RETINOIDS IRREVERSIBLY INHIBIT IN-VITRO GROWTH OF EPSTEIN-BARR VIRUS-IMMORTALIZED B-LYMPHOCYTES

Natural and synthetic retinoids have proved to be effective in the tre atment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-in fected lymphoblastoid cell lines (LCLs), since these cells closely res emble those that give rise to EBV-related lymphoproliferative disorder s in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-reti noic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate, The antiprolife rative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in th ese cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achi evable plasma levels. Retinoid-treated cells showed a marked downregul ation of CD71 and a decreased S-phase compartment with a parallel accu mulation in G(0)/G(1) phases. These cell cycle perturbations were asso ciated with the upregulation of p27 Kip1, a nuclear protein that contr ols entrance and progression through the cell cycle by inhibiting seve ral cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated st atus. In fact, retinoid-induced modifications of cell morphology, phen otype (downregulation of CD19, HLA-DR, and s-Ig, and increased express ion of CD38 and c-Ig), and IgM production were late events, highly het erogeneous, and often slightly relevant, being therefore only partiall y indicative of a drug-related differentiative process. Moreover, EBV- encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins w ere inconstantly downregulated by retinoids, indicating that their gro wth-inhibitory effect is not mediated by a direct modulation of viral latent antigen expression. The strong antiproliferative activity exert ed by retinoids in our experimental model indicates that these compoun ds may represent a useful tool in the medical management of EBV-relate d lymphoproliferative disorders of immunosuppressed patients. (C) 1996 by The American Society of Hematology.