Bystander Killing Effect of Tymidine Kinase Gene-Transduced Adult Bone Marrow Stromal Cells With Ganciclovir on Malignant Glioma Cells

被引:17
作者
Mori, Kentaro [1 ]
Iwata, Junko [3 ]
Miyazaki, Masahiro [3 ]
Osada, Hideo [1 ]
Tange, Yuichi [1 ]
Yamamoto, Takuji [1 ]
Aiko, Yasuhisa [2 ]
Tamura, Masaru [4 ]
Shiroishi, Toshihiko [4 ]
机构
[1] Juntendo Univ, Shizuoka Hosp, Dept Neurosurg, Shizuoka 4102295, Japan
[2] Juntendo Univ, Shizuoka Hosp, Dept Radiol, Shizuoka 4102295, Japan
[3] Juntendo Casualty Ctr, Shizuoka, Japan
[4] Natl Inst Genet, Genet Strains Res Ctr, Mammalian Genet Lab, Shizuoka, Japan
关键词
bone marrow stromal cell; bystander effect; ganciclovir; glioma; rat; MESENCHYMAL STEM-CELLS; MURINE BRAIN-TUMORS; THYMIDINE KINASE; INTERCELLULAR COMMUNICATION; FUNCTIONAL RECOVERY; CEREBRAL-ISCHEMIA; SUICIDE GENE; IN-VITRO; THERAPY; RAT;
D O I
10.2176/nmc.50.545
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Transduction of the suicide gene of Herpes simplex virus thymidine kinase (Hsv-tk) into glioma cells or neural stem cells combined with pro-drug ganciclovir (GCV) treatment has been effective to treat experimental glioma in the rat through the bystander effect. Bone marrow stromal cells (MSCs) in the adult bone marrow have tropism for brain tumors and act as tumor stromal cells. Whether adult MSCs expressing Hsv-tk can also act as effector cells of the bystander killing effect on murine glioma cells was investigated. In vitro study of co-culture between 9L/LacZ (9L) glioma cells and Hsv-tk-transduced MSCs (MSCs/tk(+)) followed by GCV administration in the culture medium resulted in apparent nuclear morphological changes in the 9L glioma cells surrounding the MSCs/tk(+). 9L glioma cell survival in the presence of MSCs/tk( +) and GCV treatment was quantitatively measured and showed significant decrease of 9L glioma cell proliferation with higher MSCs/tk(+) ratio and GCV concentration. Intracerebral co-inoculation experiments in Fisher rats used 9L glioma cells and either MSCs/tk(+) or Hsv-tk-non-transduced MSCs (MSCs/tk(-)) followed by intraperitoneal injection of GCV (100 mg/kg, daily for 7 days). The animals co-inoculated with 9L glioma cells and MSCs/tk(+) showed significant retardation of tumor growth and prolongation of survival time compared with the animals with 9L glioma cells and MSCs/tk(-). Quantitative findings were established of the novel effects of adult MSCs/tk(+) as effector cells of the bystander killing effect on glioma cells.
引用
收藏
页码:545 / 553
页数:9
相关论文
共 43 条
[1]  
Arafat WO, 2000, CLIN CANCER RES, V6, P4442
[2]   Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats - similarities to astrocyte grafts [J].
Azizi, SA ;
Stokes, D ;
Augelli, BJ ;
DiGirolamo, C ;
Prockop, DJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (07) :3908-3913
[3]   Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats [J].
Chen, JL ;
Li, Y ;
Wang, L ;
Lu, M ;
Zhang, XH ;
Chopp, M .
JOURNAL OF THE NEUROLOGICAL SCIENCES, 2001, 189 (1-2) :49-57
[4]   GENE-THERAPY FOR BRAIN-TUMORS - REGRESSION OF EXPERIMENTAL GLIOMAS BY ADENOVIRUS-MEDIATED GENE-TRANSFER IN-VIVO [J].
CHEN, SH ;
SHINE, HD ;
GOODMAN, JC ;
GROSSMAN, RG ;
WOO, SLC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (08) :3054-3057
[5]   Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: Growth factor production [J].
Chen, XG ;
Katakowski, M ;
Li, Y ;
Lu, DY ;
Wang, L ;
Zhang, LJ ;
Chen, JL ;
Xu, YX ;
Gautam, S ;
Mahmood, A ;
Chopp, M .
JOURNAL OF NEUROSCIENCE RESEARCH, 2002, 69 (05) :687-691
[6]   INVIVO GENE-TRANSFER WITH RETROVIRAL VECTOR PRODUCER CELLS FOR TREATMENT OF EXPERIMENTAL BRAIN-TUMORS [J].
CULVER, KW ;
RAM, Z ;
WALLBRIDGE, S ;
ISHII, H ;
OLDFIELD, EH ;
BLAESE, RM .
SCIENCE, 1992, 256 (5063) :1550-1552
[7]   Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation [J].
Dezawa, M ;
Kanno, H ;
Hoshino, M ;
Cho, H ;
Matsumoto, N ;
Itokazu, Y ;
Tajima, N ;
Yamada, H ;
Sawada, H ;
Ishikawa, H ;
Mimura, T ;
Kitada, M ;
Suzuki, Y ;
Ide, C .
JOURNAL OF CLINICAL INVESTIGATION, 2004, 113 (12) :1701-1710
[8]   Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells [J].
Dezawa, M ;
Takahashi, I ;
Esaki, M ;
Takano, M ;
Sawada, H .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2001, 14 (11) :1771-1776
[9]   CONNEXIN-43 TYPE GAP-JUNCTIONS MEDIATE COMMUNICATION BETWEEN BONE-MARROW STROMAL CELLS [J].
DORSHKIND, K ;
GREEN, L ;
GODWIN, A ;
FLETCHER, WH .
BLOOD, 1993, 82 (01) :38-45
[10]   Connexins are expressed in primary brain tumors and enhance the bystander effect in gene therapy [J].
Estin, D ;
Li, MW ;
Spray, D ;
Wu, JK .
NEUROSURGERY, 1999, 44 (02) :361-368