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Preclinical Experimental Therapeutics |
Divisions of Hematology and Hematopoietic Cell Transplantation and Neurosciences and Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA (K.S.A., J.N.); Neurosurgical Oncology Laboratory, Department of Neurosurgery, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, MA 02115, USA (K.S.A., N.O.S., W.Y., W.P., R.C., P.M.B.); Department of Neurosurgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany (N.O.S.); Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA (J.K.W., Y.Z., G.P.); and Departments of Surgery and Neurosurgery, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA (J.K.W., G.P.)
2 Address correspondence to Karen S. Aboody, City of Hope National Medical Center and Beckman Research Institute, Miller 109, 1500 East Duarte Road, Duarte, CA 91010-3000 (kaboody{at}coh.org).
Brain metastases are an increasingly frequent and serious clinical problem for cancer patients, especially those with advanced melanoma. Given the extensive tropism of neural stem/progenitor cells (NSPCs) for pathological areas in the central nervous system, we expanded investigations to determine whether NSPCs could also target multiple sites of brain metastases in a syngeneic experimental melanoma model. Using cytosine deaminase-expressing NSPCs (CD-NSPCs) and systemic 5-fluorocytosine (5-FC) pro-drug administration, we explored their potential as a cell-based targeted drug delivery system to disseminated brain metastases. Our results indicate a strong tropism of NSPCs for intracerebral melanoma metastases. Furthermore, in our therapeutic paradigm, animals with established melanoma brain metastasis received intracranial implantation of CD-NSPCs followed by systemic 5-FC treatment, resulting in a significant (71%) reduction in tumor burden. These data provide proof of principle for the use of NSPCs for targeted delivery of therapeutic gene products to melanoma brain metastases.
Key Words: brain metastases • cytosine deaminase • gene therapy • melanoma • neural progenitor cells • neural stem cells • tumor targeting
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