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See detailIdentification of factors important for the success of suicide gene therapy after a comparative study of Varicella zoster and Herpes simplex viral thymidine kinases efficacy on breast cancer cells
Grignet-Debrus, Christine ULg; Noël, Agnès ULg; Foidart, Jean-Michel ULg et al

in Cellular and Molecular Biology (2005), 51(1), 37-48

One of the most frequently studied therapeutic strategies in the field of suicide gene therapy is based on the expression by tumor cells of the Herpes simplex virus thymidine kinase gene (HSVtk) followed ... [more ▼]

One of the most frequently studied therapeutic strategies in the field of suicide gene therapy is based on the expression by tumor cells of the Herpes simplex virus thymidine kinase gene (HSVtk) followed by a ganciclovir (GCV) treatment. In order to investigate the potential of other enzyme/prodrug strategies, we studied in vitro and in vivo the ability of the Varicella zoster virus thymidine kinase gene (VZVtk) to act as a suicide gene and to kill non-transduced bystander cells, and compared this activity to that of its HSV counterpart. Four different antiviral compounds were tested as prodrugs. Our comparative study demonstrates the superiority of the HSVtk/GCV system among the different combinations tested and underlines the importance of both the tumor cell type and the prodrug in the success of a prodrug/suicide gene strategy. [less ▲]

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See detailMouse Aortic Ring Assay: A New Approach of the Molecular Genetics of Angiogenesis
Masson, Véronique ULg; Devy, L.; Grignet-Debrus, Christine ULg et al

in Biological Procedures Online (2002), 4

Angiogenesis, a key step in many physiological and pathological processes, involves proteolysis of the extracellular matrix. To study the role of two enzymatic families, serine-proteases and matrix ... [more ▼]

Angiogenesis, a key step in many physiological and pathological processes, involves proteolysis of the extracellular matrix. To study the role of two enzymatic families, serine-proteases and matrix metalloproteases in angiogenesis, we have adapted to the mouse, the aortic ring assay initially developed in the rat. The use of deficient mice allowed us to demonstrate that PAI-1 is essential for angiogenesis while the absence of an MMP, MMP-11, did not affect vessel sprouting. We report here that this model is attractive to elucidate the cellular and molecular mechanisms of angiogenesis, to identify, characterise or screen "pro- or anti-angiogenic agents that could be used for the treatment of angiogenesis-dependent diseases. Approaches include using recombinant proteins, synthetic molecules and adenovirus-mediated gene transfer. [less ▲]

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See detailThe pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent
Devy, L.; Blacher, Silvia ULg; Grignet-Debrus, Christine ULg et al

in FASEB Journal (2002), 16(2), 147-54

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for ... [more ▼]

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for optimal tumor invasion and vascularization. We also showed that PAI-1 angiogenic activity is associated with its control of plasminogen activation but not with the regulation of cell-matrix interaction. To dissect the role of the various components of the plasminogen activation system during angiogenesis, we have adapted the aortic ring assay to use vessels from gene-inactivated mice. The single deficiency of tPA, uPA, or uPAR, as well as combined deficiencies of uPA and tPA, did not dramatically affect microvessel formation. Deficiency of plasminogen delayed microvessel outgrowth. Lack of PAI-1 completely abolished angiogenesis, demonstrating its importance in the control of plasmin-mediated proteolysis. Microvessel outgrowth from PAI-1(-/-) aortic rings could be restored by adding exogenous PAI-1 (wild-type serum or purified recombinant PAI-1). Addition of recombinant PAI-1 led to a bell-shaped angiogenic response clearly showing that PAI-1 is proangiogenic at physiological concentrations and antiangiogenic at higher levels. Using specific PAI-1 mutants, we could demonstrate that PAI-1 promotes angiogenesis at physiological (nanomolar) concentrations through its antiproteolytic activity rather than by interacting with vitronectin. [less ▲]

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See detailDown-Regulation of Vascular Endothelial Growth Factor by Tissue Inhibitor of Metalloproteinase-2: Effect on in Vivo Mammary Tumor Growth and Angiogenesis
Hajitou, Amin; Sounni, Nor Eddine ULg; Devy, Laetitia et al

in Cancer Research (2001), 61(8), 3450-7

The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of ... [more ▼]

The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of TIMP-2 overexpression, induced by retroviral mediated gene transfer, on the in vivo development of mammary tumors in syngeneic mice inoculated with EF43.fgf-4 cells. The EF43.fgf-4 cells established by stably infecting the normal mouse mammary EF43 cells with a retroviral expression vector for the fgf-4 oncogene, are highly tumorigenic and overproduce vascular endothelial growth factor (VEGF). Despite a promotion of the in vitro growth rate of EF43.fgf-4 cells overexpressing timp-2, the in vivo tumor growth was delayed. At day 17 post-cell injection, the volume of tumor derived from TIMP-2-overexpressing cells was reduced by 80% as compared with that obtained with control cells. Overexpression of TIMP-2 was associated with a down-regulation of VEGF expression in vitro and in vivo, a reduction of vessel size, density, and blood supply in the induced tumors. In addition, TIMP-2 completely inhibited the angiogenic activity of EF43.fgf-4 cell-conditioned medium in vitro using a rat aortic ring model. Our findings suggest that overexpression of TIMP-2 delays growth and angiogenesis of mammary carcinoma in vivo and that down-regulation of VEGF expression may play an important role in this TIMP-2-mediated antitumoral and antiangiogenic effects. Finally the in vivo delivery of TIMP-2, as assessed by i.v. injection of recombinant adenoviruses vectors, significantly reduced the growth of the EF43.fgf-4-induced tumors. This effect of TIMP-2 was shown to be equally comparable with that of angiostatin, a known potent inhibitor of angiogenesis. [less ▲]

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