http://hdl.handle.net/10171/186 2013-05-25T07:39:15Z 2013-05-25T07:39:15Z Vilas-Zornoza, A. (Amaya) Aguirre, X. (Xavier) Abizanda, G. (Gloria) Moreno, C. (Cristina) Segura, V. (Víctor) Martino-Rodriguez, A. (Alba) de San-Jose-Eneriz, E. (Edurne) Miranda, E. (Estibaliz) Martin-Subero, J.I. (José Ignacio) Garate, L. (Leire) Blanco-Prieto, M.J. (María José) Garcia-de-Jalon, J.A. (José A.) Rio, P. (Paula) Rifon, J. (José) Cigudosa, J.C. (Juan Cruz) Martinez-Climent, J.A. (José Angel.) Roman-Gomez, J. (José) Calasanz, M.J. (María José) Ribera, J.M. (José María) Prosper, F. (Felipe) http://hdl.handle.net/10171/27601 2013-01-10T01:57:14Z 2011-12-31T23:00:00Z

Title: Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia. Author(s) : Vilas-Zornoza, A. (Amaya); Aguirre, X. (Xavier); Abizanda, G. (Gloria); Moreno, C. (Cristina); Segura, V. (Víctor); Martino-Rodriguez, A. (Alba) de; San-Jose-Eneriz, E. (Edurne); Miranda, E. (Estibaliz); Martin-Subero, J.I. (José Ignacio); Garate, L. (Leire); Blanco-Prieto, M.J. (María José); Garcia-de-Jalon, J.A. (José A.); Rio, P. (Paula); Rifon, J. (José); Cigudosa, J.C. (Juan Cruz); Martinez-Climent, J.A. (José Angel.); Roman-Gomez, J. (José); Calasanz, M.J. (María José); Ribera, J.M. (José María); Prosper, F. (Felipe) Abstract: Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.

2011-12-31T23:00:00Z Vilas-Zornoza, A. (Amaya) Aguirre, X. (Xavier) Abizanda, G. (Gloria) Moreno, C. (Cristina) Segura, V. (Víctor) Martino-Rodriguez, A. (Alba) de San-Jose-Eneriz, E. (Edurne) Miranda, E. (Estibaliz) Martin-Subero, J.I. (José Ignacio) Garate, L. (Leire) Blanco-Prieto, M.J. (María José) Garcia-de-Jalon, J.A. (José A.) Rio, P. (Paula) Rifon, J. (José) Cigudosa, J.C. (Juan Cruz) Martinez-Climent, J.A. (José Angel.) Roman-Gomez, J. (José) Calasanz, M.J. (María José) Ribera, J.M. (José María) Prosper, F. (Felipe) http://hdl.handle.net/10171/27601 2013-01-10T01:57:14Z 2011-12-31T23:00:00Z

Title: Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia. Author(s) : Vilas-Zornoza, A. (Amaya); Aguirre, X. (Xavier); Abizanda, G. (Gloria); Moreno, C. (Cristina); Segura, V. (Víctor); Martino-Rodriguez, A. (Alba) de; San-Jose-Eneriz, E. (Edurne); Miranda, E. (Estibaliz); Martin-Subero, J.I. (José Ignacio); Garate, L. (Leire); Blanco-Prieto, M.J. (María José); Garcia-de-Jalon, J.A. (José A.); Rio, P. (Paula); Rifon, J. (José); Cigudosa, J.C. (Juan Cruz); Martinez-Climent, J.A. (José Angel.); Roman-Gomez, J. (José); Calasanz, M.J. (María José); Ribera, J.M. (José María); Prosper, F. (Felipe) Abstract: Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.

2011-12-31T23:00:00Z Rouzaut, A. (Ana) Subira, M.L. (María L.) Miguel, C. (Carlos) de Domingo-de-Miguel, E. (Eduardo) Gonzalez, A. (Alvaro) Santiago, E. (Esteban) Lopez-Moratalla, N. (Natalia) http://hdl.handle.net/10171/20318 2012-04-04T12:37:27Z 1998-12-31T23:00:00Z

Title: Co-expression of inducible nitric oxide synthase and arginases in different human monocyte subsets. Apoptosis regulated by endogenous NO Author(s) : Rouzaut, A. (Ana); Subira, M.L. (María L.); Miguel, C. (Carlos) de; Domingo-de-Miguel, E. (Eduardo); Gonzalez, A. (Alvaro); Santiago, E. (Esteban); Lopez-Moratalla, N. (Natalia) Abstract: Human monocyte subsets, isolated from cultures of mononuclear cells, or freshly obtained from patients with multiple sclerosis, Graves' disease or pemphigus vulgaris, differed in phenotype, apoptotic features, mRNA levels of arginase II (A-II) and the inducible form of nitric oxide synthase (iNOS). Liver-type arginase I mRNA was present in all subsets. Apoptosis was followed by the expression of T cell intracellular antigen (TIA) and the simultaneous detection of DNA stainability by propidium iodine and annexin V binding. Apoptosis was practically absent both in activated CD14(++)CD33(++)DR(++)CD25(++)CD69(++)CD71(++/+) CD16(-) cells, expressing A-II mRNA and having arginase activity, but not iNOS mRNA, and in not fully mature large CD14(++)CD16(+)CD23(+)DR(++) monocytes, expressing simultaneously both mRNAs and having both enzyme activities. However, differentiated small CD14(+/++)CD16(+)CD69(+)CD25(+/-)CD71(++)CD23(+) DR(++) monocytes, expressing high levels of iNOS mRNA, exhibited apoptotic signs. Amounts of NO synthesised by monocytes co-expressing iNOS and arginase changed with the addition of arginine or an iNOS inhibitor; in that case a correlation of NO production and apoptotic features was observed. Data suggest a regulatory role for endogenous NO in apoptosis of stimulated and differentiated monocytes, and also that iNOS and A-II, when simultaneously present, could control the production of NO as a consequence of their competition for arginine.

1998-12-31T23:00:00Z