The Experts below are selected from a list of 6618 Experts worldwide ranked by ideXlab platform
Vincent Bours - One of the best experts on this subject based on the ideXlab platform.
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pharmacological modulation of the Bystander Effect in the herpes simplex virus thymidine kinase ganciclovir gene therapy system Effects of dibutyryl adenosine 3 5 cyclic monophosphate alpha glycyrrhetinic acid and cytosine arabinoside
Biochemical Pharmacology, 2000Co-Authors: Pierre Robe, Frederic Princen, Didier Martin, Brigitte Malgrange, Achille Stevenaert, Gustave Moonen, Jacques E Gielen, Mariepaule Merville, Vincent BoursAbstract:The herpes simplex virus type 1 thymidine kinase (HSV1-tk) suicide gene/ganciclovir system was first applied to the treatment of glioblastoma tumors, but was hampered by the low gene transfection yield. Fortunately, the gap junction-dependent diffusion of phosphorylated ganciclovir metabolites from transfected cells to their neighbors proved to enhance the overall benefit of this strategy. However, as tumor cells are often gap junction-deficient, we sought to restore this property pharmacologically and hence to improve the efficacy of the treatment. We demonstrated that this approach was feasible in glioblastoma cells using dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) (100 microM) as a pharmacological inducer of gap junctions. alpha-Glycyrrhetinic acid (25 microM), on the other hand, strongly inhibited both gap junction-mediated intercellular communication and the Bystander Effect, thus confirming the role of gap junctions in HSV-tk-mediated Bystander killing. Using cytosine arabinoside as a growth inhibitor, we underlined the role of tumor cell proliferation in the sensitivity of HSV-tk-transfected cells to ganciclovir and demonstrated its correlation with the importance of the Bystander Effect.
Marc Mesnil - One of the best experts on this subject based on the ideXlab platform.
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stimulation of intercellular communication of poor communicating cells by gap junction competent cells enhances the hsv tk gcv Bystander Effect in vitro
International Journal of Cancer, 2001Co-Authors: Toshiaki Tanaka, Marc Mesnil, Hiroshi YamasakiAbstract:We have previously shown that gap-junctional intercellular communication (GJIC) appears to play a role in the Bystander Effect that is observed in anticancer suicide gene therapy mediated by herpes simplex virus (HSV) thymidine kinase (tk) and ganciclovir (GCV). We now report that when connexin-expressing (Cx+) cells are present within a noncommunicating population of cells (Cx−), there is GJIC between the Cx+ and Cx− cells and that due to this stimulation of GJIC, the Bystander Effect also occurs when the 2 cell types are mixed. We transfected HeLa cells, which do not express any detectable level of connexin, with Cx43. The Cx+ and Cx− HeLa cells were further transfected with the tk gene, giving 4 phenotypes: Cx+tk−, Cx+tk+, Cx−tk+ and Cx−tk−. We observed GJIC between Cx+ and Cx− cells, but not between Cx− and Cx− cells, regardless of the tk genotype. Similarly, we observed the HSV-tk/GCV Bystander Effect in Cx+tk−/Cx−tk+ and Cx+tk+/Cx−tk− cocultures. The extent of the Bystander Effect in cocultures of Cx+tk− and Cx−tk+ cells was stronger than in cocultures of Cx+tk+ and Cx−tk− cells when each mixture had the same ratio of Cx+ and tk+ cells. These results suggest that Cx-expressing HeLa cells stimulate GJIC capacity between them and non-Cx-expressing HeLa cells, which mediates the Bystander Effect in mixtures of Cx+ cells and Cx− cells in vitro. Thus, Cx expression even in only a limited fraction of tumor cells may enhance the efficacy of the HSV-tk/GCV strategy by inducing a Bystander Effect. © 2001 Wiley-Liss, Inc.
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Bystander Effect in herpes simplex virus thymidine kinase ganciclovir cancer gene therapy role of gap junctional intercellular communication
Cancer Research, 2000Co-Authors: Marc Mesnil, Hiroshi YamasakiAbstract:Antitumor suicide gene therapy is one of the emerging strategies against cancer. It consists of the introduction into cancer cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Because this therapeutic gene cannot be easily introduced into the whole cell population of a tumor, the successful eradication of tumors depends on a phenomenon called the "Bystander Effect," by which the introduced gene can affect even cells in which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumor eradication. One such suicide gene, the thymidine kinase gene from the herpes simplex virus, in combination with the prodrug ganciclovir, has been extensively and successfully used in some animal models exhibiting a strong Bystander Effect. Among the mechanisms involved in this phenomenon, gap junctional intercellular communication (GJIC) is directly involved in the transfer of the toxic metabolites of ganciclovir, which pass directly from herpes simplex virus thymidine kinase-expressing cells to surrounding cells that do not express it. Because GJIC appears to be a mediator of the Bystander Effect both in vitro and in vivo, here we review possible molecular strategies for enhancing the extent of tumor cell death by increasing the intratumoral GJIC capacity.
Hiroshi Yamasaki - One of the best experts on this subject based on the ideXlab platform.
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stimulation of intercellular communication of poor communicating cells by gap junction competent cells enhances the hsv tk gcv Bystander Effect in vitro
International Journal of Cancer, 2001Co-Authors: Toshiaki Tanaka, Marc Mesnil, Hiroshi YamasakiAbstract:We have previously shown that gap-junctional intercellular communication (GJIC) appears to play a role in the Bystander Effect that is observed in anticancer suicide gene therapy mediated by herpes simplex virus (HSV) thymidine kinase (tk) and ganciclovir (GCV). We now report that when connexin-expressing (Cx+) cells are present within a noncommunicating population of cells (Cx−), there is GJIC between the Cx+ and Cx− cells and that due to this stimulation of GJIC, the Bystander Effect also occurs when the 2 cell types are mixed. We transfected HeLa cells, which do not express any detectable level of connexin, with Cx43. The Cx+ and Cx− HeLa cells were further transfected with the tk gene, giving 4 phenotypes: Cx+tk−, Cx+tk+, Cx−tk+ and Cx−tk−. We observed GJIC between Cx+ and Cx− cells, but not between Cx− and Cx− cells, regardless of the tk genotype. Similarly, we observed the HSV-tk/GCV Bystander Effect in Cx+tk−/Cx−tk+ and Cx+tk+/Cx−tk− cocultures. The extent of the Bystander Effect in cocultures of Cx+tk− and Cx−tk+ cells was stronger than in cocultures of Cx+tk+ and Cx−tk− cells when each mixture had the same ratio of Cx+ and tk+ cells. These results suggest that Cx-expressing HeLa cells stimulate GJIC capacity between them and non-Cx-expressing HeLa cells, which mediates the Bystander Effect in mixtures of Cx+ cells and Cx− cells in vitro. Thus, Cx expression even in only a limited fraction of tumor cells may enhance the efficacy of the HSV-tk/GCV strategy by inducing a Bystander Effect. © 2001 Wiley-Liss, Inc.
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Bystander Effect in herpes simplex virus thymidine kinase ganciclovir cancer gene therapy role of gap junctional intercellular communication
Cancer Research, 2000Co-Authors: Marc Mesnil, Hiroshi YamasakiAbstract:Antitumor suicide gene therapy is one of the emerging strategies against cancer. It consists of the introduction into cancer cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Because this therapeutic gene cannot be easily introduced into the whole cell population of a tumor, the successful eradication of tumors depends on a phenomenon called the "Bystander Effect," by which the introduced gene can affect even cells in which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumor eradication. One such suicide gene, the thymidine kinase gene from the herpes simplex virus, in combination with the prodrug ganciclovir, has been extensively and successfully used in some animal models exhibiting a strong Bystander Effect. Among the mechanisms involved in this phenomenon, gap junctional intercellular communication (GJIC) is directly involved in the transfer of the toxic metabolites of ganciclovir, which pass directly from herpes simplex virus thymidine kinase-expressing cells to surrounding cells that do not express it. Because GJIC appears to be a mediator of the Bystander Effect both in vitro and in vivo, here we review possible molecular strategies for enhancing the extent of tumor cell death by increasing the intratumoral GJIC capacity.
Pierre Robe - One of the best experts on this subject based on the ideXlab platform.
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pharmacological modulation of the Bystander Effect in the herpes simplex virus thymidine kinase ganciclovir gene therapy system Effects of dibutyryl adenosine 3 5 cyclic monophosphate alpha glycyrrhetinic acid and cytosine arabinoside
Biochemical Pharmacology, 2000Co-Authors: Pierre Robe, Frederic Princen, Didier Martin, Brigitte Malgrange, Achille Stevenaert, Gustave Moonen, Jacques E Gielen, Mariepaule Merville, Vincent BoursAbstract:The herpes simplex virus type 1 thymidine kinase (HSV1-tk) suicide gene/ganciclovir system was first applied to the treatment of glioblastoma tumors, but was hampered by the low gene transfection yield. Fortunately, the gap junction-dependent diffusion of phosphorylated ganciclovir metabolites from transfected cells to their neighbors proved to enhance the overall benefit of this strategy. However, as tumor cells are often gap junction-deficient, we sought to restore this property pharmacologically and hence to improve the efficacy of the treatment. We demonstrated that this approach was feasible in glioblastoma cells using dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) (100 microM) as a pharmacological inducer of gap junctions. alpha-Glycyrrhetinic acid (25 microM), on the other hand, strongly inhibited both gap junction-mediated intercellular communication and the Bystander Effect, thus confirming the role of gap junctions in HSV-tk-mediated Bystander killing. Using cytosine arabinoside as a growth inhibitor, we underlined the role of tumor cell proliferation in the sensitivity of HSV-tk-transfected cells to ganciclovir and demonstrated its correlation with the importance of the Bystander Effect.
Masatoshi Tagawa - One of the best experts on this subject based on the ideXlab platform.
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Bystander Effect in uracil phosphoribosyltransferase 5 fluorouracil mediated suicide gene therapy is correlated with the level of intercellular communication
International Journal of Oncology, 2001Co-Authors: Kiyoko Kawamura, Keizo Takenaga, Shigeru Sakiyama, Rumana Bahar, Hiroki Namba, Hirofumi Hamada, Mika Seimiya, Masatoshi TagawaAbstract:We examined whether a suicide gene/prodrug system using the uracil phosphoribosyltransferase (UPRT) of E. coli origin and 5-fluorouracil (5-FU) could achieve a Bystander Effect in two rodent tumor cell lines, murine colon carcinoma (Colon 26) and rat gliosarcoma (9L) cells. Cytotoxicity tests of mixed populations consisting of parent and transduced cells showed that the Bystander Effect was not produced in Colon 26 cells in either the UPRT/5-FU system or the herpes simplex virus-thymidine kinase/ganciclovir system but a strong Bystander Effect was evidenced by both suicide gene systems in 9L cells. The expression level of connexin 43, a protein that constitutes gap junctions, was high in 9L but low in Colon 26 cells. A gap junction-permeable fluorescein dye could be transferred among 9L cells but hardly at all among Colon 26 cells. Taken together, the efficacy of the Bystander Effect in the UPRT/5-FU system can be affected by gap junction-mediated intercellular communication.
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Bystander Effect mediated therapy of experimental brain tumor by genetically engineered tumor cells
Human Gene Therapy, 1998Co-Authors: Hiroki Namba, Masatoshi Tagawa, Yasuo Iwadate, Masaki Kimura, Kanji Sueyoshi, Shigeru SakiyamaAbstract:ABSTRACT Transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene, followed by administration of ganciclovir (GCV), generates the “Bystander Effect,” in which HSV-tk-negative wild-type cells, as well as HSV-tk-expressing cells, are killed by GCV. To eradicate an intracranial tumor by this Bystander Effect, we injected the tumor cells transduced with the HSV-tk gene (TK cells) in the vicinity of the preimplanted wild-type tumor and then administered GCV. Wild-type 9L-gliosarcoma cells (1 × 105) were implanted into the brain of syngeneic Fisher rats. On the next day, rats were injected with TK cells (1 × 105 or 3 × 105) or medium alone at the same brain coordinate and then treated with GCV or saline. Administration of GCV significantly prolonged the survival of the rats injected with TK cells compared with that injected with medium alone (p < 0.01). Reduction in tumor size and retardation of tumor growth were observed by serial magnetic resonance imaging in the rats that received the combination ...
