Despite recent technical improvements in surgical excision techniques and adjuvant radio- and
chemotherapy, the clinical outcome of patients with
grade IV astrocytoma (
glioblastoma) remains very poor, with a median survival of less than 12 months. A promising approach to
therapy employs gene-engineered neural stem/progenitor cells (NSCs) as a cellular therapeutic delivery system, to track
glioblastoma cells and deliver anticancer molecules. However, most results on their
tumor tropism have been derived by immortalized NSCs. We now report that primary murine gene-engineered NSCs displayed in vivo tropism for
glioblastoma cells. Ten days after injection into the brain, many NSCs continued to express the transgene and the NSC marker,
nestin. NSCs transduced with a retroviral vector co-expressing a secretable form of human
endostatin and eGFP (NSC/endo-eGFP) released potentially antiangiogenetic concentrations of
endostatin into the culture medium.
Conditioned medium of NSC/endo-eGFP cells inhibited the growth of mouse pulmonary microvascular endothelial cells (PMVECs). A good correlation between
endostatin levels and PMVEC growth inhibition was observed. In NSCs co-expressing
cytochrome P450 2B6 (
CYP2B6) and eGFP (NSC/
CYP2B6-eGFP), the forced expression of
CYP2B6 resulted in intracellular activation of CPA and subsequent cell death. In the presence of NSC/
CYP2B6-eGFP, we observed CPA cytotoxicity to
DsRed-expressing U87Mg
glioma cells. In vivo treatment of intracranial GL-261
glioblastoma with NSC/endo-eGFP caused a 65% reduction in
tumor size, compared to untreated control mice or mice treated with NSC/eGFP cells. Our data suggest that primary NSCs transduced with retroviral vectors expressing
endostatin and/or
CYP2B6 have a potential role in
glioblastoma therapy.