Human neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases.
The tumor-tropic properties of neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to tumors in the brain. To apply this strategy to the treatment of brain metastases, we made a human NSC line expressing cytosine deaminase (F3.CD), which converts 5-fluorocytosine (5-FC) into 5-fluorouracil, an anticancer agent. In vitro, the F3.CD cells significantly inhibited the growth of tumor cell lines in the presence of the prodrug 5-FC. In vivo, MDA-MB-435 human breast cancer cells were implanted into the brain of immune-deficient mouse stereotactically, and F3.CD cells were injected into the contralateral hemisphere followed by systemic 5-FC administration. The F3.CD cells migrated selectively into the brain metastases located in the opposite hemisphere and resulted in significantly reduced volumes. The F3.CD and 5-FC treatment also decreased both tumor volume and number of tumor mass significantly, when immune-deficient mouse had MDA-MB-435 cells injected into the internal carotid artery and F3.CD cells were transplanted into the contralateral brain hemisphere stereotactically. Taken together, brain transplantation of human NSCs, encoding the suicide enzyme CD, combined with systemic administration of the prodrug 5-FC, is an effective treatment regimen for brain metastases of tumors.
Joo
Kyeung Min
KM
Department of Neurosurgery, Sungkyunkwan University School of Medicine, Seoul, Korea.
Park
In H
IH
Shin
Ji Y
JY
Jin
Juyoun
J
Kang
Bong Gu
BG
Kim
Mi Hyun
MH
Lee
Se Jeong
SJ
Jo
Mi-young
MY
Kim
Seung U
SU
Nam
Do-Hyun
DH
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000556:secondary / Q000628:therapy*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D005437:Flucytosine / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013234:Stem Cells / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D005437:Flucytosine; D043525:Cytosine Deaminase