Suicide genes have recently emerged as an attractive alternative
therapy for the treatment of various types of intractable
cancers. The efficacy of suicide gene therapy relies on efficient gene delivery to target tissues and the localized concentration of final gene products. Here, we showed a potential ex vivo
therapy that used mesenchymal stem cells (MSCs) as cellular vehicles to deliver a bacterial suicide gene,
cytosine deaminase (CD) to
brain tumors. MSCs were engineered to produce CD
enzymes at various levels using different promoters. When co-cultured, CD-expressing MSCs had a bystander, anti-
cancer effect on neighboring C6
glioma cells in proportion to the levels of CD
enzymes that could convert a nontoxic
prodrug,
5-fluorocytosine (5-FC) into cytotoxic
5-fluorouracil (5-FU) in vitro. Consistent with the in vitro results, for early stage
brain tumors induced by intracranial inoculation of C6 cells,
transplantation of CD-expressing MSCs reduced
tumor mass in proportion to 5-FC dosages. However, for later stage, established
tumors, a single treatment was insufficient, but only multiple
transplantations were able to successfully repress
tumor growth. Our findings indicate that the level of total CD
enzyme activity is a critical parameter that is likely to affect the clinical efficacy for CD gene therapy. Our results also highlight the potential advantages of autograftable MSCs compared with other types of allogeneic stem cells for the treatment of recurrent
glioblastomas through repetitive treatments.