RESEARCH - Reactivation of latent Epstein-Barr virus by MTX: a potential contributor to MTX-associated lymphomas

[Guest guest]

J Natl Cancer Inst. 2004 Nov 17;96(22):1691-702.

Reactivation of latent Epstein-Barr virus by methotrexate: a potential

contributor to methotrexate-associated lymphomas.

Feng WH, Cohen JI, Fischer S, Li L, Sneller M, Goldbach-Mansky R, Raab-Traub

N, Delecluse HJ, Kenney SC.

Department of Medicine and Microbiology and Lineberger Comprehensive Cancer

Center, University of North Carolina at Chapel Hill 27599-7295, USA.

BACKGROUND: Patients with rheumatoid arthritis or polymyositis treated with

methotrexate (MTX) develop Epstein-Barr virus (EBV)-positive lymphomas more

frequently than patients treated with other, equally immunosuppressive

regimens. Here we determined whether MTX, in contrast to other commonly used

medications for rheumatoid arthritis or polymyositis, is unique in its

ability to induce the release of infectious EBV from latently infected

cells. METHODS: The effect of MTX and other immunosuppressant drugs on EBV

replication in vitro was assessed using latently infected EBV-positive

lymphoblastoid and gastric carcinoma cell lines. Inhibitors of signal

transduction pathways were used to define requirements for induction of

lytic infection. Drug effects on transcription of the two EBV

immediate-early promoters (BRLF1 and BZLF1) and on promoter constructs

lacking cis-acting sequences required for activation by other effectors was

examined using reporter gene assays. EBV viral load in rheumatoid arthritis

and polymyositis patients receiving MTX was compared with that in patients

receiving other immunosuppressive medications. Statistical tests were

two-sided. RESULTS: MTX activated the release of infectious EBV from

latently infected cell lines in vitro, and MTX treatment was associated with

activation of the two viral immediate-early promoters in reporter gene

assays. Induction of lytic EBV infection by MTX required the p38 MAP kinase,

PI3 kinase, and MEK pathways and specific cis-acting motifs in the two viral

immediate-early promoters. Patients treated with MTX-containing regimens had

statistically significantly higher mean EBV loads in their blood than

patients treated with immunosuppressing regimens that did not include MTX

(40 EBV copies per 10(6) cellular genomes versus 5.1 copies; geometric mean

fold difference in copies = 10.8, 95%, confidence interval = 3.0 to 38; P =

011).

CONCLUSION: MTX may promote EBV-positive lymphomas in rheumatoid arthritis

and polymyositis patients by its immunosuppressive properties as well as by

reactivating latent EBV.

PMID: 15547182

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=15547182

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org