Human neural stem cells target and deliver therapeutic gene to experimental leptomeningeal medulloblastoma.
Medulloblastomas are highly malignant neuroectodermal cerebellar tumors of children. One of the reasons for the difficulty for the treatment of medulloblastomas is their inherent tendency to metastasize through the cerebrospinal fluid (CSF) pathway leading to leptomeningeal dissemination. Recently, genetically modified neural stem cells (NSCs) were shown to have the capability of selectively migrating into glioma mass and delivering therapeutic agents with significant therapeutic benefits. In the present study, we applied the NSC strategy to target medulloblastomas, particularly their leptomeningeal dissemination. We used NSCs that were retrovirally transduced with the cytosine deaminase gene (CD-NSCs). In vitro studies demonstrated that CD-NSCs had sufficient migratory activity toward medulloblastoma cells and exerted a remarkable bystander effect on these cells following the application of 5-fluorocytosine (5-FC). It is noteworthy that neutralization of the hepatocyte growth factor blocked their migration In animal studies using our leptomeningeal dissemination model, CD-NSCs implanted directly into CSF space were shown to distribute diffusely within the disseminated tumor cells and could provide remarkable antitumor effect after intraperitoneal administration of 5-FC. Furthermore, CD-NSC treatment followed by 5-FC administration prolonged survival periods significantly in experimental animals. Our data suggest that the CD-NSC strategy can also be applied to target leptomeningeal dissemination of medulloblastomas.
Shimato
S
S
Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Natsume
A
A
Takeuchi
H
H
Wakabayashi
T
T
Fujii
M
M
Ito
M
M
Ito
S
S
Park
I H
IH
Bang
J H
JH
Kim
S U
SU
Yoshida
J
J
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D024201:Bystander Effect; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002946:Cisterna Magna; D043525:Cytosine Deaminase / Q000235:genetics*; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D005910:Glioma / Q000628:therapy; D006801:Humans; D020287:In Situ Nick-End Labeling; D007267:Injections; D008527:Medulloblastoma / Q000628:therapy*; D008577:Meningeal Neoplasms / Q000628:therapy*; D008578:Meninges / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009474:Neurons / Q000201:enzymology / Q000637:transplantation; D033581:Stem Cell Transplantation / Q000379:methods*
D000963:Antimetabolites; D005437:Flucytosine; D043525:Cytosine Deaminase