU Wenjie,ZENG Zuojun.. In Vivo Antitumor Activity of HSV tk/CD Combinative Gene Toward Human Cholangiocarcinoma Cells(QBC939). CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2005, 12(6): 581-584. doi: Copy

1 Namba H, Tagawa M, Miyagawa T, et al. Treatment of rat experimental brain tumors by herpes simplex virus thymidine kinase gene transduced allogeneic tumor cells and ganciclovir [Ｊ]. Cancer Gene Ther, 2000; 7(6)9472 Huber BE, Austin EA, Good SS, et al. In vivo antitumor activity of 5fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase [Ｊ]. Cancer Res, 1993; 53(19)46193 Tanaka T, Kanai F, Okabe S, et al. Adenovirusmediated prodrug gene therapy for carcinoembryonic antigenproducing human gastric carcinoma cells in vitro [Ｊ]. Cancer Res, 1996; 56(6)13414 Cool V, Pirotte B, Gerard C, et al. Curative potential of herpes simplex virus thymidine kinase gene transfer in rats with 9L gliosarcoma [Ｊ]. Hum Gene Ther, 1996; 7(5)6275 Uckert W, Kammertons T, Haack K, et al. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo [Ｊ]. Hum Gene Ther, 1998; 9(6)8556 Rogulski KR, Wing MS, Paielli DL, et al. Double suicide gene therapy augments the antitumor activity of a replicationcompetent lytic adenovirus through enhanced cytotoxicity and radiosensitization [Ｊ]. Hum Gene Ther, 2000; 11(1)677 魏道严，糜军，陈诗书. 细菌内同源重组法高效制备含CD、TK融合自杀基因重组体腺病毒 [Ｊ]. 癌症， 2000； 19（5）3998 Klatzmann D, Valery CA, Bensimon G, et al. A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma [Ｊ]. Hum Gene Ther， 1998; 9(17)25959 Shand N, Weber F, Mariani L, et al. 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. GLI328 European-Canadian Study Group [Ｊ]. Hum Gene Ther, 1999; 10(14)232510 Palu G, Cavaggioni A, Calvi P, et al. Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: a pilot study in humans [Ｊ]. Gene Ther, 1999; 6(3)330.

1. 1 Namba H, Tagawa M, Miyagawa T, et al. Treatment of rat experimental brain tumors by herpes simplex virus thymidine kinase gene transduced allogeneic tumor cells and ganciclovir [Ｊ]. Cancer Gene Ther, 2000; 7(6)9472 Huber BE, Austin EA, Good SS, et al. In vivo antitumor activity of 5fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase [Ｊ]. Cancer Res, 1993; 53(19)46193 Tanaka T, Kanai F, Okabe S, et al. Adenovirusmediated prodrug gene therapy for carcinoembryonic antigenproducing human gastric carcinoma cells in vitro [Ｊ]. Cancer Res, 1996; 56(6)13414 Cool V, Pirotte B, Gerard C, et al. Curative potential of herpes simplex virus thymidine kinase gene transfer in rats with 9L gliosarcoma [Ｊ]. Hum Gene Ther, 1996; 7(5)6275 Uckert W, Kammertons T, Haack K, et al. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo [Ｊ]. Hum Gene Ther, 1998; 9(6)8556 Rogulski KR, Wing MS, Paielli DL, et al. Double suicide gene therapy augments the antitumor activity of a replicationcompetent lytic adenovirus through enhanced cytotoxicity and radiosensitization [Ｊ]. Hum Gene Ther, 2000; 11(1)677 魏道严，糜军，陈诗书. 细菌内同源重组法高效制备含CD、TK融合自杀基因重组体腺病毒 [Ｊ]. 癌症， 2000； 19（5）3998 Klatzmann D, Valery CA, Bensimon G, et al. A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma [Ｊ]. Hum Gene Ther， 1998; 9(17)25959 Shand N, Weber F, Mariani L, et al. 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. GLI328 European-Canadian Study Group [Ｊ]. Hum Gene Ther, 1999; 10(14)232510 Palu G, Cavaggioni A, Calvi P, et al. Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: a pilot study in humans [Ｊ]. Gene Ther, 1999; 6(3)330.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

In Vivo Antitumor Activity of HSV tk/CD Combinative Gene Toward Human Cholangiocarcinoma Cells(QBC939)

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