Figure 1.

Concept of tumor therapy by using suicide gene expressing stem cells that are able to track tumor cells. It has been shown that certain stem cells are able to track infiltrating tumor cells [5, 14–17, 22]. In addition, the therapeutic cells must carry a suicide gene, in this case the herpes simplex virus thymidine kinase (HSV-TK). When a substrate for the HSV-TK enzyme, ganciclovir (GCV), is provided, it enters the cell and is converted by HSV-TK into GCV-monophosphate. The HSV-TK displays a 1000-fold higher affinity for GCV than the mammalian thymidine kinase so that systemic toxicity is limited while the increased affinity boosts tumor therapy capabilities [5]. Cellular kinases will phosphorylate the GCV-monophosphate further to GCV-triphosphate, a guanine nucleoside analogue which inhibits cellular DNA polymerase and results in chain termination with subsequent cell death. While this would erase the therapeutic cell but not the targeted tumor cell, a means for transferring the cytotoxic compound to the tumor cell is required. GCV-monophosphate can passively diffuse into neighboring cells after the formation of gap junctions between adjacent cells, which results mostly in tumor and therapeutic cell killing as normal adult brain cells usually do not replicate [36]. This is also known as “the bystander killing effect” [18, 37]. This approach can in theory terminate both primary and infiltrating tumor cells, thus eliminating sources of possible recurrent tumors [5].