Although mortality related with primary
tumors is approximately 10%,
metastasis leads to 90% of
cancer-associated death. The majority of
brain metastases result from
lung cancer, but the metastatic mechanism remains unclear. In general,
chemotherapy for treating
brain diseases is disrupted by the brain blood barrier (BBB). As an approach to improve treatment of
lung cancer metastasis to the brain, we employed genetically engineered stem cells (GESTECs), consisting of neural stem cells (NSCs) expressing a suicide gene.
Cytosine deaminase (CD), one of the suicide genes, originating from bacterial (bCD) or yeast (yCD), which can convert the non-toxic
prodrug,
5-fluorocytosine (5-FC), into
5-fluorouracil (5-FU), can inhibit
cancer cell growth. We examined the therapeutic efficacy and migratory properties of GESTECs expressing yCD, designated as HB1.F3.yCD, in a xenograft mouse model of
lung cancer metastasis to the brain. In this model, A549
lung cancer cells were implanted in the right hemisphere of the mouse brain, while
CM-DiI pre-stained HB1.F3.yCD cells were implanted in the contralateral brain. Two days after the injection of stem cells, 5-FC was administered via
intraperitoneal injection. The
tumor-tropic effect of HB1.F3.yCD was evident by fluorescent analysis, in which red-colored stem cells migrated to the lung
tumor mass of the contralateral brain. By histological analysis of extracted brain, the therapeutic efficacy of HB1.F3.yCD in the presence of 5-FC was confirmed by the reduction in density and aggressive tendency of
lung cancer cells following treatment with 5-FC, compared to a negative control or HB1.F3.yCD injection without 5-FC. Taken together, these results indicate that HB1.F3.yCD expressing a suicide gene may be a new therapeutic strategy for
lung cancer metastases to the brain in the presence of a
prodrug.