Gene therapy strategies for treating Epstein-Barr virus-associated lymphomas: Comparison of two different Epstein-Barr virus-based vectors

被引:28
作者
Kenney, S
Ge, JQ
Westphal, EM
Olsen, J
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC 27599 USA
关键词
D O I
10.1089/hum.1998.9.8-1131
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
B cell lymphomas in immunocompromised patients frequently contain the Epstein-Barr virus (EBV) genome (MacMahon et al., 1991), suggesting that gene therapy strategies that target EBV-positive cells for destruction might be useful for the therapy of such tumors. We have previously shown that stable expression of the cytosine deaminase (CD) gene in EBV-positive lymphoblastoid cell lines induces cell killing in the presence of the prodrug 5-fluorocytosine, with a substantial bystander killing effect (Rogers et al., 1996). To promote specific killing of EBV-positive tumor cells, we have constructed two different EBV-based vectors containing the cytosine deaminase gene. The first vector (OriP-CD), which contains the intact EBV oriP enhancer/replication element, replicates as an episome specifically in EBV-positive cells and likewise enhances transcription in an EBV-specific manner. The OriP-CD vector cannot be packaged or spread from cell to cell. The second vector (OriLyt-CD) contains the EBV lytic origin of replication (oriLyt), the EBV packaging sequences (located in the viral termini), the oriP enhancer element (but not the complete replication origin), and the EBV BZLF1 gene (which induces expression of the EBV proteins required for replication of oriLyt). The OriLyt-CD vector is replicated through the oriLyt origin specifically in EBV-positive cells and packaged as an EBV pseudovirion. The packaged oriLyt-CD virion can subsequently infect cells containing the EBV receptor, CD21, and initiate another round of replication in EBV-positive cells. Here we demonstrate that each of these two different EBV-based gene therapy strategies induces specific killing of EBV-positive B cells in vitro (in the presence of 5-FC). The advantages and disadvantages of each strategy are discussed.
引用
收藏
页码:1131 / 1141
页数:11
相关论文
共 38 条
[1]  
[Anonymous], 1996, Fields virology
[2]  
AUSTIN EA, 1993, MOL PHARMACOL, V43, P380
[3]   THERAPEUTIC GENE DELIVERY IN HUMAN BETA-LYMPHOBLASTOID CELLS BY ENGINEERED NON-TRANSFORMING INFECTIOUS EPSTEIN-BARR-VIRUS [J].
BANERJEE, S ;
LIVANOS, E ;
VOS, JMH .
NATURE MEDICINE, 1995, 1 (12) :1303-1308
[4]  
BLAESE M, 1995, CANCER GENE THER, V2, P291
[5]   BOTH EPSTEIN-BARR-VIRUS (EBV)-ENCODED TRANS-ACTING FACTORS, EB1 AND EB2, ARE REQUIRED TO ACTIVATE TRANSCRIPTION FROM AN EBV EARLY PROMOTER [J].
CHEVALLIERGRECO, A ;
MANET, E ;
CHAVRIER, P ;
MOSNIER, C ;
DAILLIE, J ;
SERGEANT, A .
EMBO JOURNAL, 1986, 5 (12) :3243-3249
[6]  
Connors TA, 1995, GENE THER, V2, P702
[7]   ACTIVATION OF EXPRESSION OF LATENT EPSTEIN-BARR HERPESVIRUS AFTER GENE-TRANSFER WITH A SMALL CLONED SUBFRAGMENT OF HETEROGENEOUS VIRAL-DNA [J].
COUNTRYMAN, J ;
MILLER, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1985, 82 (12) :4085-4089
[8]   TRANS-ACTING REQUIREMENTS FOR REPLICATION OF EPSTEIN-BARR-VIRUS ORI-LYT [J].
FIXMAN, ED ;
HAYWARD, GS ;
HAYWARD, SD .
JOURNAL OF VIROLOGY, 1992, 66 (08) :5030-5039
[9]   Helper virus-free transfer of herpes simplex virus type 1 plasmid vectors into neural cells [J].
Fraefel, C ;
Song, S ;
Lim, F ;
Lang, P ;
Yu, L ;
Wang, YM ;
Wild, P ;
Geller, AI .
JOURNAL OF VIROLOGY, 1996, 70 (10) :7190-7197
[10]   Epstein-Barr virus-driven gene therapy for EBV-related lymphomas [J].
Franken, M ;
Estabrooks, A ;
Cavacini, L ;
Sherburne, B ;
Wang, F ;
Scadden, DT .
NATURE MEDICINE, 1996, 2 (12) :1379-1382