title: Phenotypic and functional analysis of Fas (CD95) expression in primary central nervous system lymphoma of patients with acquired immunodeficiency syndrome.
abstract: The poor prognosis associated with patients afflicted with the acquired immunodeficiency syndrome and primary central nervous system lymphoma (AIDS-PCNSL) is due in part to the intrinsic resistance of this Epstein-Barr virus (EBV)-associated tumor to conventional antineoplastic therapy. Fas (CD95) is a transmembrane protein receptor that transmits an intracellular signal leading to rapid programmed cell death following ligation with its natural ligand or anti-Fas antibodies. Fas expression and function were assessed in AIDS-PCNSL biopsy samples and in EBV+ human B-cell tumors that spontaneously developed in severe combined immune deficient (SCID) mice engrafted with human lymphocytes (hu-PBL-SCID mice). All tumors samples showed high-density surface expression of Fas by flow cytometry or immunohistochemical staining. Cells from two AIDS-PCNSL biopsy samples that did not express pan B-cell markers did not express Fas antigen. All tumors examined were susceptible to Fas-mediated apoptosis, as measured by standard assays for endonucleolytic cleavage of DNA. The response to Fas-mediated apoptosis was dependent on log-fold increases in the concentration of immobilized anti-Fas antibody, but could also be induced with a mobilized anti-Fas antibody. No evidence for intrinsic resistance to Fas-mediated apoptosis (ie, secreted or truncated forms of Fas) could be shown. Radiation-induced apoptosis of neoplastic EBV+ B cells was enhanced by activation of Fas, and prolonged exposure to interleukin-2 increased both Fas expression and Fas-induced apoptosis. As the normal brain parenchyma appears to have either low-density or absent expression of Fas, and antineoplastic therapy can be selectively delivered to the CNS with little systemic toxicity, local delivery of Fas-activating molecules could prove to be a useful component in the multimodal treatment of AIDS-PCNSL.
authors.affiliation: Division of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: V P
authors.initials: VP
authors.lastname: Khatri
authors.forename: M J
authors.initials: MJ
authors.lastname: Lindemann
authors.forename: M E
authors.initials: ME
authors.lastname: Ross
authors.forename: G
authors.initials: G
authors.lastname: Papoff
authors.forename: A J
authors.initials: AJ
authors.lastname: Caprio
authors.forename: T V
authors.initials: TV
authors.lastname: Caprio
authors.forename: R
authors.initials: R
authors.lastname: Fenstermaker
authors.forename: G
authors.initials: G
authors.lastname: Ruberti
authors.forename: Z P
authors.initials: ZP
authors.lastname: Bernstein
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D019014:fas Receptor / Q000032:analysis* / Q000276:immunology
chemical_list: D019014:fas Receptor