TERAPIAS DE COMBINACION PARA TRATAR CELULAS DEFICIENTES EN METILTIOADENOSINA-FOSFORILASA

• Main Authors: KUHN LESLIE ANN, ZHENDER LUKE RAYMOND, SKALITZKY DONALD JAMES, MENG JERRY JIALUM, BORITZKI THEODORE JAMES, KUNG PEI-PEI, BLOOM LAURA ANNE, OGDEN RICHARD CHARLES
• Format: Patent
• Language: Spanish
• Published: 29.10.2003
• Edition: 7
• Subjects: HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

SE REFIERE A UN METODO PARA DESTRUIR CELULAS DEFICIENTES EN METILTIOADENOSINA-FOSFORILASA (MTAP) QUE COMPRENDE ADMINISTRAR a)INHIBIDOR DE GLICINAMIDA-RIBONUCLEOTIDO-FORMILTRANSFERASA, AMINOIMIDAZOLCARBOXIMIDA-RIBONUCLEOTIDO-FORMILTRANSFERASA DE FORMULA A (ACIDO N-(5-[2-(2-AMINO-4(3H)-OXO-5,6,7,8-TETRAHIDROPIRIDO[2,3-d]-PIRIMIDIN-6-IL)-(R)-ETIL]-4-METILTIENO-2-IL)-L-GLUTAMICO, O UN COMPUESTO OXOPIRIDO DE FORMULA II; A ES S, Se; GRUPO ES UN INTERCALADOR NO CICLICO; ANILLO ES CICLOALQUILO, HETEROCICLOALQUILO, ARILO, HETEROARILO; R1 Y R2 SON H, ALQUILO, GRUPO HIDROLIZABLE; R3 ES H, ALQUILO, CICLOALQUILO; b)UN AGENTE ANTITOXICO (ANALOGO DE METILADENOSINA FOSFORILASA) EN UNA CANTIDAD PARA INCREMENTAR LA DOSIS TOLERADA MAXIMA DEL INHIBIDOR DE FORMULA X; DONDE R41 ES Rg, RgYRhRi, CONRjRk, COORh; Rg ES ALQUILO, ALQUENILENO, ALQUINILENO; Y ES O, NH, S, METILENO; Rh, Ri SON H, ALQUILO, ALQUENILO, ALQUINILO; Rj Y Rk SON H, ALQUILO, AMINO, HALOALQUILO, ENTRE OTROS; SON COMPUESTOS PREFERIDOS (2S,3R,4R,5R)-5-(6-AMINO-9H-PURIN-9-IL)-4-(METILTIO)-2-[(METIL-TIO)METIL]TETRAHIDROFURAN-3-OL; (2S,3S,4R,5R)-2-(6-AMINO-9H-PURIN-9-IL)-5-{[(4-CLOROBENCIL)TIO]-METIL}-TETRAHIDROFURAN-3,4-DIOL, ENTRE OTROS The present invention is directed to combination therapies for treating cell proliferative disorders associated with methylthioadenosine phosphorylase (MTAP) deficient cells in a mammal. The combination therapies selectively kill MTAP-deficient cells by administering an inhibitor of de novo inosinate synthesis and administering an anti-toxicity agent, wherein the inhibitors of de novo inosinate synthesis are inhibitors of glycinamide ribonucleotide formyltransferase ("GARFT") and/or aminoinidazolecarboximide ribonucleotide formyltransferase ("AICARFT"), and the anti-toxicity agent is an MTAP substrate (e.g. methylthioadenosine or "MTA"), a precursor of MTA, an analog of an MTA precursor or a prodrug of an MTAP substrate.