Article
Pro-drug converting neural stem cells for the local intracerebral chemotherapy of human glioblastoma xenografts
Genetisch-modifizierte neurale Stammzellen zur lokalen Chemotherapie in einem experimentellen Glioblastom-Modell
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Authors
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Nils Ole Schmidt
- Neurosurgical Oncology Laboratory, Brigham & Women's Hospital / Harvard Medical School, Boston /USA; Klinik für Neurochirurgie, Universitätsklinikum HH-Eppendorf, Hamburg
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M. Ziu
- Neurosurgical Oncology Laboratory, Brigham & Women's Hospital / Harvard Medical School, Boston /USA
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P. M. Black
- Neurosurgical Oncology Laboratory, Brigham & Women's Hospital / Harvard Medical School, Boston /USA
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R. S. Carroll
- Neurosurgical Oncology Laboratory, Brigham & Women's Hospital / Harvard Medical School, Boston /USA
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K. Aboody
- City of Hope Cancer Center & Beckman Research Institute, Duarte /USA
| Published: | April 23, 2004 |
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Outline
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Objective
Previous reports have demonstrated that neural stem cells (NSCs) distribute throughout experimental intracranial gliomas and are able to “track” invading tumor cells when implanted in the adult rodent brain. Based on this extensive tumor tropism NSCs are attractive candidates as a potential delivery system for therapeutic gene products in the treatment of invasive gliomas.
Methods
Here, we investigated the therapeutic effectiveness of glioma-targeting NSCs expressing cytosine deaminase (CD) to convert systemically administered non-toxic pro-drug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), which diffuses out of the NSCs and selectively kills dividing tumor cells. Murine NSCs C17.2 (lacZ/cytosine deaminase positive or negative) were stereotactically implanted distant (occipital) to well-established intracerebral U87 human glioblastoma xenografts in adult nude mice. Systemic treatment with 5-FC at 500 mg/kg/d started three days after NSCs injection. Tumor growth was assessed by T1-Gd enhanced magnetic resonance imaging and NSCs distribution by X-gal immunohistochemistry.
Results
Intracerebral implantation of 1.5 x 105 NSCs-CD followed by systemic administration of 5-FC inhibited the tumor growth as assessed by MRI 14 days after treatment start. Furthermore, the survival was significantly prolonged when compared to the animals of the control groups (no NSC implantation, implantation of NSC-mock plus 5-FC treatment or implantation of NSC-CD but no 5-FC). Histological analysis demonstrated the intratumoral distribution of NSCs although the cells were initially implanted distant from the main tumor mass. However, we were not able to detect any NSCs based on X-gal immunohistochemistry in the brains of nude mice analyzed later than 22 days after NSC injection.
Conclusions
These results indicate that NSCs represent a potent new delivery system for the local intracerebral treatment of gliomas. However, NSCs may not survive within the tumor environment for a prolonged time and therefore larger numbers of NSCs or multiple injections should be considered. Future studies need to address the interaction of transplanted NSCs with the tumor environment.
