Combined treatment of tumor-tropic human neural stem cells containing the CD suicide gene effectively targets brain tumors provoking a mild immune response.
Previous studies showed promise of coupling genetically engineered neural stem cells (NSCs) with blood-brain barrier permeable prodrugs as an effective anti-brain tumor therapy. Here, we further advance those findings by testing the suicide gene therapeutic system in syngenic glioblastoma immunocompetent mice. After intracranial injection of HB1.F3.CD, an immortalized human NSC cell line engineered to constitutively produce cytosine deaminase (CD), the prodrug 5-fluorocytosine (5-FC) was administered for five days, q.d., via intraperitoneal injection. The HB1. F3.CD hNSCs migrated specifically to the brain tumor site via the corpus callosum and significantly reduced the tumor volume (67%) by converting 5-FC into the cytotoxic 5-fluorouracil. A corresponding increase in F4/80-positive population was observed in the treatment group, although CD3-positive population remained unchanged compared to control. No toxic effects or morphological changes were observed in the spleen and the lymph nodes. The data suggest that the NSC-enzyme/prodrug treatment is an effective anti-tumor therapeutic strategy that specifically targets only the tumor site with little or no systemic side effects. In addition, the treatment modeled here successfully elicited a macrophagic immune response which seemed to have a synergistic role in reducing tumor volume, thus showing promise for treatment-mediated enhancement of inherent immune responses against brain tumors.
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Se Jeong
SJ
Lee
Yonghyun
Y
Kim
Mi-Young
MY
Jo
Hyeong-Seok
HS
Kim
Younggeon
Y
Jin
Seung U
SU
Kim
Juyoun
J
Jin
Kyeung Min
KM
Joo
Do-Hyun
DH
Nam
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D002465:Cell Movement; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics*; D005437:Flucytosine / Q000008:administration & dosage / Q000378:metabolism; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000637:transplantation*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism
D000970:Antineoplastic Agents; D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase