[en] Tumor cells expressing the herpes simplex virus type 1 thymidine kinase (HSV-tk) gene are killed by nucleoside analogues such as ganciclovir (GCV). GCV affects not only the cells expressing HSV-tk but also neighboring cells that do not express the gene; this phenomenon commonly is called "bystander effect." GCV metabolites transfer via gap junctional intercellular communication (GJIC) accounts for the bystander effect in different cell lines, but other mechanisms have also been described. In this study, we analyzed the mechanisms of the bystander effect in two cell lines exhibiting different capacities of communication (DHD/K12 and 9L). The 9L cells exhibited a very good bystander effect, which was completely blocked by a long-term inhibitor of GJIC, 18 alpha-glycyrrhetinic acid. DHD/K12 cells exhibited a moderate bystander effect that was not abolished by 18 alpha-glycyrrhetinic acid or 1-octanol, another strong inhibitor of GJIC. Interestingly, we also observed a bystander effect in cultures where HSV-tk-expressing DHD/K12 cells were physically separated from their untransfected counterparts but grown in the same medium. Moreover, the transfer of filtered conditioned medium from GCV-treated HSV-tk-expressing DHD/K12 cells to DHD/K12 parental cells induced a decrease of survival in a concentration-dependent manner, suggesting that the bystander effect in this cell line was mediated by a soluble factor.
Disciplines :
Oncology
Author, co-author :
Princen, Frederic
Robe, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Lechanteur, Chantal ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Mesnil, M.
Rigo, Jean-Marie ; Université de Liège - ULiège > Département Argenco : Secteur GeMMe > Matériaux non métal. & Procédés d'exécution des construct.
Gielen, Jacques
Merville, Marie-Paule ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Language :
English
Title :
A Cell Type-Specific and Gap Junction-Independent Mechanism for the Herpes Simplex Virus-1 Thymidine Kinase Gene/Ganciclovir-Mediated Bystander Effect
Publication date :
November 1999
Journal title :
Clinical Cancer Research
ISSN :
1078-0432
eISSN :
1557-3265
Publisher :
American Association for Cancer Research, Inc. (AACR)
Esandi, M. C., Van Someren, G. D., Vincent, A. J. P. E., Van Bekkum, D. W., Valerio, D., Bout, A., and Noteboom, J. L. Gene therapy of experimental malignant mesothelioma using adenovirus vectors encoding the HSVtk gene. Gene Ther., 4: 280-287, 1997.
Yee, D., McGuire, S. E., Brynner, N., Kozelsky, T. W., Allred, D. C., Chen, S., and Woo, S. L. C. Adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase in an ascites model of human breast cancer. Hum. Gene Ther., 7: 1251-1257, 1996.
Yoshida, K., Kawami, H., Yamaguchi, Y., Kumiyasu, H., Nishiyama, M., Hirai, T., Yanagihara, K., and Tahara, E. Retrovirally transmitted gene therapy for gastric carcinoma using herpes simplex virus thymidine kinase gene. Cancer (Phila.), 75: 1467-1471, 1995.
Beck, C., Cayeux, S., Lupton, S. D., Dörken, B., and Blankenstein, T. The thymidine kinase/ganciclovir-mediated "suicide" effect is variable in different tumor cells. Hum. Gene Ther., 6: 1525-1530, 1995.
Culver, K. W., Ram, Z., Wallbridge, S., Ishii, H., Oldfield, E. H., and Blaese, R. M. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science (Washington DC), 256: 1550-1552, 1992.
Smythe, W. R., Hwang, H. C., Elshami, A. A., Amin, K. M., Eck, S. L., Davidson, B. L., Wilson, J. M., Kaiser, L. R., and Abelda, S. M. Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene. Ann. Surg., 222: 78-86, 1995.
Caruso, M., Panis, Y., Gagandeep, S., Houssin, D., Salzmann, J., and Klatzmann, D. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc. Natl. Acad. Sci. USA, 90: 7024-7028, 1993.
Ezzeddine, Z. D., Martuza, R. L., Platika, D., Short, M. P., Malick, A., Choi, B., and Breakefield, X. O. Selective killing of glioma cells in culture and in vivo by retrovirus transfer of herpes simplex virus thymidine kinase. New Biol., 3: 608-614, 1991.
Culver, K. W., Van Gilder, J., Link, C. J., Carlstrom, C., Buroker, T., Yuh, W., Koch, K., Schabold, K., Doornbas, S., Wetjen, B., and Blaese, R. M. Gene therapy for the treatment of malignant brain tumors with in vivo tumor transduction with the herpes simplex thymidine kinase gene/ganciclovir system. Hum. Gene Ther., 5: 343-379, 1994.
Oldfield, E. H., Ram, Z., Culver, K. W., Blaese, R. M., and DeVroom, H. L. Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum. Gene Ther., 4: 39-69, 1993.
Field, A. K., Davies, M. E., DeWitt, C., Perry, H. C., Liou, R., Germershausen, J., Karkas, J. D., Ashton, W. T., Johnston, D. B. R., and Tolman, R. L. 9-2-Hydroxy-1-(hydroxymethyl)ethoxy-methyl-guanine: a selective inhibitor of herpes group virus replication. Proc. Natl. Acad. Sci. USA, 80: 4139-4143, 1983.
Davidson, R. L., Kaufman, E. R., Crumpacker, C. S., and Schnipper, L. E. Inhibition of herpes simplex virus transformed cells by acycloguanosine: mechanisms of uptake and toxicity. Virology, 113: 9-19, 1981.
Elion, G. B., Furma;, P. A., Fyfe, J. A., de Miranda, P., Beauchamp, L., and Schaeffer, H. J. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proc. Natl. Acad. Sc. USA, 74: 5716-5720, 1977.
Ram, Z., Culver, K. W., Walbridge, S., Blaese, R. M., and Oldfield, E. H. In situ retroviral-mediated gene transfer for treatment of brain tumors in rats. Cancer Res., 53: 83-88, 1993.
Chen, C.-Y., Chang, Y.-N., Ryan, P., Linscott, M., McGarrity, G. J., and Chiang, Y. L. Effect of herpes simplex virus thymidine kinase expression levels on ganciclovir-mediated cytotoxicity and the "bystander effect." Hum. Gene Ther., 6: 1467-1476, 1995.
Freeman, S. M., Abboud, C. N., Whartenby, K. A., Packman, C. H., Koeplin, D. S., Moolten, F. L., and Abraham, G. N. The. "bystander-effect": tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res., 53: 5274-5283, 1993.
Bi, W. L., Parysek, L. M., Wamick, R., and Stamhrook, P. J. In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV-TK retroviral gene therapy. Hum. Gene Ther., 4: 725-731, 1993.
Pitts, J. D. Cancer gene therapy: a bystander effect using the gap junctional pathway. Mol. Carcinog., 11: 127-130, 1994.
Fick, J., Barker, F. G., II, Dazin, P., Westphalle, E. M., Beyer, E. C., and Israel, M. A. The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc. Natl. Acad. Sci. USA, 92: 11071-11075, 1995.
Mesnil, M., Piccoli, C., Tiraby, G., Willecke, K., and Yamasaki, H. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc. Natl. Acad. Sci. USA, 93: 1831-1835, 1996.
Elshami, A. A., Saavedra, A., Zhang, H., Kucharczuk, J. C., Spray, D. C., Fishman, G. I., Amin, K. M., Kaiser, L. R., and Albelda, S. M. Gap junctions play a role in the "bystander effect" of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther., 3: 85-92, 1996.
Siraç Dilber, M., Abedi, M. R., Christensson, B., Björkstrand, B., Kidder, G. M., Naus, C. C. G., Gahrton, G., and Smith, C. I. E. Gap junctions promote the bystander effect of herpes simplex virus thymidine kinase in vivo. Cancer Res., 57: 1523-1528, 1997.
Ramesh, R., Marrogi, A. J., Munshi, A., Abboud, C. N., and Freeman, S. M. In vivo analysis of the "bystander effect": a cytokine cascade. Exp. Hematol., 24: 829-838, 1996.
Freeman, S. M., Ramesh, R., Shastri, M., Munshi, A., Jensen, A. K., and Marrogi, A. J. The role of cytokines in mediating the bystander effect using HSV-TK xenogeneic cells. Cancer Lett., 92: 167-174, 1995.
Ram, Z., Walbridge, S., Shawker, T., Culver, K. W., Blaese, R. M., and Oldfield, E. H. The effect of thymidine kinase transduction and ganciclovir on tumor vasculature and growth of 9L gliomas in rats. J. Neurosurg., 81: 256-260, 1994.
Stewart, W. W. Functional connections between cells as revealed by dye-coupling with a highly fluorescent naphtalimide tracer. Cell, 14: 741-759, 1978.
Davidson, J. S., Baumgarten, I. M., and Harley, E. H. Reversible inhibition of intercellular junctional communication by glycyrrhetinic acid. Biochem. Biophys. Res. Commun., 134: 29-36, 1986.
Imaizumi, K., Hasegawa, Y., Kawabe, T., Emi, N., Saito, H., Naruse, K., and Shimokata, K. Bystander tumoricidal effect and gap communication in lung cancer cell lines. Am. J. Respir. Cell Mol. Biol., 18: 205-212, 1998.
Johnston, M. F., Simon, S. A., and Ramon, F. Interaction of anaesthetics with electrical synapses. Nature (Lond.), 286: 498-499, 1980.
Reynhout, J. K., Lampe, P. D., and Johnson, R. G. An activator of protein kinase C inhibits gap junction communication between cultured bovine lens cells. Exp. Cell Res., 198: 337-342, 1992.
Li, H., Liu, T., Lazrak, A., Peracchia, C., Goldberg, G. S., Lampe, P. D., and Johnson, R. G. Properties and regulation of gap junctional hemichannels in the plasma membranes of cultured cells. J. Cell Biol., 134: 1019-1030, 1996.
Boucher, P. D., Ruch, R. J., and Shewach, D. S. Differential ganciclovir-mediated cytotoxicity and bystander killing in human colon carcinoma cell lines expressing herpes simplex virus thymidine kinase. Hum. Gene Then., 9: 801-814, 1998.
Touraine, R. L., Vahanian, N., Ramsey, W. J., and Blaese, R. M. Enhancement of the herpes simplex thymidine kinase/ganciclovir bystander effect and its antitumor efficacy in vivo by pharmacologic manipulation of gap junctions. Hum. Gene Ther., 9: 2385-2391, 1998.
Park, J. Y., Elshami, A. A., Amin, K., Rizk, N., Kaiser, L. R., and Albelda, S. M. Retinoids augment the bystander effect in vitro and in viva in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy. Gene Ther., 4: 909-917, 1997.