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Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.
Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S; Manziello, Ann; Mount, David W; Persky, Daniel O; Fisher, Richard I; Miller, Thomas P; Qi, Wenqing.
Afiliación
  • Mahadevan D; Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Morales C; Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Cooke LS; Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Manziello A; Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
  • Mount DW; Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
  • Persky DO; Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
  • Fisher RI; Department of Medicine, Fox Chase Cancer Center - Temple Health, Philadelphia, Pennsylvania, United States of America.
  • Miller TP; Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
  • Qi W; Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
PLoS One ; 9(6): e95184, 2014.
Article en En | MEDLINE | ID: mdl-24893165
Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Azepinas / Vincristina / Protocolos de Quimioterapia Combinada Antineoplásica / Proteínas Proto-Oncogénicas c-myc / Linfoma de Células B Grandes Difuso / Proteínas Proto-Oncogénicas c-bcl-2 / Anticuerpos Monoclonales de Origen Murino Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Azepinas / Vincristina / Protocolos de Quimioterapia Combinada Antineoplásica / Proteínas Proto-Oncogénicas c-myc / Linfoma de Células B Grandes Difuso / Proteínas Proto-Oncogénicas c-bcl-2 / Anticuerpos Monoclonales de Origen Murino Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos