In vivo use of glutathionone s-transferase activated nitric...

A - Human Necessities – 61 – K

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A61K 31/655 (2006.01) A61K 45/06 (2006.01) A61P 31/00 (2006.01) A61P 35/00 (2006.01)

Patent

CA 2480033

The present invention provides for a method of simultaneously treating both cancer and the Multidrug Resistance Phenotype via inhibition of cellular thiols, such as Glutathione S-Transferase (GST). This enzyme is overproduced in leukemia and solid tumor cells and is one of the main pathways involved in the Multidrug Resistance phenotype. The treatment provides for the administration of a chemically inert pro-drug, designed to be a specific substrate for the GST enzyme that, once cleaved, liberates the bioactive toxin Nitric Oxide (NO) intracellularly at the site of a malignant growth. NO then acts to inhibit the growth of the malignant cells and to induce cellular differentiation and apoptosis therein, effectively treating an existing cancerous condition. Additionally, once NO is liberated from the pro-drug, the remaining structure acts to inhibit further GST activity, providing a treatment for the Multidrug Resistant phenotype.

La présente invention concerne un procédé qui permet de traiter simultanément le cancer et le phénotype de multirésistance aux médicaments via l'inhibition de thiols cellulaires tels que la Glutathion S-Transférase (GST). Cette enzyme est produite en excès dans les cellules leucémiques et les cellules de tumeur solide et constitue un des principaux mécanismes impliqués dans le phénotype de multirésistance aux médicaments. Le traitement consiste à administrer un promédicament chimiquement inerte, préparé pour être un substrat spécifique pour l'enzyme GST qui, une fois coupé, libère l'oxyde nitrique de toxine bioactive intracellulairement au site d'une croissance maligne. L'oxyde nitrique a ensuite pour effet d'inhiber la croissance des cellules malignes et d'induire la différenciation cellulaire et l'apoptose dans ces dernières, ce qui traite ainsi efficacement une pathologie cancéreuse existante. De plus, lorsque l'oxyde nitrique est libéré par le promédicament, la structure restante a pour effet d'inhiber plus encore l'activité de la GST, ceci constituant un traitement pour le phénotype de multirésistance aux médicaments.

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