Phenylbutyrate induces cell differentiation and modulates Epstein-Barr virus gene expression in Burkitt's lymphoma cells.
Although Burkitt's lymphoma (BL) is a readily treated malignancy, recurrences, as well as disease arising in immunosuppressed patients, are notoriously resistant to conventional therapeutic approaches. The EBV is associated with a significant proportion of these lymphomas that evade immune surveillance through decreased expression of both viral and cellular antigens. Increasing the immunogenicity of BL cells may, therefore, represent a potentially beneficial therapeutic maneuver. Using in vitro models of EBV-transformed lymphoblastoid as well as BL cell lines, we demonstrate increased expression of genes coding for HLA class I and EBV latent proteins by the differentiation inducer phenylbutyrate (PB). The aromatic fatty acid also caused cytostasis associated with sustained declines in c-myc expression, a direct antitumor effect that was independent of the EBV status. We conclude, therefore, that differentiation therapy of BL with PB may lead to growth arrest with increased tumor immunogenicity in vivo. The findings may have clinical relevance because the in vitro activity has been observed with PB concentrations that are well tolerated and nonimmunosuppressive in humans, a desirable feature for the different patient populations afflicted with this disease.
Bar-Ner
M
M
Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Thibault
A
A
Tsokos
M
M
Magrath
I T
IT
Samid
D
D
D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004279:DNA, Viral / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000254:growth & development; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D010654:Phenylbutyrates / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000096:biosynthesis; D014775:Virus Activation / Q000187:drug effects
D004279:DNA, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015395:Histocompatibility Antigens Class I; D010654:Phenylbutyrates; D014763:Viral Matrix Proteins