The growth of brain tumors can be suppressed by multiple transplantation of mesenchymal stem cells expressing cytosine deaminase

Suicide genes have recently emerged as an attractive alternative therapy for the treatment of various types of intractable cancers. The efficacy of suicide gene therapy relies on efficient gene delivery to target tissues and the localized concentration of final gene products. Here, we showed a poten...

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Bibliographic Details
Published in:International journal of cancer 2010-10, Vol.127 (8), p.1975-1983
Main Authors: Chang, Da‐Young, Yoo, Seung‐Wan, Hong, Youngtae, Kim, Sujeong, Kim, Se Joong, Yoon, Sung‐Hwa, Cho, Kyung‐Gi, Paek, Sun Ha, Lee, Young‐Don, Kim, Sung‐Soo, Suh‐Kim, Haeyoung
Format: Article
Language:English
Subjects:
5‐fluorocytosine
Adolescent
Animals
Biological and medical sciences
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
Brain Neoplasms - prevention & control
Bystander Effect
Child
Chromatography, High Pressure Liquid
cytosine deaminase
Cytosine Deaminase - metabolism
Flucytosine - metabolism
Fluorouracil - metabolism
Genetic Therapy
glioma
Humans
Male
Medical sciences
Mesenchymal Stem Cell Transplantation
mesenchymal stem cells
Mesenchymal Stromal Cells - enzymology
Neurology
Rats
Rats, Sprague-Dawley
spleen forming focus virus
suicide gene
Tumor Cells, Cultured
Tumors
Tumors of the nervous system. Phacomatoses
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Summary:Suicide genes have recently emerged as an attractive alternative therapy for the treatment of various types of intractable cancers. The efficacy of suicide gene therapy relies on efficient gene delivery to target tissues and the localized concentration of final gene products. Here, we showed a potential ex vivo therapy that used mesenchymal stem cells (MSCs) as cellular vehicles to deliver a bacterial suicide gene, cytosine deaminase (CD) to brain tumors. MSCs were engineered to produce CD enzymes at various levels using different promoters. When co‐cultured, CD‐expressing MSCs had a bystander, anti‐cancer effect on neighboring C6 glioma cells in proportion to the levels of CD enzymes that could convert a nontoxic prodrug, 5‐fluorocytosine (5‐FC) into cytotoxic 5‐fluorouracil (5‐FU) in vitro. Consistent with the in vitro results, for early stage brain tumors induced by intracranial inoculation of C6 cells, transplantation of CD‐expressing MSCs reduced tumor mass in proportion to 5‐FC dosages. However, for later stage, established tumors, a single treatment was insufficient, but only multiple transplantations were able to successfully repress tumor growth. Our findings indicate that the level of total CD enzyme activity is a critical parameter that is likely to affect the clinical efficacy for CD gene therapy. Our results also highlight the potential advantages of autograftable MSCs compared with other types of allogeneic stem cells for the treatment of recurrent glioblastomas through repetitive treatments.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.25383