Death of solid tumor cells induced by Fas ligand expressing primary myoblasts

被引:13
作者
Hofmann, A [1 ]
Blau, HM [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Mol Pharmacol, Stanford, CA 94305 USA
关键词
D O I
10.1007/BF02674416
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Anticancer therapy for solid tumors suffers from inadequate methods for the localized administration of cytotoxic agents. Fas ligand (FasL) has been reported to be cytotoxic to a variety of cells, including certain tumor cell lines. We therefore postulated that myoblasts could serve as non-transformed gene therapy vehicles for the continuous localized delivery of cytotoxic anticancer agents such as FasL. However, contrary to previous reports, fluorescence activated cell sorting (FACS) analyses revealed that both primary mouse and human myoblasts express Fas, the receptor for FasL. To avoid self-destruction and test the cytotoxic potential of myoblasts, the cells were isolated from mice deficient in Fas (lpr/lpr), the mouse counterpart of human autoimmune lymphoproliferative syndrome (ALPS). These primary mouse myoblasts were transduced with a retroviral vector encoding mouse FasL and expression of a biologically active and soluble form of the molecule was confirmed by the apoptotic demise of cocultured Fas-expressing Jurkat cells, the standard in the field To test whether the lpr myoblasts expressing FasL could be used in anticancer therapy, human rhabdomyosarcoma derived cell lines were assayed for Fas and then tested in the apoptosis coculture assay. The majority of Fas-expressing muscle tumor cells were rapidly killed. Moreover, FasL expressing myoblasts were remarkably potent; indeed well characterized cytotoxic antibodies to Fas were only 20% as efficient at killing rhabdomyosarcoma cells as FasL expressing myoblasts. These findings together with previous findings suggest that primary myoblasts, defective in Fas but genetically engineered to express FasL, could function as potent anticancer agents for use in the localized destruction of solid tumors in vivo by three synergist ic mechanisms: (1) directly via Fas/FasL mediated apoptosis, (2) indirectly via neutrophil infiltration and immunodestruction, and (3) as allogeneic inducers of a bystander effect via B and T cells.
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收藏
页码:249 / 257
页数:9
相关论文
共 27 条
[1]   Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts [J].
Allison, J ;
Georgiou, HM ;
Strasser, A ;
Vaux, DL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (08) :3943-3947
[2]   A ROLE FOR CD95 LIGAND IN PREVENTING GRAFT-REJECTION [J].
BELLGRAU, D ;
GOLD, D ;
SELAWRY, H ;
MOORE, J ;
FRANZUSOFF, A ;
DUKE, RC .
NATURE, 1995, 377 (6550) :630-632
[3]  
BEZWODA WR, 1991, CANCER, V68, P867, DOI 10.1002/1097-0142(19910815)68:4<867::AID-CNCR2820680432>3.0.CO
[4]  
2-H
[5]   A SPECIFIC CHROMOSOMAL ABNORMALITY IN RHABDOMYOSARCOMA [J].
DOUGLASS, EC ;
VALENTINE, M ;
ETCUBANAS, E ;
PARHAM, D ;
WEBBER, BL ;
HOUGHTON, PJ ;
GREEN, AA .
CYTOGENETICS AND CELL GENETICS, 1987, 45 (3-4) :148-155
[6]   DOMINANT INTERFERING FAS GENE-MUTATIONS IMPAIR APOPTOSIS IN A HUMAN AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME [J].
FISHER, GH ;
ROSENBERG, FJ ;
STRAUS, SE ;
DALE, JK ;
MIDDELTON, LA ;
LIN, AY ;
STROBER, W ;
LENARDO, MJ ;
PUCK, JM .
CELL, 1995, 81 (06) :935-946
[7]   FAS LIGAND-INDUCED APOPTOSIS AS A MECHANISM OF IMMUNE PRIVILEGE [J].
GRIFFITH, TS ;
BRUNNER, T ;
FLETCHER, SM ;
GREEN, DR ;
FERGUSON, TA .
SCIENCE, 1995, 270 (5239) :1189-1192
[8]   The fate of individual myoblasts after transplantation into muscles of DMD patients [J].
Gussoni, E ;
Blau, HM ;
Kunkel, LM .
NATURE MEDICINE, 1997, 3 (09) :970-977
[9]   Melanoma cell expression of Fas(Apo-1/CD95) ligand: Implications for tumor immune escape [J].
Hahne, M ;
Rimoldi, D ;
Schroter, M ;
Romero, P ;
Schreier, M ;
French, LE ;
Schneider, P ;
Bornand, T ;
Fontana, A ;
Lienard, D ;
Cerottini, JC ;
Tschopp, J .
SCIENCE, 1996, 274 (5291) :1363-1366
[10]  
HAZELTON BJ, 1987, CANCER RES, V47, P4501