Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivoReportar como inadecuado




Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Experimental Hematology and Oncology

, 4:4

First Online: 26 January 2015Accepted: 17 January 2015DOI: 10.1186-2162-3619-4-4

Cite this article as: Damm, J.K., Gordon, S., Ehinger, M. et al. Exp Hematol Oncol 2015 4: 4. doi:10.1186-2162-3619-4-4

Abstract

BackgroundEpigenetic code modifications by histone deacetylase inhibitors HDACi have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma DLBCL is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP cyclophosphamide, doxorubicin, vincristine and prednisone combined with the monoclonal anti-CD20 antibody rituximab R-CHOP. The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma.

FindingsPretreatment with valproate at oral doses comparable to anti-convulsive therapy, resulted in upregulation of CD20 mRNA and CD20 protein on the cell surface as measured by qPCR and FACS analysis in lymphoma biopsies from three evaluated patients from the VALFRID study. Valproate-treatment corresponded to increased acetylation of Histone3Lysine9 H3K9ac in peripheral blood mononuclear cells PBMCs, which were employed as surrogate tissue for valproate-related epigenetic modifications.

ConclusionsValproate treatment at pharmacologically relevant doses resulted in upregulation of CD20 in vivo, and also in expected epigenetic modifications. This suggests that pre-treatment with valproate or other HDACis before anti-CD20 therapy could be advantageous in CD20-low B-cell lymphomas. Further studies are warranted to evaluate this conclusion.

KeywordsValproate Valproic acid CD20 DLBCL Rituximab HDACi AbbreviationsHDACiHistone deacetylase inhibitor

DLBCLDiffuse large B-cell lymphoma

R- CHOPRituximab-, cyclophosphamide, anthracyclin doxorubicin, vincristine and prednisone

MFIMean fluorescence intensity

PBMCPeripheral blood mononuclear cells

GABAGamma-Aminobutyric acid

FNBFine needle biopsy

H3K9acHistone 3 Lysine 9-acetylation

H3K4me3Histone 3 Lysine 4-trimethylation.

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Autor: Jesper Kofoed Damm - Sandra Gordon - Mats Ehinger - Mats Jerkeman - Urban Gullberg - Anne Hultquist - Kristina Drott

Fuente: https://link.springer.com/



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