The outcome of malignat gliomas remains extremely poor, in spite of aggressive use of currently available therapies. Recent advances in elucidating the molecular biology of gliomas has led to the development of innovative therapeutic strategies. The more promising approaches involve gene therapy, aiming at increasing tumor cell chemosensitivity, by transfer of genes expressing prodrug activating enzymes. Glioblastoma multiforme is one of the most highly vascularized solid neoplasm; therefore treatments that target neoangiogenesis would be of great interest in clinical practice. The discovery of specific endothelial inhibitors such as angiostatin, endostatin and kringle 5 provide an important therapeutic strategy for cancer treatment. Although these molecules are potent inhibitors of angiogenesis and tumor growth, the need of high dosage, repeated injections and long term administration of these proteins into the body have made them less attractive for clinical trials. Since one fundamental problem in gene therapy is to deliver the therapeutic gene to the target tissue, new delivery systems and therapeutic approaches are highly desirable. The research described in this proposal is directed to evaluate the potential role of Herpes simplex virus (HSV) vectors in delivering anti-angiogenic genes for brain tumor therapy. Our strategy will combine two different modalities, angiostatic factors promoting tumor regression along with the enzyme-directed prodrug activation (tumor suicide), devised to enhance the tumor destruction. Two distinct type of vectors will be created and tested for their ability to eliminate the tumor: (i) a replicative defective HSV vectors which express single or multiple anti-angiogenic molecules, such as angiostatin, endostatin and kringle 5, and (ii) a replicative defective HSV vectors which express TK and CD suicide gene alone or in combination with Connexin43 gene, that has been shown to improve the efficiency of HSV-TK anti-tumor gene therapy. Therefore, the principal goals of this project are to develop: (1) HSV vectors containing multiple anti-angiogenic factors, and (2) HSV vectors expressing CX43 and carrying TK and /or CD suicide genes. In both vectors the anti-angiogenic and the suicide genes will be expressed under the control of human cytomegalovirus immediate early promoter (HCMV) or HSV ICP0 immediate early promoter. These promoters have been chosen for their relative short time expression which will eliminate concerns over-dosing and long term expression of these proteins. These vectors will be tested in vitro, for their cytotoxicity activity, in presence of ganciclovir (GCV) or 5-fluorocytosine (5FC), and for the biological activity of anti-angiogenic factors. Subsequently, the vectors will be tested, in vivo, in an appropriate animal model for gliomas. This last experiment will be done in two phases that provide a first stereotactic injection, using vectors expressing anti-angiogenic factors, in order to inhibit tumor growth and reduce its mass and a second injection, using vectors expressing CX43 and TK or CD, for the purpose to eliminate the remaining tumor cells.
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|Titolo:||Herpetic vectors inhibiting angiogenesis and Inducing cell suicide in gliomas|
|Data di pubblicazione:||2002|
|Appare nelle tipologie:||08.1 Coordinamento Prog.Ricerca Naz. ed Internaz.|